Physicians' Desk Reference, 70th edition 9781563638343

Table of contents :
Cover
CONTENTS
MANUFACTURERS’ INDEX
BRAND AND GENERIC NAME INDEX
GENERIC/BRAND CROSS-REFERENCE TABLE
PRODUCT CATEGORY INDEX
PRODUCT IDENTIFICATION GUIDE
IMAGES BY MANUFACTURER
PRODUCT INFORMATION
A&Z Pharmaceutical
Bayer Healthcare
Concordia Pharmaceuticals
GlaxoSmithKline
Kowa Pharmaceuticals
Merck
Novartis Pharmaceuticals
Otsuka Pharmaceutical
Pivotal Therapeutics
Ranbaxy Laboratories
Supernus Pharmaceuticals
Takeda Pharmaceuticals
Unicity International,
DIETARY SUPPLEMENTS
4Life Research
Alto Pharmaceuticals
Essentia Water
Immunotec
LifePharm Global
NSE Products,
Perque Integrative
Synergy Worldwide
Unicity International,

Citation preview

IBDC LIBRARY

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EDITION

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PDR* 2 0 16

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70 EDITION

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Chief Executive Officer: Mark Heinold Chief Medical Officer: Salvatore Volpe, MD, FAAP. FACP, CHCQM

Associate Manager, Clinical Operations: Pauline Lee, PharmD Senior Drug Information Specialists: Vanessa Azevedo, PharmD:

Chief Technology Officer: David Cheng Executive Vice President and Chief Financial Officer: Michael Burnett Senior Vice President, Digital Products: Eugene Lee Senior Vice President, General Counsel and Corporate Secretary:

Drug Information Specialists: Caroline Gadalla. PharmD:

Kristine Mecca, PharmD: Autri Sajedeen, PharmD

Ruth Williams

Jasmine Kim, PharmD Managing Clinical Editor: Julia Tonelli, MD Medical Editor: Christa Mary Kronick, MA

Senior Vice President, Product Marketing and Market Research:

Barbara Senich, BSN. MBA, MPH Vice President of Operations: Lisa Collins Director, Communications and Database Channel Lifecycle Management: David Weatherbee Executive Vice President and Chief Revenue Officer: Doug Rutz Vice President, Clinical and Regulatory Solutions: Mukesh Mehta Vice Presidents, Business Development: Dan Clifford, Chad Gottfnd,

Brian Peterson, Jeff Wiltrout Associate Director, Clinical ODeratlons: Anita Patel. PharmD Associate Manager, Clinical Content Development:

Demyana Farag. PhannD

Senior Director, Marketing: Kim Marich Manager. Marketing Services: Livio Udina Associate Vice President. Operations: Jeffrey D. Schaefer Director, Manufacturing and Distribution: Thomas Westburgh Director, Operations: Noel Deloughery Senior Content Operations Specialist: Allison O’Hare Senior Production Coordinator: Yasmin Hernandez Production Coordinator: Eric LkJina Manager, Fulfillment and DMS Operations: Gary Lew Manager, Communication Operations: Don Pond Search Marketing Strategist: Richard Pearce Senior Project Manager: Chris Whalen Customer Service Supervisor: Ricardo Plaisir

Copyright 02015 PDR LLC Pubh^ned by PDR, LLC at Montvale. NJ 07645-1725 All rights reserved None of the content of this publication may be reproduced, stored m a retrieval system resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the pnor written permission ot PDR. LLC. Physicians' Desk Reference*. PDR net*. moPr/ePDR*. and PDR* are registered trademarks of PDR Network. LLC ScnptGuide*. eCopay* and CarePoints* are registered trademarks of LDM Group. L.L.C . a subsidiary of PDR. LLC. Other trademarks appearing are property of their respective owners

ISBN 978-1-56363-834-3

consult these PDR sources before prescribing or administering any medications described in the following pages. Electronic PDR Resources PDR.net, a web portal designed specifically for prescribers, provides trusted, professional drug information, including full FDA-approved labeling, concise point-of-care drug information, as well as other relevant professional resources. PDR.net provides prescribers with online access to the authoritative drug information they need to support their treatment decisions. mob//ePDR is the official drug information and comparison app from PDR, allowing healthcare professionals free access to current drug prescribing information using an Apple® or Android™ device. Fast and easy to use, mob/7ePDR employs a simple, but powerful, search tool with access to thousands of drug summaries continually updated by PDR PharmDs. Also available is a drug comparison tool that allows users to compare characteristics of two or more drugs, a drug interaction tool that indicates the nature and severity of drug-drug interactions, and a pill identification tool. Registration is required. Please visit PDR.net/mobilePDR for more information. PDR Services Within EMRs PDR provides current prescribing information, patient education, and other services in eRx/EMR systems. These

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services for healthcare providers and their patients are convenient and readily accessible within clinical workflow at no cost to prescribers or their patients: • For Healthcare Providers: In-EMR drug and condition messaging and prescribing information • For Patients: In-EMR patient-friendly drug and condition information as well as patient savings opportunities To request PDR’s services in your EMR, email PDR at [email protected] telling us the name of your EMR vendor and we will contact them for you. '

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PDR Safety Communications Critical communications are delivered electronically to physicians and other prescribers who register to receive them at PDR.net/registration. through participating medical societies, or by returning the verification form distributed with complimentary copies of the PDR.

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2222

AMINOSALICYLIC ACID

AGELOC TR90 CONTROL CAPSULES (NSE Products)... AGELOC TR90 FIT CAPSULES (NSE Produc ts

2222 2222

..

2222

311, 1971

2222

ALBIGLUTIDE 1097

304. 605

Snnatanc Cap'ule' iStwfrl I

2001

ACTTVE CALCIUM TABLETS / L'aarltl I. .

2231

303,459

ADVA1R DISKUS UHV50 INHALATION POWDER (GlaxoSmithKline).817

AMYLASE

AMYLOLYTIC ENZYMES (see under: AMYLASE) ANAS BARBAKIAE Oseilkicxxxinum Quick-Dissolstng Pellets iBojrtvji. ...

305,673

1118

Eotfamu Plus D Tablets (Merck).

307, 1305 307, 1312

agcLOC TRW Fit Capsules I VSE ProductsI...

2222

ANORO ELLIPTA INHALATION POWDER (GlaxoSmithKline)..

303, 408

844

Bios Life Vision Essentials Capsules tVniciry)....

2227

F.liouis Tablets (Brisnsl-Mvers .

817

ALOgliptin

Emend Capsules (\ten-L).

311. 2070 Nesma Tablets (Takedo).311, 2079 Own Tablets > T.-.o-.c. 311. 2087

305. 706

307, 1262

2223

LifePak Capsules t.VSF Products 817 ALPHA 1JPOIC ACID

..

.ADVAIR HFA 11V2I INHALATION AEROSOL tfrliunS'/riitlKli/ir/.

830

830

ADVAIR HFA 2W21 INHALATION AEROSOL (GlaxoSmithKline).

830

Ads anted HI,"I Sugar Control Capsules . Andorra).

305, 2213

ageLOC Youth Capsules / .VSE Prodmts) . LifePak Capsules i .VM Prods, r, Optimal M Capsules .Amt

2222 2223 305, 2217

ALPHA TOCOPHEROL ACETATE (see under VITAMIN El 1989

AIA1MOPAN

in Product IdrntlhcaOun l.uidr

Entereg Capsules

Knit1

Inununi/en Capsules fL'rucity)

2228

Ability Mamteiu Friended Release Injectable Suspension (O:\uiti I .

310, 1918

ARNICA MONTANA

ALTAR AX OINTMENT Sue/U’ 305, 2213

ASCORBY L PALM1TATE (see also under: VITAMIN C) Bio-C Tablets (l’un ity). 2226 Cardio-Basics Tablets 1rue tty).2228 Vinlli Capsules (Inn).

305, 2218

ASMANEX TW1STHALER (Merckl.

1180

ASTAXANTH1N agcLOC Youth Capsules (AfSE PnMlm'ti).

2222

Evota/ Tablets < Rrixti'IMwn Squibb).....*..

306, 715

Rcvaia/ Capsules •Bristol Mven Squibb).

306, 746

Kcyjia; Oral Powder (Rrixiol-Mxrr* Squibb)...

746

Malaronc Tablets iGlaxoSmithKline).

1028

Malaronc Pediatric Tablets i GlaxoSmithKline >.

1028

Mcpron Suspension (GlaxoSmithKline). ...

1036

.

ATROPINE SULFATE Donnatal Elixir (Gwnn/id) .

306, 790

lVnnat.il Tablets (Omcorduii.

306, 791

AVANDLA TABLETS lGlaxoSmithKline)

858

AVELOX I.V. iMenkl

1187

♦AVELOX TABLETS Merck

ARAB INOGALACTAN

AR1PIPRAZOLE

ALPHA CAROTENE

ADVAIR DISKUS 50IV50 1NHA1ATION POWDER GlaxoSmithKline)

IYoAtsi-9* Dteiarj Supplement (Synergy Worldwide).311, 2226

APREPITANT IGuano Tablets (Takeda i.

ADVA1R DISKUS 2.W50 INHALATION POWDER (GlaxoSmithKline).

ASCORBIC' ACID (see also under: VITAMIN C)

ATOVAQUONE

APIXABAN

ALLIUM CEPA

♦ARZERRA INJECTION (Nocariis).308, 1672

303, 403

ANTHOCYANIDINS

Fosamav Tablets (Merck). ...

prescribing

^TAZANAVTR

1513

AlJENDRONATE SQDIUM

ADALIMUMAB

311,2036

♦ANDROGEL 1.62T (AbhVte)..

Prvvcmil HFA Inhalation Aerosol (Menk). Ventolin HFA Inhalation Aerosol (GlatoSmilhKlineI...

ACITRETIN

♦AMITIZA CAPSULES (Thkcda).

♦ANDROGEL IT lAbbVte).

ALBUTEROL SULFATE

ACETAMINOPHEN

4-AMINO-SALICYLIC ACID (sis under: AMINOSALICYLIC ACID)

En/ygcn Plus Capsules (L’niciryl.. 2228

Tan/cum for Injection (GI.LieSmnhKhne I...

full

Bkr-C Tablets ((tmein 1. 2226 Canfio-Basics Tablets lUnum).2228

AGELOC R* DAY CAPSLT.ES (NSE Products).

AGELOC YOUTH CAPSULES (NSE Products)...

305, 2218

4 Shown

AM 1NOBF.N7.OATE POTASSIUM

AM1NOHIPPURATE SODIITH

2222

305.2217

♦ADVANCED BLOOD SUGAR CONTROL CAPSULUS Imlivni

840

.AFINTTOR DISPERZ TABLETS (Novartis).

310, 1918

V mail Cap>ule' lAnuj.

ADVAIR HFA 4V21 INHALATION AEROSOL GlaxoSmithKline)

indicate

■ The ♦ symbol marks drugs shown in the Product Identification Guide.

AGELOC TR90 TRIMSHAKE POWDER (NSE Products).

Optimal-V Capsules (Anil).

Humira Injection Ssrmge and Pen ■ AW'Vi, .

numbers

■ Italic page numbers signify partial information.

305, 2214

AGELOC TR90 JUMPSTART POWDER (NSE Products'

ACEROl-A CHERRY

VicodiiWicodin ES/Yicodir HP Tablet' ctWAIci.

■ Bold page information.

Paser Granules (Jacobus).1166

Orencia Injection (BristolMsers SqtMn.

♦ABII.IFY MAENTENA EXTENDED- RELEASE INJECTABLE SUSPENSION (Otsuka1

appear, the first one refers to images of the product; the last one refers to its prescribing information. Under a generic heading, all fully described brands are listed first, followed by those with only partial information.

1278

Amjcane Gel (Boiron)... ♦ARNTCARE GEL Boironi ARNUITY ELLIPTA INHALATION POWDER 100 MCG (GlaxoSmithKline). ARNUITY ELLHTA INHALATION POWDER *00 MCG (HaioSouthKitne ARRANON INJECTION Novartis)

l ndrrlHH lb-notes Generic Name

305, 673 305.673

852

867

B BABYCARE PRENATAL CHELATED MINERAL TABLETS fWiot

2232

BABYCARE PRENATAL MEGA ANTIOXIDANT TABLETS Cmnai . BA4TROBAN CREAM Nf • ••

852

307, 1187

AVODART SOFT GELATIN CAPSULES (GlaxoSmithKline

BAtTROBAN NASAL tSbefrl

2232 ..

1991 1992

BACTROBAN OLNTMENT

1667

1995 Itulic Pure Sards-r Indwaln Brief I 1st me

BRAND AND GENERIC NAME INDEX

This index includes all entries in the Product Information section. Products are listed alphabetically by both brand and generic name. Generic names are underlined; brand names are not. Under each generic name, you will find a list of the brand names that are associated with the generic product. This enables you to find a product by either of its names. For example, the brand Amerge appears once in the A‘s, and again under its generic name, naratriptan hydrochloride.

102/BARACLUDE ORAL SOLUTION BARACLUDE ORAL SOLUTION (Bristol-Myers Squibb).687 ♦BARACLUDE TABLETS (Bristol-Myers Squibb). 305, 687 BASILIXIMAB Simulect for Injection (Novartis)..

309, 1800

BECLOMETHASONE 1)1 PHOPK>N ATE MONOHYDRATE Beconase AQ Nasal Spray (GlaxoSmithKline).

873

BECONASE AQ NASAL SPRAY (GlaxoSmithKline).873

PHYSICIANS’ DESK REFERENCE®

BIOTIN

CALCIUM FOLINATE

CHLORELLA PLUS SHIITAKE

BabyCare Prenatal Mega Antioxidant Tablets (Usana). 2232 Cardio-Basics Tablets (Unicity).2228 LifePak Capsules (NSE Products).2223 Mega Antioxidant Tablets (Usana). 2231 Optimal-V Capsules (Ariix).305, 2217 Perque Life Guard Tabsules (Perque). 2224

Perque Life Guard Tabsules (Perque).2224

beyonde Life Scntial Tablets (Unilever Thai). 312, 2230

CALCIUM FUMARATE

CALCIUM MALATE

CHLOROXYLENOI.

BOCEPREVIR

Perque Life Guard Tabsules (Perque).2224

Gordochom Solution (Gonlon). 306, 1157

Victrelis Capsules (Merck).308, 1590

CALCIUM PANTOTHENATE

BONEMATE PLUS TABLETS (Unicity).2227

Perque Life Guard Tabsules (Perque).2224

CHOLECALCIFEROL (see also under: VITAMIN D3)

BORON

Nulojix Injection (Bristol-Myers Squibb).

BoneMate Plus Tablets (Unicity).2227 LifePak Capsules (NSE Products).2223

BELIMUMAB Benlysta for Injection (GlaxoSmithKline).

BRAND AND GENERIC NAME INDEX

.875

Duac Gel (Stiefel).

.1996

BERACTANT Survanta Intratracheal Suspension (AbbVie).

304, 578

BERBERINE Advanced Blood Sugar Control Capsules (Andorra). 305, 2213

BabyCare Prenatal Mega Antioxidant Tablets (Usana).

2232

CAMELLIA SINENSIS Tegreen 97 Capsules (NSE Products). 2223

Perque Life Guard Tabsules (Perque). 2224

Active Calcium Tablets (Usana). 2231 Chelated Mineral Tablets (Usana).2231 Optimal-M Capsules (Ariix). 305, 2217

CANAKINUMAB

Joint Mobility Capsules (Unicity).312, 2229 BRASSICA OLERACEA ageLOC R2 Night Capsules {NSE Products). 2222 BREO ELLIPTA INHALATION POWDER 100/25 (GlaxoSmithKline).885

♦BRINTELLIX TABLETS (Takeda).311,2040

2224

BETA-GLUCAN Immumzen Capsules (Unicity).

2228

BETA-GLUCANASE Enzygen Plus Capsules (Unicity)....

2228

BETAINE HYDROCHLORIDE Perque Life Guard Tabsules (Perque).

2224

BETAMETHASONE ACETATE

ageLOC TR90 Fit Capsules (NSE Products)...

Mega Antioxidant Tablets (Usana). 2231 Optimal-M Capsules (Ariix). 305, 2217 2222

♦CARBAGLU TABLETS (Recordati).311, 1977

Duopa Enteral Suspension * (AbbVie).. 303, 439 Sinemet Tablets (Merck).1550

Perque Life Guard Tabsules (Perque).2224

Butrans Transdcrmal System (Purdue).310, 1946

CARDIO-BASICS TABLETS (Unicity).2228

Chelated Mineral Tablets (Usana).2231

BUPROPION HYDROCHLORIDE

CARDIO-ESSENTIALS CAPSULES (Unicity). 2228

CHROMIUM POLYNICOTINATE

BUPRENORPHINE

Contrave Extended-Release Tablets (Takeda). 311, 2054 Wellbutrin Tablets (GlaxoSmithKline).1129 Wellbutrin SR Sustained-Release Tablets (GlaxoSmithKline).1137 Zyban Sustained-Release Tablets (GlaxoSmithKline).1147 ♦BUTRANS TRANSDERMAL SYSTEM (Purdue).310, 1946

c

Chelated Mineral Tablets (Usana).2231 CARFHZOM1B Kyprolis for Injection (Amgen). 305, 633

Carbaglu Tablels (Recordati). ..311, 1977

Bios Life Cardio Advanced Fiber and Nutrient Drink (Unicity).312, 2226

CARVEDILOL

Unicity Balance Packets (Unicity).312, 2229

CARGLUMIC ACID

Coreg Tablets (GlaxoSmithKline).909

Primaxin I.'V. (Merck).1484

Coreg CR Extended-Release Capsules (GlaxoSmithKline).916

CINNAMON

CASPOFUNGIN ACETATE

Advanced Blood Sugar Control Capsules (Andorra).

Cancidas for Injection (Merck).307, 1204

♦CIRCULATION PLUS CAPSULES (Andorra). 305, 2216

CITRATE

CEFTIN FOR ORAL SUSPENSION (GlaxoSmithKline).896

Perque Life Guard Tabsules (Perque).2224

BIAXIN XL FILMTAB TABLETS (AbbVie).

414

2227

BIFIDOBACTERIUM LACTIS BS 01

BabyCare Prenatal Mega Antioxidant Tablets (Usana)... 2232 Bio-C Tablets (Unicity). 2226

Enzygen Plus Capsules (Unicity). 2228

CISATRACURIUM BESYLATE

CATE CHINS

Nimhex Injection 1AhbVie1.304, 546

CEFTIN TABLETS (GlaxoSmithKline).896

2217 2224 2224 2232 2218

Zerbaxa for Injection (Men k).1619

Bio-C Tablets (Unicity).2226 LifePak Capsules (NSE Pmducis). 2223

CEFUROXIME AXETIL Ceftin for Oral Suspension (GlaxoSmithKline).896

ageLOC R: Night Capsules (NSE Products). 2222

Active Calcium Tablets (Usana).2231 BabyCare Prenatal Chelated Mineral Tablets (Usana). 2232

CELLULASE

Chelated Mineral Tablets (Usana).2231

Enzygen Plus Capsules < Unicity). 2228

D-Cal Chcwahle Tablets lAJcZ).303, 402 D-Cal Kids Granules (A&.Z). 303, 402

CERITINIB

Essentia Water (Essentia Water). 306, 2218 CALCIUM CITRATE

305,2218

CELESTONE SOLUSPAN INJECTABLE SUSPENSION (Merck).1213

2226

312, 2226

ViriBi Capsules (Anu). CITRUS SINENSIS

BIO-C TABLETS (Unicity).

CALCIUM CHLORIDE

Optimal-M Capsules (Ariix). 305, 2217

Ceftin Tablets (GlaxoSmithKline).896

CALCIUM CARBONATE

2231

ageLOC TR90 Fit Capsules (NSE Pnnlucts). 2222 ageLOC Youth Capsules (NSE Products). 2222

2227

BIOFLAVONOIDS

CITRUS BIOFLAVONOIDS

CEFTOLOZANE

Mega Antioxidant Tablets (Usana). 2231 Optimai-V Capsules (Ariix).305, Perque Life Guard Tabsules (Perque). Perque Potent C Guard Powder (Perque). Procosa Tablets (Usana). Vinali Capsules iAriix).305,

Bios Life ProBionic Packets (Unicity)

♦ Shown in Product Idcntitkatlon Guide

305, 2213

CALCIUM ASCORBATE (see also under: VITAMIN C)

303, 414

BIOS LIFE VISION ESSENTIALS CAPSULES (UntcUy)....

CILASTATIN

CARVEDILOL PHOSPHATE

LifePak Capsules (NSE Products).2223

♦BIAXIN GRANULES (AbbVie)..

BIOS LIFE PROBIONIC PACKETS i Unicity).

CHRYSANTHEMUM MORIFOLIUM

2223

303, 414

BIOS LIFE E (UNICITY MATCHAl PACKETS (Unicity)..

Perque Life Guard Tabsules (Perque).2224

CATALASE

♦ BIAXIN FILMTAB TABLETS (AbbVie)..

♦BIOS LIFE CARDIO ADVANCED FIBER AND NUTRIENT DRINK (Unicity)..

CHROMIUM PICOLINATE

Advanced Lung Cleanse Capsules (Andorra). 305, 2214 BoneMate Plus Tablets (Unicity).2227 Cardio-Basics Tablets (Unicity).2228 LifePak Capsules (NSE Products).. 2223

♦BEYONDE MAQUI PLUS+ CONCENTRATE DRINK /Unilever Thai). 312, 2231

.

LifePak Capsules (NSE Products).2223

CALCIUM

♦BEYONDE LIFE SENTIAL TABLETS (Unilever Thai). 312, 2230

Mega Antioxidant Tablets (Usana)...

Cardio-Basics Tablets (Unicity).2228

1213

BETA-TOCOPHEROL

Bios Life ProBionic Packets (Uniciry)

Advanced Blood Sugar Control Capsules (Andorra). 305, 2213

CHROMIUM ASCORBATE

Sorilux Foam. 0,005% (Stiefel).2009

LifePak Capsules 1 NSE Products)....

CHORIONIC GONADOTROPIN Pregnyl for Injection, USP (Merck).1483 CHROMIUM

CARBIDOPA

CALCIPOTRIENE

Celcstone Soluspan Injectable Suspension (Merck).

CHOLINE BITARTRATE

ageLOC TR90 TrimShake Powder (NSE Products). 2222

Cclestone Soluspan Injectable Suspension (Merck). .1213 BETAMETHASONE SODIUM PHOSPHATE

CAPSICUM ANNUUM

♦CHOLESTERIGHT CAPSULES (Andorra). 305, 2215

CARBOHYDRATES

Enzygen Plus Capsules (Unicity). 2228 Optimal-V Capsules (Ariix).305, 2217

Perque Life Guard Tabsules (Perque)..

Ilaris injection (Novartis).309, 1742 ♦CANCIDAS FOR INJECTION (Merck).307, 1204

Optimal-M Capsules (Ariix). 305, 2217

BROMELAIN

Optimal-V Capsules (Ariix). 305, 2217

ProArgi-9+ Dietary Supplement (Synergy Worldwide). 311, 2226

Sinemet CR Sustained-Release Tablets (Merck).1553

2227

2231

Fosamax Plus D Tablets (Merck).307, 1312

BORON CITRATE

2228 .2223

2232

Cardio-Basics Tablets (Unicity).2228

Mega Antioxidant Tablets (Usana)........ 2231

Cardio-Basics Tablets I Unicirv). Mega Antioxidant Tablets (Usana)...

BabyCare Prenatal Mega Antioxidant Tablets (Usana).

Optimal-V Capsules (Ariix).305, 2217

Bios Life Vision Essentials Capsules (Unicity)... LifePak Capsules (NSE Products)...

Active Calcium Tablets (Usana).2231

CALENDULA OFFICINALIS

BREO ELLIPTA INHALATION POWDER 200/25 (GlaxoSmithKline).885

BETA-CAROTENE (see also under: VITAMIN A)

♦CALENDULA CREAM (Boiron).305, 673

Perque Repair Guard Tabsules (Perque). 2224

Calendula Cream (Boiron). 305, 673

BOSWELLIA EXTRACT

BENZOYL PEROXIDE

Perque Life Guard Tabsules (Perque).2224

CHLOROPHYLL

BORON ASCORBATE Perque Life Guard Tabsules (Perque).2224 .875

BELSOMRA TABLETS (Merck) .1198 BENLYSTA FOR INJECTION (GlaxoSmithKline).

Perque Life Guard Tabsules (Perque).2224

CALCIUM SUCCINATE BOOSTRIX INJECTION VACCINE (GlaxoSmithKline).880

BELATACEPT 306, 724

Perque Vessel Health Guard Lozenges (Perque).2224

Zykadta Capsules (Novartist.310, 1874

ageLOC TR90 Fit Capsules (NSE Products). 2222 ageLOC TR90 JumpStart Powder (NSE Pmducis).

2222

CLARINEX ORAL SOLUTION (Merck).

1216

CERVAR1X INJECTION VACCINE i GlaxoSmithKlinel.902

♦CLARINEX TABLETS (Merck).

307. 1216

♦CLARINEX-D 12-HOUR EXTENDED RELEASE TABLETS 'Merck).

307, 1220

2227

Active Calcium Tablets (Usana). 2231

CHELATED MINERAL TABLETS (Usana).2231

2227

BabvCarc Prenatal Chelated Mineral Tablets (Vsan. t. 2232 Chelated Mini l.ihlct, (Usana).2231

♦( HEMET CAPSULES I Recordati i.311, 1980

2227

Opttntal-M Capsules I \riix). 305, 2217 Perque Li(e Guard Tabsules (Perque) .2224

Perque Vessel Health Guard Lozenges (Perquet.

l ndcrlinc Denotes Generic Name

CI.ARITHKOMYCIN Btaxin Filmtab Tablets (AhbVie). 303, 414

CHERRY EXTRACT

Btaxtn Granules (AhbVie).303, 414 2224

Busin XL Filmtab Tablets (.AhbVie 1.

414

Italic Page Number Indicates Brief Listing

FENOFIBRATE/103

BRAND AND GENERIC NAME INDEX CYSTEINE Immunocal Powder Sachets (Jnirnunotec).2219

£LONJDINE HYDROCHLORIDE Kapvay Extended-Release TableLs (Concordia)... 306, 797

D

♦CM PLEX CREAM (Unicity).

312, 2228

♦CM PLEX SOFTGELS (Unicity).312, 2228 COBICISTAT Evotaz Tablets (Bristol-Myers Squibb)..306, 715 COENZYME Q-10 Advanced Lung Cleanse Capsules (Andorra).305, 2214 ageLOC Youth Capsules (NSE . Products).2222 Cardio-Basics Tablets (Unicity).2228 Cardio-E&sentials Capsules (Unicity). 2228 CoQuinone 30 Capsules (Usana). 2231 Mega Antioxidant Tablets (Usana). 2231 Ubiquinol-CoQlO Soflgels (Unicity).2229 COLCHICINE Colcrys Tablets (Takeda). 311, 2047 ♦COLCRYS TABLETS (Takeda).311, 2047 COLOSTRUM Immunizcn Capsules (Unicity). 2228 COMBIVIR TABLETS (ViiV).2110 COMVAX VACCINE (Merck).1225 ♦CONTRAVE EXTENDED-REIJEASE TABLETS (Takeda). 311, 2054 COPPER BoneMatc Plus Tablets (Unicity).2227 Cardio-Basics Tablets (Unicity).2228 LifcPak Capsules (NSE Products).2223 COPPER GLUCONATE BabyCare Prenatal Chelated Mineral Tablets (Usana). 2232 Chelated Mineral Tablets (Usana).2231 Optimal-M Capsules (Ariix). 305, 2217

DABRAFENIB Tafinlar Capsules (Noi-artis). 309. 1803 DACLATASVIR Daklinza Tablets (Bristol-Myers Squibb)... • - 305, 701 ♦DAKLINZA TABLETS __ (Bristol-Myers Squibb). 305, 701 P-ALPHA TOCOPHEROL (see also under: VITAMIN E) Cardio-Basics Tablets (Unicity).2228 D-ALPHA TOCOPHERYL SUCCINATE (see also under: VITAMIN E) BabyCare Prenatal Mega Antioxidant Tablets (Usana).2232 Mega Antioxidant Tablets (Usana). 2231 Optimal-V Capsules (Ariix).305, 2217 DAPSONE Dapsonc Tablets USP (Jacobus).1165 DAPTOMY C IN Cubicin for Injection (Merck).1242 DASABUV1R Viekira Pak (AbbVie)...... 304, 610 DASATINIB Sprvcel Tablets (Bristol-Myers Squibb). 306, 766 ♦D-CAL CHEWABLE TABLETS tA&Z).303, 402 ♦D-CAL KIDS GRANULES (A&Z). 303, 402 D-CALCIUM PANTOTHENATE BabyCare Prenatal Mega Antioxidant Tablets (Usana).2232 Cardio-Basics Tablets (Unicity).2228 Mega Antioxidant Tablets (Usana). 2231 Optimal-V Capsules (Ariir).305, 2217 Perquc Life Guard Tabsules 2224 (Pert/ue)...

COQUINONE 30 CAPSULES (Usana).2231

DEFERASIROX Exjadc Tablets (Novartis). 309, 1695 Jadenu Tablets (Novartis). 309, 1746

COREG TABLETS (GlaxoSmithKline).909

DEI AVIRDINE MESYLATE Rcscriptor Tablets (ViiV)..2142

COREG CR EXTENDED-RELEASE CAPSULES (GlaxoSmithKline).916

DELTA-TOCOPHEROL LifePak Capsules (NSE Products).2223

♦CORLANOR TABLETS (Amgen). 305, 629

DENQSUMAB Prolia for Injection (Amgen). 305, 640

CORN SI IJK Experience Capsules (PureTrim).310, 2225

♦DEPAKENE CAPSULES (AbbVie). 303, 402

♦COSENTYX INJECTION (Novartis).308, 1676

♦DEPAKOTE ER TABLET, EXTENDED RELEASE FOR ORAL USE (AbbVie). 303, 429

♦COSOPT PF OPHTHALMIC SOLUTION 2^70.5'V (Merck).307, 1229 COUMADIN FOR INJECTION (Bristol-Myers Squibb).695 ♦COUMADIN TABLETS (Bristol Myers Squibb). 305, 695 ♦CREON DEI AYED-RE LEASE CAPSULES (AbbVie). ♦CRIXIVAN CAPSULES (Merck).

303, 425 307, 1233

. CROCUS SATIVUS ageLOC TR90 JumpStan Powder (NSE Pn ductsI.

2222

CUBICIN FOR INJECTION tMerck).

1242

CYANOCOBAI AMIN (.ny also under VITAMIN Bj*) BabyCare Prenatal Mega Antioxidant Tablets (l/sana). Cardio-Basics Tablets (Unicity). Mega Antioxidant Tablets.(Usana). ProArgi-9* Dietary Supplement 311, I Synergy Worldwide).. CYCM1SPORINK Gengraf Capsules (AhhXU). Ncor.il Oral Solution (Novartis I. . Ncoral Soft Gelatin Capsules (Novartis)....

♦DEPAKOTE TABLETS FOR ORAL USE tAbbVie). 303, 402 DESLORATADINE Clarincx Oral Solution (Memk).1216 Clarincx Tablets (Merck).307, 1216 Clarincx D 12-Hour Extended Release Tablets iMercki 307, 1220 ♦DEXILANT DEI.AYED RELEASE CAPSULES (Takeda)... DEXLAN SOPRAZOLE Dexilant Delayed Release Capsules (Takeda).

2232 2228 2231 2226

309, 1768

Sandimmune Oral Sdatuxi (Novartis I.. Sandimmune Ingctiiw iNmartis). Sandimmune Soft Gelatin Capsule

1788 1788

(N*n\irUs).

1788

DIETARY SUPPLEMENT Liquid Daily Complete (PureTrim). LaserMaster Capsules tPureTrim)... PureTrim Gum tPureTrim). PureTrim Mediterranean Wellness Shakes (PunrTnm). . .

DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS ADSORBED, HEPATITIS B (RECOMBINANT! AND INACTIVATED POLIOVIRUS VACCINE Pediarix Injection Vaccine (GlaxoSmithKline).1040 DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS ADSORBED AND INACTIVATED POLIOVIRUS VACCINE Kinrix Injection Vaccine (GlaxoSmithKline)....

311, 2065

310, 2225 310, 2225 310. 2226 . 1250

D1FICID TABLETS (Merck)

DIGESTIVE ENZYMES (see under: AMY 1 _\SE; CELLLLASE; LIPASE; PANCRKLIPASE; PROTEASE) DIGOX1N l_anoAin Tablet!. iCtuuonhai.

801

ENGERIX-B INJECTION VACCINE (GlaxoSmithKline

926

ENTECAVTR Baracludc Oral Solution (Bristol Myers SquibbI. 687 Baracludc Tablets (Bristol-Myers Squibb)...--- 305, 687 ENTEREG CAPSULES (Merck).1278 ♦ENTRESTO TABLETS (Novartis).

309, 1683 2228

ENZYMES. DEBRIDEMENT (see under: PAPAIN) 998

DIVALPROEX SODIUM Depakote F.R Tablet, Extended Release for Oral Use (AbbVie). 303, 429 Depakote Sprinkle Capsules for Oral Use (AbbVie). . 303. 402 Depakote Tablets for Oral Use (AbbVe). . 303, 402 DL-ALPHA TOCOPHERYL ACETATE (see under: VITAMIN E) D-LIMONENE ageLOC Youth Capsules (NSE Products). .

ENZYMES. DIGESTIVE (see under: AMYLASE; CKLLULCSE; LIPASE; PANCRELIPASE; PROTEASE) ENZYMES, PROTEOLYTIC (see under: PAPAIN; PROTEASE) EPIVIR ORAL SOLUTION (ViiV).2115 EPIVIR TABLETS (ViiV).2115 EPTVIR-HBV ORAL SOLUTION (GlaxoSmithKline).929 EPIV1R-HBV TABLETS (GlaxoSmithKline).929

2222

EPOPROSTENOL SODIUM Flolan for Injection (GlaxoSmithKline).934

DOCOSAHEXAENOIC ACID (DHAJ ageLOC Youth Capsules (NSE 2222 Products). MarineOmega Softgel Capsules (NSE 2223 Products). 2229 OmegaLifc-3 Softgcls (Unicity).

EPTIFIBATIDE Intcgrilin Injection (Merck). 307. 1352

DOLUTEGRAVIR Tivicay Tablets (ViiV).2165 Triumcq Tablets (ViiV).2174

♦ESSENTIA WATER (Essentia Water)...306, 2218

♦DONNATAL ELIXIR (Concordia). 306, 790 ♦DONNATAL TABLETS (Concordia). 306, 791 DORZOLAM1DE HYDROCHLORIDE Cosopt PF Ophthalmic Solution 2‘*/0.5 (Merck).307, 1229 Trusopl Sterile Ophthalmic Solution (Merck).1578 D-RIBOSE ProArgi-9* Dietary Supplement (Synergy Worldwide).

311, 2226

DUAC GEL (Stiefel).1996

EPZ1COM TABLETS (ViiV)

ETHINYL ESTRADIOL NuvaRing Vaginal Ring (Menkl... .. .308, 1454 ETONOCESTREL Implanon Implant tMcrckt.307. 1345 Ncxplanon Implant (Merck).1432 NuvaRing Vaginal Ring (MerrO . . . .308, 1454 EVEROLIMUS A tumor Tablets (,Vm urns)...308, 1652 Afimtor Dispcr/ Tablets (Novartis). 1652 Zortress Tablets (Novartis). 310, 1864 EVOLOCUMAB Rcpatha for Injection lAmgem. 305, 647 ♦EVOTAZ TABLETS

♦DUOPA ENTERAL SUSPENSION (AbbVie). 303, 439

♦EXELON PATCH (Novartis

DUTASTKRIDE Avodart Soft Gelatin Capsules (GlaxoSmithKline I. 867 Jalyn Capsules (GlaxoSmithKlineJ.. 991 DUTOPROL TABLETS (Concordia).791 DYAZIDE CAPSULES (GlaxoSmithKline).

924

DYRKNIUM CAPSULES (Concordia).

795

EFAV1RENZ Sustiva Capsules (Bristol-Myers Squibb). Sustiva Tablets (Bristol-Myers Squibb)..

(Bristol-Myers Squibb)...

306, 773 306, 773

Products

MurmcOmcg i Softgel Capsules (NSE Pnrducts t.. OmegaLtfe-3 Softgcls iUnicuy).

2222 2223 2229

ELECAMPANE ROOT EXTRACT Advanced Lung C 305, 2214 Capsules t Ando

.. 306, 715 308, 1687

♦EXJADE TABLETS (Novartis). .309, 1695 ♦EXPERIENCE CAPSULES (PureTrim).310, 2225 EZET1MIBE V)torn! KVI0 Tablets (Mercki. Vytorin 10/20 Tablets (Menkl. Vytorin 10/40 Tablets tMenkt... Vytorin 10/HO Tablets tMervki... Zetia Tablets (Mere!). EZOGABLNE Potiga Tablets (GiaiirSmithKIine)

E

2123

ERTAPENEM Invan/, for Injection iMcrvk).1371

♦DULERA INHALATION AEROSOL (Merck).307, 1252

EICOSAPENTAENOIC ACID I.EPA) ageLOC Youth Capsules (NSE 310, 2225

EMEND FOR INJECTION (Merck).1270

ENZYGEN PLUS CAPSULES (Unicity).

DIPOTASSIUM PHOSPHATE Essentia Water (Essentia Warer). 306, 2218 |

311, 2065

DHA (DOCOSAHEXAENOIC ACID) (see under DOCOSAHEXAENOIC ACID I DHA))

303, 450 309, 1768

♦ Shown in Produit Idrnliflcalton (inWc

♦DEPAKOTE SPRINKLE CAPSULES FOR ORAL USE (AbbVie).303. 402

DIPHTHERIA & TETANUS TOXOIDS AND ACELLULAR PERTUSSIS VACCINE ADSORBED Infanrix Injection Vaccine (GlaxoSmithKline).987

EABIOR FOAM (Stiqfhl) .

308, 308, 308, 3t)8, 308,

1603 1603 1603 1603 1625 1044

1998

♦ FANAIT TAB1 .ETS Vanda)

312, 2102

♦FARYDAK CAPSULES (Novartis).

309, 1700

FATTY ACIDS CM Plcx Cream (Unicitv) CM Plev Softgcls t (bin in

312, 2228 312. 2228

FKBUXQ8TAT Clone Tablets (Takeda). FEMARA TABLETS

311, 2098

♦ ELIQU1S TABLETS IBristol Myers Squibb)...

(Novartis).

1707

305, 706

ELTROMBOPAG Pr.Miucta Tablets (Nomrtis l. .

FENNEL Experience Cajv,ules t Pur

310, 2225

.1781

♦EMEND CAPSULES (Met

307, 1262

I ENOFIBRATE Tneor Tablets (AkbXie) .,

304, 590

l ndt rlmr Denote* (ienerk N*m«

hatu Page K

Indiratrt Brkf Uuini

BRAND AND GENERIC NAME INDEX

CLINDAMYCIN PHOSPHATE Duac Gel (Stiefel).1996 Veltin Gel 946 FOLATE Cirdio-8*xK Mi ky).2228 LtfePak Capsules (SSE Produ, in.. 2223 FOLIC ACID Baby Care Prenatal Mega Antioxidant Table''(L'tarun. . 2232 Mega Antioxidant Tablets ■ i 2231 Optimal-V Capsules Anix). 305, 2217 ProArgi-9" Dietary Supplement Xsnergx ♦ Shown

W. r..'tridr).

in Product

311,2226

ldmtitkation Guide

307, 1305

FOSAMPRENAVIR CALCIUM Lcxiva Oral Suspension (ViiV).2129 Lexiva Tablets (ViiV).2129 FOSAPREPITANT DIMEGLUMINE Emend for Injection (Merck).1270 ♦4LIFE TRANSFER FACTOR TRI-FACTOR FORMULA (4Life Research). 303, 2212

ILOPERIDONE Fanapl Tablets (Vanda).312, 2102

H

1281

HAEMOPHILUS B CONJUGATE 'MENINGOCOCCAL PROTEIN CONJUGATE) AND HEPATITIS B i RECOMBINANT) VACCINE Comvax Vaccine (Merck)..... 1225 HAEMOPHILUS B CONJUGATE VACCINE (MENINGOCOCCAL PROTEIN CONJUGATE) PedvaxHIB Vaccine (Merck).

1461

HAVRIX INJECTION VACCINE (GlaxoSmithKline).... 963 HAWTHORN BERRY EXTRACT Advanced Lung Cleanse Capsules (Andorra). 305, 2214 HF.MICELLULASE Enzygen Plus Capsules (Unicity). 2228 HEMIN Panhcmatin for Injection (Recordati).311, 1983 HEPATITIS A VACCINE Havrix Injection Vaccine (GlaxoSmithKline).963 HEPATITIS A VACCINE. INACTIVATED Vaqta Vaccine (Merck)...1580 HEPATITIS A & HEPATITIS B (RECOMBINANT) VACCINE Twinrix Injection Vaccine (GlaxoSmithKline).1109

FUMARATE Perque Life Guard Tabsules (Perdue).2224

G

HESPERIDIN Optimal-M Capsules (Ariix). 305, 2217

GANIRELIX ACETATE Ganirelix Acetate Injection (Merck).1320 GANODERMA I.UCIDUM MUSHROOM EXTRACT ReishiMax GLp Capsules (NSE Products). 2223 GARDASIL VACCINE (Merck).1322 GARDASIL 9 VACCINE (Merck).1334 GARLIC EXTRACT Circulation Plus Capsules (Andorra).305, 2216 ♦GENGRAF CAPSULES (AbbVte). 303, 450

IM1PENEM Primaxin I V. (Merck).1484 IMITREX INJECTION (GlaxoSmithKline).966

HEPATITIS B VACCINE (RECOMBINANT) Engerix-B Injection Vaccine (GlaxoSmithKline).926 Recombivax HB Vaccine (Merck).1531

GAMMA TOCOPHEROL LifePak Capsules (NSE Products).2223

IMATINIB MESYLATE Glccvcc Tablets (Novartis). 309, 1721

♦HETLIOZ CAPSULES (Vanda).312, 2108 HEXACOSANOL Perque Life Guard Tabsules (Perque).2224 HUMAN PAPILLOMAVIRUS 9-VALENT VACCINE. RECOMBINANT Gardasil 9 Vaccine (Merck).1334 HUMAN PAPILLOMAVIRUS BIVALENT (TYPES 16 AND 18) VACCINE. RECOMBINANT Cervarix Injection Vaccine (GlaxoSmithKline).902 HUMAN PAPILLOMAVIRUS QUADRIVALENT (TYPES 6. 11. 16, AND 18) VACCINE. RECOMBINANT Gardasil Vaccine (Merck).1322

IMITREX NASAL SPRAY (GlaxoSmithKline).973 IMITREX TABLETS (GlaxoSmithKline).977 IMMUNIZEN CAPSULES (Unicity).2228 IMMUNOCAL POWDER SACHETS (Immunotec).2219 ♦ IMPLANON IMPLANT (Merck).

307, 1345

INCRUSE ELLIPTA INHALATION POWDER (GlaxoSmithKline).982 INDINAVIR SULFATE Crixivan Capsules (Merck). 307, 1233 INFANRIX INJECTION VACCINE (GlaxoSmithKline).987 INFLUENZA VACCINE Fluarix Quadrivalent Injection Vaccine (GlaxoSmithKline).954 Flulaval Quadrivalent Injection Vaccine (GlaxoSmithKline).958 INLAND SEA TRACE MINERALS Optimal-M Capsules (Ariix). 305, 2217 INOSITOL Cardio-B&sics Tablets (Unicity).2228 LifePak Capsules (NSE Products).2223 Mega Antioxidant Tablets (Usana). 2231 Optitnal-V Capsules (Ariix).305, 2217 msuiJN aspart (rdna origin) NovoLog NovoLog NovoLog NovoLog

FlcxPcn (Novo Noidisk).1889 FlexTouch (Novo Nordisk).1889 Injection (Novo Nordisk).1889 Mix 70/30 FlexPen (Novo Nordisk).1900 NovoLog Mix 70/30 Injection (Novo Nordisk).1900 INSULIN ASPART PROTAMINE (RDNA ORIGIN) NovoLog Mix 70/30 FlexPen (Novo Nordisk).1900 NovoLog Mix 70/30 Injection Nordisk).1879 Levcmir FlexTouch (Novo Nordisk).310, 1879 Levcmir Injection (Novo Nordisk).1879

HYCAMTIN FOR INJECTION (Novartis).1737

♦INTEGRILIN INJECTION (Merck). 307, 1352

G1NKO BILBOA EXTRACT Circulation Plus Capsules (Andorra).

305, 2216

♦GLEEVEC TABLETS (Novartis).309, 1721 GLUCOSAMINE HYDROCHLORIDE Procosa Tablets (UsanaI. 2232 GLYCERYL TRINITRATE (see under NITROGLYCERIN) ♦GORDOCHOM SOLUTION (Gordon),...'.

306, 1157

GRAPE SEED EXTRACT LifePak Capsules (NSE Products).2223 OPC Supreme Capsules (Andorran .. 305, 2217 Optimal-V Capsules (Ariix).305, 2217 ProAavanol C 100 Tablets (Usana).. 2232 Vinali Capsules (Ariix1.305, 2218 ♦GRASTEK TABLETS (Merck).

hydrochlorothiazide Dutoprol Tablets (Concordia).791 Dyazidc Capsules (GlaxoSmithKline).924 HYDROCODONE bitartrate Hysingla ER Tablets (Purdue).310, 1955 Vtcodin/Vicodin ES/Vtcodin HP Tablets (Abb Vie).304, 605 Vicoprofcn Tablets (AbbVie). 304, 607

Intron A for Injection (Merck).307, 1357 ♦INTRON A FOR INJECTION fMerck). 307, 1357 INVANZ FOR INJECTION (Merck).1371 INVKRTASK

11YDROXOCOBALAM1N Perque Life Guaixi Tabsules (Perque). 2224

Enzygen Plus Capsules I Unicitu. 2228

HYOSCINE HYDROBROMIDE iSCOPOLAMINE HYDROBROMIDE)

LifePak Capsules I NSE Products)

HYOSCYAMINE SULFATE Donnatal Elixir (Concordia). 306, 790 Donnatal Thblels (Concordia). 306, 791

Yervoy Injection t Bristol Mxers Squibbt.

♦HYSINGLA ER TABLETS (Purduei.

IODINE

310, 1955

307, 1341

GREEN TEA EXTRACT ageLOC TR90 Control Capsules (NSE PohIiu u). 2222 ageLOC TR90 Fit Capsules tNSE Pmdui ti). 2222 OPC Supreme Capsules 305, 2217 Optimal-M Capsules (4nu).. 305,2217

INTERFERON ALFA-2B, RECOMBINANT

I IBUPROFEN Vicoprofcn Tablets tAbbVie).

304, 607

IBUPROFEN LYSINE NeoProfen Injection (Resunlatil...

311. 1981

♦1LARIS INJECTION (Noixirtu).

l nderline Denotes Generic Name

2223

IPIL1MUMAB 306, 786

IKON (are under FERROUS FUMARATE) ♦ISENTRESS CHEWABLE TABLETS Merck

307, 1379

ISENTRESS FOR ORAL SUSPENSION Merck).

.... 1379

♦ISENTRESS TABLETS i Merck).

307, 1379

ISOTRETINOIN 309. 1742

Absorica Capsules (Ranbaxy).

311, 1971

halts Puge Number Indicates Brief Lasting

MOLYBDENUM ASCORBATE/105

IVABRAPINE Corlanor Tablet' (Amgen). 305, 629 IVERMECTIN Stromectol Tablets (Merck). 308, 1561

♦JADENU TABLETS __ (Novartis).309, 1746 JAKAF1 TABLETS (Incyte).1157 JALYN CAPSULES (GlaxoSmithKline).

991

♦JANUMET TABLETS _ (Merck)... 307, 1389 ♦JANUMET XR EXTENDED-RELEASE TABLETS (Merck). 307, 1399 ♦JANUVTA TABLETS (Merck).

307, 1410

♦JOINT MOBILITY „„„„ CAPSULES (Unicity). 312, 2229

Kaletra Oral Solution (AbbVie). 303, 475 Kaletra Tablets (Abb\ie)...303, 475

1828

L-ARGININE 2228 Cardio-Basics Tablets (Unicity). Circulation Plus Capsules (Andorra). 305, 2216 ProArgi-9* Dietarv Supplement (Synergy WorUf\hride). 311, 2226 L-ASCORBATES (see also under: VITAMIN C) Perque Life Guard Tabsules (Perque) Perque Potent C Guard Powder (Perque).

♦KALETRA ORAL SOLUTION (AbbVie)... 303, 475 ♦KALETRA TABLETS (AbbVie).. 303, 475 ♦KAPVAY EXTENDED-RELEASE TABLETS (Concordia).306, 797 ♦KAZANO TABLETS ... .... (Takeda).311, 2070 KELP Experience Capsules (PureTrim).310, 2225 KETOROI-AC TROMETILAMINE Sprix Nasal Spray (Egaletl. 306, 2202 KEYTRUDA FOR INJECTION (Merck).1*17 KEYTRUDA INJECTION (Merck).1417 KINRIX INJECTION VACCINE (GlaxoSmithKline).998

MarincOmcga Softgel Capsules (NSE Products).

LACTASE Enzygen Plus Capsules (Unicity). 2228

2227

Bios Life ProBionic Packets (Unicity)-

2227

Bios Life ProBionic Packets (Unicily)-

2228

Pcrquc Life Guard Tabsules (Perque).2224

LifePak Capsules (NSE Products).. ■

2223

2224

LUBIPROSTONE

MANGANESE ASCORBATE

Amiliza Capsules (Takeda). 311. 2036

Perquc Life Guard Tabsules f Perqtie)

L-CARNITINE (see under I.EVOCARNITINE)

♦LUPANETA PACK 3.75 MG (AbbVie). 303, 491

L-CITRULLINE ProArgi-1)* Dietary Supplement (Synergy Worldwide). 311, 2226 L-CYSTEINE Cardio-Basics Tablets (Unicity).

♦LUPANETA PACK 11.25 MG (AbbVie). 303. 498 ♦LUPRON DEPOT 3.75 MG (AbbVie). 303, 504

303, 514

♦LUPRON DEPOT— 3 MONTH 11.25 MG (AbbVie) ..

303, 509

♦LUPRON DEPOT— 22.5 MG FOR 3-MONTH ADMINISTRATION (AbbVie).

303, 514

LEUPROLIDE ACETATE 303, 491 303, 498 303, 504

Lupron Depot— 3 Month 303, 509 11.25 mg (AbbVie). Lupron Depot— 22.5 mg for 3-Month Administration 303, 514 (AbbVe). Lupron Depot— 30 mg for 4-Month Administration 303, 514 (AbbVie). Lupron Depot— 45 mg for 6-Month Administration (AbbVie). .514

520

2228

lmnium/cn Capsules (Unicity). LAM1CTAL CHEWABLE DISPERSIBLE TABLETS (GlaxoSmithKline).

1001

LAM1CTAL ODT ORALLY DISINTEGRATING TABLETS (GlaxoSmithKline).

1001

303, 514

LUTEIN agcl.OC Youth Capsules (NSE 2222 Products).... Bios Life Vision Essentials Capsules (Unicity).2227 LifePak Capsules (NSE Products).2223 Mega Antioxidant Tablets (Usana).2231 LYCOPENE agcLOC Youth Capsules (NSE Products). 2222 LifePak Capsules (NSE Prtxiucts).2223

LEVEMIR INJECTION (Novo Nordisk).1879

Mega Antioxidant Tablets (Usana). 2231

Sinetnel Tablets (Merck).1550 1553

LEVOTHYROXINE SODIUM Synthroid Tablets (AbbVie).

304, 581

LEXIVA ORAL SUSPENSION (ViiV).2129

M MAGNESIUM BoneMatc Plus Tablets (Unicily).. ■ ■ Cardio-Basics Tablets (Unicity).

2227 2228

LifePak Capsules (NSE Products).. ■ Pcrquc Life Guard Tabsules (Perque)

2223 2224

Perque Repair Guard Tabsules (Perque).,. Pcrquc Vessel Health Guard Lozenges (Perque).

LAMICTAL TABLETS (GlaxoSmithKline).

1001

L1DOCAINE LidoFlex Patch (Ru hmar).1984 LIDO FLEX PATCH (Thchmar)

LAMICTAL XR EXTENDED-RELEASE TABLETS /GlaxoSmithKline).

2224

1015

.

307 2220

LAMIVUDINE Combivtr Tablets (WiV!. Epi'ir Oral Solution (WiV)....

2110

Eptsir Tablets |MiV),...,, •

2115

Epivir-HBV Oral Solution I GlaxoSmithKline I.. .... Epi'ir-HBV Tablets (GlaxoSmithKline)

929

Ep/icom Tablets (VtiV). Tnumeq Tablets i VfiVl.,-•*>-

2123 2174

Tiuivir Tablets (ViiVl .........

2183

2115

929

2223

LIPASE 2228

Enzygen Plus Capsules (Unicily). L1POIC ACID CoQumone 30 Capsules (Usana)........ LIPOLYTIC ENZYMES (see under LIPASE)

♦LIQUID DAILY COMPLETE (PureTrim).310, 2225

(GlaxoSmithKline)

LANOXIN TABLETS Conconh*) ♦ Shown la Product ldentihiatioo Guide

801

MEASLES, MUMPS, RUBELl-A AND VARICELLA VIRUS VACCINE LIVE ProQuad Vaccine (Merck).

♦MEKINIST TABLETS _ (Novartis).309, 1753 MENAQUINONE (see also under: VITAMIN K) ProArgi-9* Dietary Supplement (Synergy WurhlVide).311, 2226 MENHIBRIX INJECTION VACCINE (GlaxoSmithKline).1033 MENINGOCOCCAL GROUPS C AND Y AND HAEMOPHILUS B TETANUS TOXOID CONJUGATE VACCINE Menhibrix Injection Vaccine (GlaxoSmithKline).

MERIVA BIOAVAIIABLE CCRCCMIN COMPLEX

Janumct Tablets (Men'k).. Junumcl XR Extended-Release Tablets (Merck).

397, 1399

Ka/ano Tablets (Takeda).

311, 2070

M ETH YI J'OBAI AM IN MAGNESIUM ASCORBATE (see also under VITAMIN C) BabyCare Prenatal Mega Antioxidant Tablets (Usana1.

Optimal-V Capsules (Anil).

Bio-C Tablets (Unicity).^. 2226 Mega Antioxidant Tablets (UsanaI - . 2231 Optimal-V Capsules lAnix). 305,2217 Pcrquc Potent C Guard Powder (Perque). Pcrquc Vessel Health Guard Lozenges (Perque).1

MIRTAZAPINE Remeron Tablets (Merck).

308, 1534

RcnKixmSolTab Tablets iMrn k). .

308, 1540

2224 2224

MIVACRON INJECTION (AhbVur).

2231

LI.YS1NK

Cardav Basic- Tablets lUn

2228

791

Duloprol Tablets (Com onha)

Chelated Mineral Tablets (Usana) . ■

528

528 1422

M-M-a II VACCINE (Merck) ♦MODKKIBA TABLETS AbbVie.

304, 533

MOLYBDENUM

MAGNESIUM OXIDE Active Calcium Tablets lUxanai. .

305, 2217

METOPROLOL SUCCINATE 2232

2232

310. 2225

307, 1389

2231

BabyCare Prenatal Chelaled Mineral Tablets i Usana). 2232 Chelated Mineral Tablets (Usana).... 2231 Optimal M Capsules I Ann 1. 305. 2217

BabyCare Prenatal Chelaled Mineral Tablets (Usana).

♦LIVERMASTEK CAPSULES IPureTrimI.

2232

METFORMIN HYDROCHLORIDE

Vtcto/a Injection (Slow Slordok).

307. 1174

1033

MEPRON SUSPENSION (GlaxoSmithKline).1036

2231

308, 1489

1497

MEGA ANTIOXIDANT TABLETS i Usana).2231

Active Calcium Tablets I Usana)....

♦LTVALO TABLETS hV 200 mg) (AbhVie)

574

PROGUANIL HYDROCHLORIDE Malaronc Tablets (GlaxoSmithKline)...... 1028 Malarone Pediatric Tablets (GlaxoSmithKline)..1028 ♦PROLLA FOR INJECTION (Amgen). 305, 640 PROMACTA TABLETS (Novartis).1781 PROMETRIUM CAPSULES (100 MG, 200 MG) (AbbVie).574 PROPAFENONE HYDROCHLORIDE Rythmol Tablets (GlaxoSmithKline).1079 Rythmol SR Emended-Release Capsules (GlaxoSmithKline).1083 ♦PROPECIA TABLETS (Merck).308, 1493

RALTEGRAVIR Isenlress Chewable Tablets (Merck).307, 1379 Isentress lor Oral Suspension (Merck).1379 Isentress Tablets (Merck). 307, 1379 RANITIDINE HYDROCHLORIDE Zantac 150 Tablets {GlaxoSmithKline!.1144 Zantac 300 Tablets (GlaxoSmithKline).1144

PROTEASE Enzygen Plus Capsules (Unicity).

2228

PROTEIN PREPARATIONS ageEOC. TR90 TrimShake Powder (NSE Pntducts). 2222

Raxibacumab Injection (GlaxoSmithKline).1051 ♦REBETOL CAPSULES (Merck). 308, 1519 ♦REBETOL ORAL SOLUTION (Merck).308, 1519 RECOMBIVAX HB VACCINE (Merck).1531

PROVENTIL UFA INHALATION AEROSOL (Merck).1513 PRUNUS CERASL'S agel.OC TR90 Control Capsules (NSE Pnxiucts I.2222 PSEUDOEPHEDRINE SULFATE Clanncx-D 12-Hour Extended Release Tablets (Meick).. 307, 1220 PSY1JLIUM PREPARATIONS Experience Capsules (PureTrimt.310, 2225

REGORAFENIB Stivarga Tablets (Bayer).305, 663 RE1SHIMAX GLP CAPSULES (NSE Products). 2223

♦REMERON TABLETS (Merck). 308, 1534 ♦REMERONSOLTAB TABLETS (Merck). 308, 1540 ♦REPATHA FOR INJECTION (Amgen). 305, 647 REQUIP TABLETS (GlaxoSmithKline).1060 REQUIP XI. EXTENDED-RELEASE TABLETS (GlaxoSmithKline).1067 RESCRIPTOR TABLETS % ll li f EXTRACTi I’Ll S COI NZ5 M* Q10

SKCUKINUMAB Czwentyx Injection (Nomefin...

heyonde Ufc 1 i Unitrvir Th

L ndtrtiiw Denotes Generic Name

308. 1676

Italic Puier !

312. 2230 ’ Indicate* Brief LMinf

BRAND AND GENERIC NAME INDEX

BRAND AND GENERIC NAME INDEX

PHYSICIANS’ DESK REFERENCE®

10 8/SU RVANTA ♦SURVANTA INTRATRACHEAL SUSPENSION (AbbVie). 304, 578 ♦SUSTIVA CAPSUI.ES

Janumct Tablets (Merck). . Januinct XR Ex. tended- Re lease Tablets (Men k • Janusia Tablets (Men 11 Ka/ano Tablets iTaked*i‘ Levcmtr FlcxPen • Vnr> Nordisk i

(see under:

ANTIGLAUCOMA AGENTS (see under: OPHTHALMIC PREPARATIONS

NAIL PREPARATIONS (see under;

SKIN & MUCOUS MEMBRANE AGENTS)

BETAADRFNERGK BLOCKING AGENTS & COMBINATIONS CARBONIC' ANHYDRASK INHIBITORS A COMBINATIONS)

NARCOTICS

BETA ADRENERGIC BLOCKING AGENTS A COMBINATIONS

(see under:

ANALGESICS NARCOTICS)

Cosopt PP Ophthalmic Solution 2^/03T (Menk,. 307, 1229

ANALGESICS

CARBONIC ANHYDRASE INHIBITORS & COMBINATIONS

Sprix N.isal Spray (Ei-aletl.306, 2202

Cosopt PF Ophthalmic Solution

ANTIBIOTICS & COMBINATIONS

Trusopt Sterile Ophthalmic Solution

SKIN & MUCOUS MEMBRANE AGENTS Baclrohan Nasal (Sliefel)...

1992

ANTMNFIAMMATORY AGENTS MISCELLANEOUS ANTI-INFLAMMATORY AGENTS

2‘370.5'S (Menk). 307, 1229 (Men'k).1578 GLAUCOMA, AGENTS FOR (aee under: OPHTHALMIC PREPARATIONS BETA ADRENERGIC BLOCKING AGENTS A COMBINATIONS CARBONIC ANHYDRASK INHIBITORS A COMBINATIONS)

Sprix Nasal Spray (Egulri). 306, 2202

VITAMINS & COMBINATIONS

STEROIDAL ANTI - INFLAMMATORY AGENTS

Bios Life Vision Essentials

Bcconasc AQ Nasal Spray iOlaxoSrnuh Kline t..873

_ _

Capsules (Uniciry).

I see under:

PSYC HOTHERAPEUTIC AGENTS ANTIPSYCHOTIC AGENTS)

M

MEDICAL FOODS METAL POISONING (see under:

ANTIDOTES CHELATING AGENTS)

NONSTEROIDAL ANTI-INFI-AMMATORY AGENTS (NSAIDS) (are under: ANALGESICS NONSTEROIDAL ANTI-INHA.MMAH IRY DRUGS iNSAIDS, A COMBINATIONS!

HAIR GROWTH STIMITANTH) \U*if£n(Po'!ut)

2227

OSTEOPOROSIS PREPARATIONS BISPHOSPHONATES A COMBINATIONS Fosamax Tablets (Menk). Fosamax Plus D Tablets (Menrk).

307, 1305 307, 1312

MISCELLANEOUS AGENTS . 305, 640

Prolu for Injection (Amyen).

P PAIN RELIEVERS (mc under: ANALGESICS)

PARKINSONISM DRUGS (aee under: ANTIPARKINSONIAN AGENTS)

NEUROLEPTICS

(•e* under:

AGENTS

307,1399 307, 1410 311, 2070 1879

ONCOLYTIC AGENTS

OPHTHALMIC PREPARATIONS

LUNG SURFACTANTS I

(*y under SKIN A MUCOUS MEMBRANE 858 307, 1389

Contrave Extended-Release Tablets (Takeda). 311, 2054

ANTINEOPLASTICS)

N

RESPIRATORY AGENTS

LEPROSTATICS)

MALE PATTERN HAIR LOSS TREATMENTS

ANTIDIABETIC AGENTS)

Mivacron Injection (AbbVie).528 Nimbex Injection (AbbVie). 304, 546 Zemuron Injection (Merck). 308, 1613

(see under:

LUNG SURFACTANTS)

(are also under:

o APPETITE SUPPRESSANTS

NEUROMUSCULAR BLOCKING AGENTS

NEONATAL RESPIRATORY DISTRESS SYNDROME THERAPY

ANTI-INFECTIVE AGENTS, SYSTEMIC

RESPIRATORY AGENTS

HYPOGLYCEMIC AGENTS

(aee under: DIETARY SUPPLEMENTS)

ANTIEMETICS)

CHELATING AGENTS LEAD)

HYPERCALCEMIA MANAGEMENT

SEDATIVES A HYPNOTICS)

NUTRITIONALS

GASTROINTESTINAL AGENTS

ANTIDOTES

LUNG SURFACTANTS

(see under:

Baraclude Oral Solution iBnrndMvers Squibb).4 .. 687 Baraclude Iablets (Bristol Mvers Squibb) . g...., 305. 687 Combivir lableLs (VuV)t.... 2110 Epivir Oral Solution (ViiV). 2115 Epivir Tablets (ViiV). 2115 Epivir HBV (M Solution (GlaxoSmithKline 1.. . . . 929 Epivir HBV Tablets (Glaxo Smith Kline». 929 Ep/icom Tablets i ViiV)... 2123 Modcriba Tablets (AbbVie). 304. 533 Rebetol Capsules iMenk). 308. 1519 Rehclol Oral Solution (Menk). 308, 1519 Retrovir Capsules (\AiV). 2150 Retrovir Injection (ViiV). 2150 Retrovir Svnip (ViiV). 2150 Triumeq Tablets (ViiV). 2174 Tnzivir Tablets (ViiV). 2183 Vallrex Caplets (GlaxoSmithKline). 1112 Ziagcn Oral Solution (ViiV). 2191 Ziagen Tablets (ViiV). 2191

OBESITY MANAGEMENT

MUSCLE RELAXANTS

(are under:

(see under:

HYPNOTICS

Cclestone Soluspan Injectable Suspension (Menk).1213 Gilcnya Capsules (Novartis).309, 1714 Orapred ODT Orally Disintegrating Tablets (Concordia).306, 807

NAUSEA MEDICATIONS

(nee under:

1857

Cardio-Basics Tablets (Uniciry). 2228 Chelated Mineral Tablets (l/sanaf.. .. . 2231

Nasoncx Nasal Spray iMen-h. 307, 1425 V'eramysl Nasal Spray tuluxoSmitMOmr i.1123

LEAD POISONING

311. 1977

Zomcta Injection Concentrate for Intravenous Infusion (Noxa/tul .

(see under:

NASAL PREPARATIONS

Gcngraf Capsules (AbbVie). 303, 450 Myfortic Tablets (Novartis). 309, 1761 Neoral Oral Solution (Novartis).309, 1768 Neoral Soft Gelatin Capsules (Novartis). 309, 1768 Nulojix Injection (Bristol-Myers Squibb).306. 724 Sandimmune Oral Solution (Novartis). 1788 Sandimmune Injection (Novartis).1788 Sandimmune Soft Gelatin Capsules (Novartis). 1788 Simulcct for Injection (Novartis)... 309, 1800 Zortrcvt Tablets (Novartis).310, 1864

LEPROSTATICS

HYPERAMMONIA REDUCTION

MINERALS

MULTIPLE SCLEROSIS MANAGEMENT

IMMUNOMODULATORS

T3 & T4 COMBINATIONS

AIDS ADJUNCT ANTI-INFIXTIVKS AIDS CHEMOTHERAPEUTIC AGENTS)

Amcrge Tablets fGlaxoSmithKline). 840 Iniilrex Injection (GlaxoSmithKline).966 Iniitrex Nasal Spray lGlaxoSmithKline).973 iuulrcx Tablets (GlaxoSmithKline)........ 977

MULTIMINERALS & COMBINATIONS

INSULINS)

(see under: ANTI-INFECTIVE AGENTS. SYSTEMIC

303, 429

SEROTONIN (5-HT) RECEPTOR AGONISTS

MINERALS & ELECTROLYTES

I

304, 581

HUMAN IMMUNODEFICIENCY VIRUS (HIV) THERAPY

Depakote ER Tablet. Extended Release for Oral Use (AbbVie) ..

CARDIOVASCULAR AGENTS

ANTIDIABETIC AGENTS

Naturc-Thmid Tablets (KLC).310, 1985 WP Thyroid Tablets (RLC). 311, 1987

NUCLEOSIDE ANALtXJUES & COMBINATIONS

MISCELLANEOUS MIGRAINE PREPARATIONS

MINERALS & ELECTROLYTES)

(see under:

(see under:

THYROID PREPARATIONS SYNTHETIC T4

MIGRAINE PREPARATIONS

DIETARY SUPPLEMENTS

HYPOLIPIDEMICS

IMPOTENCE AGENTS

SOMATOSTATIN ANALOGUES

Synlhroid Tablets (AbbVie).

Lev emir FlexTouch (Novo Nordisk). .310, 1879 Levemir Injection (Novo Nonlisk).1879 Nesma Tablets (fakeda).311, 2079 NovoLog FlcxPcn (Novo Nordisk).1889 NovoLog FlexTouch (Novo Nondisk).1889 NovoLog Injection (Novo Nordisk). . . 1889 NovoLog Mix 70/30 FlexPen (Novo Nordisk).1900 NovoLog Mix 70/30 Injection (Now Nordisk).1900 Oseni Tablets fTakeda).311, 2087 Tanzeuin for Injection (GlaxoSmithKline).1097 Vic to/.a Injection (Novo Nordisk). . . 310, 1907

310,1944

PARKINSON’S DISEASE (are under: ANTIPARKINSONIAN AGENTS)

PATENT DUCTUS ARTERIOSUS AGENTS NeoPruIen lincctkm .

-

oi >vi \j=»* m -m ,*cr ^n^3roq wo •

9

FDA REQUIREMENTS FOR PREGNANCY AND LACTATION LABELING

211

FDA Requirements for Pregnancy and Lactation Labeling The FDA has amended its regulations governing the content and format of the “Pregnancy,” “Labor and delivery,” and “Nursing mothers” subsections of the “Use in Specific Populations” section of the labeling for human prescription drug and biological products. The Pregnancy and Lactation Labeling Rule (PLLR) requires changes to the content and format for information presented in prescription drug labeling in the Physician Labeling Rule format to assist healthcare providers in assessing benefit versus risk and in subsequent counseling of pregnant women and. nursing mothers who need to take medication, thus allowing them to make informed and educated decisions for themselves and their children. The PLLR removes pregnancy letter categories - A. B, C. D, and X. The PLLR also requires the label to be updated when information becomes outdated. This rule became effective June 30, 2015. The changes are as follows: Pregnancy (8.1) - The Pregnancy subsection now includes information on labor and delivery and other content including: • information for a pregnancy exposure registry (when one is available) that collects and maintains data on the effects of approved drugs that are prescribed to and used by pregnant women; • a Risk Summary subheading that provides information on all the available data regarding risk of adverse developmental outcomes; • a Clinical Considerations subheading that provides information to further inform prescribing and risk-benefit counseling: and • a Data subheading that includes the human or animal data available that is discussed in the Risk Summary and Clinical Considerations sections. Lactation (8.2) - The “Nursing mothers” subsection was renamed the Lactation subsection and provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed child. Information is presented under the following subheadings: • Risk Summary subheading that provides information on the effects of the drug and/or its active metabolite on a breastfed child and on milk production • Clinical Considerations subheading that discusses ways to minimize exposure to the breastfed child and monitor for adverse reactions • Data subheading that describes the data on which the Risk Summary and Clinical Considerations are based Females and Males of Reproductive Potential (8.3) - This is a new subsection that is required to include information on recommendations or requirements for pregnancy testing and/or contraception before, during, or after drug therapy and/or if there are human and/or animal data suggesting drug-associated effects on fertility and/or preimplantation loss effects.

Prior Use-in-Pregnancy Ratings The FDA use-in-pregnancy rating system was previously used to weigh the degree to which available information has ruled out risk to the fetus against the drug's potential benefit to the patient. The ratings, and their interpretations, are as follows:

SCHEDULE

INTERPRETATION

A

CONTROLLED STUDIES SHOW NO RISK. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).

B

NO EVIDENCE OF RISK IN HUMANS. Adequate, well-controlled studies in pregnant women are lacking, and animal studies have not shown increased risk of fetal abnormalities. The chance of fetal harm is remote, but remains a possibility.

C

RISK CANNOT BE RULED OUT. Adequate, well-controlled human studies in pregnant women are lacking, and animal studies have shown a risk to the fetus. There is a chance of fetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk.

D

POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or postmarketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

X

CONTRAINDICATED IN PREGNANCY. Studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and risk of use clearly outweighs any possible benefit.

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SECTION 4

PRODUCT IDENTIFICATION GUIDE To aid in quick identification, this section provides full-color, actual-sized images of tablets and capsules. A variety of other dosage forms and packages are shown at less than actual size. Products in this section are arranged alphabetically by manufacturer. Some exceptions, however, have been made based on space available in this section. Late submissions appear alphabetically by manufacturer at the end of the section. In some instances, not all dosage forms and sizes are pictured. If others are available, a t symbol precedes the product’s name. Letters or numbers

representing the manufacturer’s identification code are followed by a * symbol. For more information on any of the products in this section, please turn to the Product Information section, or check directly with the manufacturer. The page number of each product’s text entry appears with its images. While every effort has been made to guarantee faithful reproduction of the images in this section, changes in size, color, and design are always a possibility. Be sure to confirm a product’s identity with the manufacturer or a pharmacist.

INDEX BY MANUFACTURER This section is made possible through the courtesy of the manufacturers whose products appear on the following pages. 4Life .303

Merck.307

A&Z Pharmaceutical .303 AbbVie Inc.303 Alto .304 Amgen Inc.305 Andorra Life .305 Ariix .305

Novartis Pharmaceuticals Corporation .308 Novo Nordisk .310

Bayer Healthcare LLC .305 Boiron .305 Bristol-Myers Squibb Company .;.305

Otsuka America Pharmaceutical, Inc.310 Pivotal Therapeutics Inc.310 Purdue Pharma L.P.310 PureTrim .310

Concordia Pharmaceuticals Inc.306

Ranbaxy Laboratories Inc.311 Recordati Rare Diseases Inc.311 RLC Labs, Inc.310

Egalet .306 Essentia Water, LLC.306

Supernus Pharmaceuticals .311 Synergy Worldwide, Inc.311

Glenwood .307 Gordon Laboratories.306

Takeda Pharmaceuticals .311

Kowa Pharmaceuticals America, Inc.307

Unicity International, Inc.312 Unilever Thai Trading Limited .312

LifePharm Global Network.307

Vanda Pharmaceuticals .312

'I

' •

V V

' ■ «. -n, V

..

.. , . ^ -W ,

PRODUCT IDENTIFICATION GUIDE/303 P 408

4LIFE

_______

4Jfc _

RX

p

423

_3

The pictured forms shown in this section may not necessarily be the only dosage forms and/or sizes available. Where a product name is preceded by a t symbol, refer to the description in the Product Information Section for other dosage forms and/or sizes.

i_

MJft TRANSFER FACTOtl

lAlonth 3.75 mg

4Life Transfer Factor8 Tri-Factor* Formula

Depakote* AndroGel* 1.62%

(divalproex sodium) Tablets for Oral Use

(testosterone gel) P. 414

A&Z PHARMACEUTICAL

prefilled synnge

RX

A4Z PHARMACEUTICAL

E)hf

SMonth 11.25 mg

40 mg/0.8 mL pen

c3 KT

HF* 250 mg KT* 250 mg

r~)

tHUMIRA*

Lupron Depot* GYN

(adahmumab)

(leuprolide acetate for depot suspension)

HC

HC* 500 mg

KL* 500 mg

Depakote* ER Biaxin* Filmtab*

(divalproex sodium) Tablets, Extended-Release for Oral Use

(clarithromycin tablets. USP) P. 414

lAAonth 7.5 mg

RX

L -

Calcium 300 mg 125 mg 60 Chewable Tablets

80 mg20 mg/mL 160 mL bottle

Depakote* Sprinkle Capsules

D-Cal* (calcium carbonate/vitamm D.)

250 mg/5 mL

TBiaxin* Granules (clarithromycin for oral suspension. USP)

11.25 mg

Kaletra*

(divalproex sodium delayed release capsules)

(lopinavir/ritonavir) Solution for Oral Use

Products in this section are arranged alphabetically by manufacturer. In some instances, not all dosage forms and/or sizes are pictured. If others are available, a t symbol precedes the product's name. Letters or numbers representing the manufacturer's identification code are followed by a * symbol.

AbbVl* Inc.

P. 475

1 Month 15 mg

100 mg/25 mg

Kaletra* (lopinavir/ritonavir) Tablet FilnvCoated for Oral Use P. 47S

tLupron Depot-PED’ (leuprolide acetate for depot suspension! RX

s_

Calcium 300 mg 10 pouches Granules

200 mg/50 mg

Kaletra* D-Cal* Kids

OtfON

(calcium carbonate)

JTT-

ABBVIE INC. For description of Abbo-Code Identifications, see Abbo-Code index at the beginning of the AbbVie information Section.

(lopinavir/ritonavir) Tablet Film-Coated for Oral Use

1 Month 7.5 mg

y&2233 4.63 mg and 20 mg/mL

e Jl )

Creon* (pancrelipase) Delayed Release Capsules

Duopa™ icarbidopa and levodopa)

3Month 22.5 mg

1 Month 3.75 mg/5 mg

4 Month 30 mg 250 mg OR* 25 mg

tDepakene*

tLupron Depot* URO

(valproic acid) Capsules and Oral Solution

AndroGel* 1% (testosterone gel) ' A kkt/. Ll

FT* 1 mg

25 meg

50 meg

45 mg

75 meg

135 FX* 2 mg

80 mg/mL 240 ml bottle

135 mg

a

c

3

88 meg

100 meg

112 meg

Norvir®

Trilipix® (fenofibric acid) Capsule. Delayed-Release for Oral Use

(ritonavir oral solution)

V VP* 7.5 mg/200 mg

F

FZ* 4 mg

-M 125 meg

137 meg

4# 150 meg

Vicoprofen®

Mavik® (trandolapril tablets) AbbVIe Inc.

I k P. 533

10 mg/5 mL (2 mg/ml)

(hydrocodone bitartrate and ibuprofen tablets)

i,

3 175 meg

W 200 meg

300 meg

250 mL

Su.

Ultane®

Synthroid® (levothyroxine sodium tablets, USP) AbbVU Inc.

(sevoflurane) Volatile Liquid for Inhalation

P. 585

12.5 mg/75 mg/50 mg: 250 mg

20 mg/10 mL (2 mg/mL) 600 mg

Moderiba"*

Viekira Pak™

(ribavirin. USP) Tablets

(ombitasvir/paritaprevir/ritonavir tablets: dasabuvir tablets)

■«n.b..

r~1 500

AbbVIo Inc.

200 mg/20 mL (10 mg/mL)

mm

5 mg/300 mg

azr 1 mg/240 mg

500 mg

P. 622

Nimbex®

Vicodin® (hydrocodone bitartrate and acetaminophen tablets. USP)

(cisatracurium besylate) Injection

AbbVI* Inc.

a 750 750 mg

mobilePDR - The official free comprehensive drug reference and comparison app from PDR - Install Now at the iTunes or Google Play Store. 1 meg

2 meg

A Vp,

3 1000 1000 mg

E

Niaspan* Tablets (niacin extended-release) Tablet, FilrrvCoated. Extended Release for Oral Use

4 mg/240 mg

32K ) 7.5 mg/300 mg

Tarka®

Vicodin ES*

(trandolapril/verapamil hydrochloride ER tablets)

(hydrocodone bitartrate and acetaminophen tablets. USP)

AbbVIn Inc.

as

4 mL 4 meg

OS* 100 mg

Norvir® FI* 48 mg

(ntonavir) Capsules. Soft Gelatin for Oral Use

Zemplar* Capsules (pancalcitol)

ALTO OS

AII0 RHARMACEUTICA15. I«C

10 mg/300 mg F0* 145 mg 100 mg

Norvir® irdonaw) Tablet for Oral Use

'Manufacturer’s Identification Code

8 ml

Survanta* (beractant) Iniiatracheal Suspension

Tricor® (fenofibratel Tablet for Oral Use

Vicodin HP*

220 mg

(hydrocodone bitartrate and acetaminophen tablets. USP)

Zinc-220® Utnc sulfate. USP)

R. 2213

PRODUCT IDENTIFICATION GUIDE/305

AMGEN INC.

P. 629

OS

ANDORRA LIFE

RX

ARIIX

ANDORRA LIFE

AMGEN INC.

P. 2213

BAYER HEALTHCARE UC

P

669

RX

BRISTOL MYERS SQOlfMI COMPANY

P

687

DS

0.5 mg

•SSL.

' Blood Sugar ^ Control

!

nutimal-M

r- ^

5/ 1000 kBq/mL

5 mg

1.0 mg Also available as 0.05 mg/mL oral solution

Advanced Blood Sugar Control ANDORRA LIFE

Xofigo™

Baraclude*

(radium Ra 223 dichloride) injection

(entecavtr) tablets

Optima l-M'“

P. 2214

RX

BOIRON

in'?- • A

BRISTOL MYERS SOU— COMPANY

P

CSS

I1 «

^5=r- :g

I*

XT utimal-V

7.5 mg

Lung Cleanse

Corlanor* (ivabradine) tablets AMGEN INC.

P. 633

1 mg

2 mg

2S mg

3 mg

4 mg

5 mg

6 mg

7S mg

10 mg

4) Optima l-V™ K^prois

I

@

Kypnolis'

Optimal

Advanced Lung Cleanse OS

ANDORRA LIFE

P. 2215

Arnicare' Gel BOIRON

! DS

P. 673

60 mg/vial SMTHiS A NEALS SKIN IRRITATIONS

ChoteitpHS*1*

M

Kyprolis*

vinali

(carfilzomib) for Injection AMGEN INC.

• CncAas (Amor Bums • Sor’bti'rT

P

CalendulaCmiw

640

Also available as 5 mg vial (or intravenous use

Vinali™

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P. 701

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P. 797

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orapr*d l. genesis Additionally, serum testosterone concentration should be • Topical testosterone pnxlucts may have different doses, 5.8 Hepatic Adverse Effects assessed periodically. (2.1) strengths or application instructions that may result in 5.9 Edema • Patients should wash hands immediately with soap and different systemic exposure (1, 12.3). 5.10 Gynecomastia water after applying AndroGel inf and cover the applica¬ 5.11 Sleep Apnea tion siteta) with clothing after the gel has dried. Wash the 2 DOSAGE AND ADMINISTRATION 5.12 Lipids application site thoroughly with soap and water prior to I Dosage and Administration for AndroGel 1% differs from 5.13 Hypercalcemia any situation where skin-to-skin contact of the application AndroGel 1.62%. For dosage and administration of 5.14 Decreased Thyroxine-binding Globulin site with another person is anticipated. (2.2) AndroGel 1 62% refer to its full prescribing information (2) 5.15 Flammnbilitv I Prior to initiating AndroGel 191, confirm the diagnosis of -DOSAGE FORMS AND STRENGTHS6 ADVERSE REACTIONS I hypogonadism by ensuring that serum testosterone concen6.1 Clinical Trial Experience AndroGel (testosterone gel) IT for topical use is available { trations have been measured in the morning on at least two as follows: 6.2 Postmarketing Experience separate days and that these serum testosterone concenlra7 DRUG INTERACTIONS • Metered-dose pump that delivers 12.5 mg of testosterone j tions are below the normal range. 7.1 Insulin per actuation. (3) 2.1 Dosing and Dose Adjustment 7.2 Oral Anticoagulants • Packets containing 25 mg of testosterone. (3 > The recommended starting dose of AndroGel IT is 50 mg of 7.3 Corticosteroids • Packets containing 50 mg of testosterone. (3> testosterone (4 pump actuations, two 25 mg packets, or one 8 USE IN SPECIFIC POPULATIONS 50 mg packet). applied topically once daily in the morning to -CONTRAINDICATIONS8.1 Pregnancy the shoulders and upper arms and/or abdomen area (pref¬ • Men with carcinoma of the breast or known or suspected 8.3 Nursing Mothers erably at the same time every day). prostate cancer. (4, 5.1) 8.4 Pediatric Use • Pregnant or breastfeeding women. Testosterone may 8.5 Geriatric Use cause* fetal harm. (4, 8.1, 8.3) 8.6 Renal Impairment Information on the AbbVie, Inc. products listed on these 8.7 Hepatic Impairment pages is from the prescribing information in use as -WARNINGS AND PRECAUTIONS9 DRUG ABUSE AND DEPENDENCE of July 31, 2015 For more information, please visit • Monitor patients with benign prostatic hy perplasia (BPH 9.1 Controlled Substance rx abb vie com or call 1-800-633-9110 for worsening of signs and symptoms of BPH. (5.1) 92 Abuse

I

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404/ABBVIE • ANDROGEL1%

ment therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for de¬ termining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when de¬ ciding whether to use or to continue to use AndroGel 191.

• In the event that unwashed or unclothed skin to which AndroGel 191 has been applied comes in direct contact with the skin of another person, the general area of con¬ tact on the other person should be washed with soap and water as soon as possible.

Dose Adjustment To ensure proper dosing, serum testosterone concentrations should be measured at intervals. If the serum testosterone concentration is below the normal range, the daily AndroGel \% dose may be increased from 50 mg to 75 mg and from 75 mg to 100 mg for adult males as instructed by the physician (see Table 1, Dosing Information for AndroGel 1%). If the serum testosterone concentration exceeds the normal range, the daily AndroGel 1% dose may be de¬ creased. If the serum testosterone concentration consis¬ tently exceeds the normal range at a daily dose of 50 mg, AndroGel 1 ri therapy should be discontinued. In addition, serum testosterone concentrations should be assessed peri¬ odically. The application site and dose of AndroGel l'i are not inter¬ changeable with other topical testosterone products.

3

DOSAGE FORMS AND STRENGTHS

AndroGel (testosterone gel) \% for topical use is available as follows: • A metered-dose pump. Each pump actuation delivers 12.5 mg of testosterone in 1.25 g of gel. • A unit dose packet containing 25 mg of testosterone pro¬ vided in 2.5 g of gel. • A unit dose packet containing 50 mg of testosterone pro¬ vided in 5 g of gel. 4

5.6

CONTRAINDICATIONS

5.7

• AndroGel 1 % is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the pros¬ tate /see Warnings and Precautions (5.1), Adverse Reac¬ tions (6.1), and Nonclinical Toxicology (13.1)1. • AndroGel 1% is contraindicated in women who are or may become pregnant, or who are breastfeeding. AndroGel 1% may cause fetal harm when administered to a pregnant woman. AndroGel 1% may cause serious adverse reactions in nursing infants. Exposure of a female fetus or nursing infant to androgens may result in varying degrees of viri¬ lization. Pregnant women or those who may become preg¬ nant need to be aware of the potential for transfer of testosterone from men treated with AndroGel 1%. If a pregnant woman is exposed to AndroGel 1%, she should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].

2.2 Administration Instructions

AndroGel 1 91 should be applied to clean, dry, healthy, intact skin of the right and left upper arms/shoulders and/or right and left abdomen. Area of application should be limited to the area that will be covered by the patient's short sleeve T-shirt. Do not apply AndroGel Iff to any other part of the body including the genitals, chest, armpits (axillae), knees, or back. AndroGel 191 should be evenly distributed between the right and left upper arms/shoulders or both sides of the abdomen. The prescribed daily dose of AndroGel 1% should be ap¬ plied to the right and left upper arms/shoulders and/or right/left abdomen as shown in the shaded areas in the figure below.

5 5.1

5.8

5.9

WARNINGS AND PRECAUTIONS Worsening of Benign Prostatic Hyperplasia (BPH)

Number of Pump Actuations

50 mg

4 (once daily)

75 mg

6 (once daily)

100 mg

8 (once daily)

5.10

Gynecomastia

Gynecomastia may develop and persist in patients being treated with androgens, including AndroGel 1'19r of patients in a 180 annually. If hematocrit becomes elevated, stop therapy until j Day, Phase 3 study. hematocrit decreases to an acceptable concentration. An in¬ Table 2: Adverse Events Possibly, Probably or Definitely crease in red blood cell mass may increase the risk of throrn- I Related to Use of AndroGel 1% in the 180-Day Controlled boembolic events.

Packets The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Al¬ ternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

5.4

I

Clinical Trial

Venous Thromboembolism

There have been postmarketing reports of venous thromboorder to minimize the potential for secondary exposure to embolic events, including deep vein thrombosis i DVT) and testosterone from AndroGel 1%-treated skin: pulmonary embolism (PEi, in patients using testosterone • Children and women should avoid contact with unwashed j products such as AndroGel 19k. Evaluate patients who re¬ or unclothed application siteof men using AndroGel 1**. | port symptoms of pain, edema, warmth and erythema in the • Patients should wash hands with soap and water immedi¬ lower extremity for DVT and those who present with acute ately after application of AndroGel 191. shortness of breath for PE. If a venous thromboembolic • Patients should cover the application sites s' with clothing event is suspected, discontinue treatment with AndroGel (e.g.. a T-shirt' after the gel has dried. 19k and initiate appropriate workup and management /see • Prior to situation in which direct skin-to-skm contact is I Adverse Reactions (6.2)]. anticipated, patients should wash the application site 5.5 Cardiovascular Risk thoroughly with soap and water to remove any Long term clinical safety trials have not been conducted to testosterone residue. assess the cardiovascular outcomes of testosterone replaceStrict adherence to the following precautions is advised in

|

Dose of AndroGel IS Adverse Event

I

! I

Acne Alopecia Application Site Reaction Asthenia Depression Emotional Lability

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50 mg

75 mg

100 mg

z II.

Amount of Testosterone

Edema

Androgens, including AndroGel 191, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease [see Adverse ■Reactions (6.2)].

Cases of secondary exposure resulting in virilization of chil¬ dren have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the pe¬ nis or clitoris, development of pubic hair, increased erec¬ tions and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained mod¬ estly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to pre¬ cautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with un¬ washed or unclothed application sites in men using AndroGel 191 [see Dosage and Administration (2.2), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)]. Inappropriate changes in genital size or development of pu¬ bic hair or libido in children, or changes in body hair distri¬ bution, significant increase in acne, or other signs of virili¬ zation in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.

Table 1: Dosing Information for AndroGel 1%

Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatis, he¬ patic neoplasms, cholestatic hepatitis, and jaundice). Pelio¬ sis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. AndroGel 1% is not known to cause these adverse effects.

• Patients with BPH treated with androgens are at an in¬ creased risk for worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symp¬ toms. • Patients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens [see Contraindications (4), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)]. 5.2

Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including AndroGel 1%, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

and Potential Risk of Prostate Cancer

After applying the gel, the application site should be al¬ lowed to dry prior to dressing. Hands should be washed thoroughly with soap and water after application. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel 191, are flammable. The patient should be advised to avoid swimming or showering for at least 5 hours after the application of AndroGel 1%. Multi-Dose Pump To obtain a full first dose, it is necessary to prime the can¬ ister pump, lb do so, with the canister in the upright (xisition, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose. After the priming procedure, patients should completely depress the pump one time actuation for every 12.5 mg of testosterone required to achieve the daily prescribed dos¬ age. The product should be delivered directly into the palm of the hand and then applied to the desired application sites. Alternatively. AndroGel \% can be applied directly to the application sites. Table 1 provides dosing information for adult males.

Use in Women

Due to lack of controlled evaluations in women and poten¬ tial virilizing effects, AndroGel 19k is not indicated for use in women [see Contraindications (4) and Use in Specific Popu¬ lations (8.1, 8.3)1.

N r 40

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8** 191 49k If 194 39k

1% 1* 59r 091 I* or

Look for PDR drug information and services in your EHR Gynecomastia Headache Hypertension Lab Tbst Abnormal* Libido Decreased Nervousness Pain Breast Prostate Disorder** Testis Disorder***

1% 4% 3% 6-2 09?

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*Lob test abnormal occurred in nine patients with one or more of the following events reported: elevated hemoglobin | or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin. "Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results. ’"Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis. 1 j

162 hypogonadal men on AndroGel 1% in the 3-year exten¬ sion study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA ob¬ served in approximately 180? of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL. Twenty-nine patients (1892) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still 6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient’s PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient’s PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.

Vascular disorders:

Hypertension, vasodilation (hot flushes), venous thromboembolism

Secondary Exposure to Testosterone In Children ! Gases oTsecomTary exposure to testosterone resulting in vir¬ ilization of children have been reported in postmarket sur¬ veillance. Signs and symptoms of these reported cases have i included enlargement of the clitoris (with surgical internedI tion) or the penis, development of pubic hair, increased erec¬ tions and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, en¬ larged genitalia did not fully return to age appropriate nor¬ mal size, and bone age remained modestly greater than j chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary expo¬ sure from items such as the testosterone gel user's shirts and/or other fabric, such as towels and sheets /see Warnings and Precautions (5.2)].

Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored | hair, dizziness, dry skin, hirsutism, hostility, impaired uri¬ 7 DRUG INTERACTIONS nation, paresthesia, penis disorder, peripheral edema, ! 7.1 Insulin sweating, and vasodilation. 6.2 Postmarketing Experience Changes in insulin sensitivity or glycemic control may occur In this 180 day clinical trial, skin reactions at the site of The following adverse reactions have been identified during in patients treated with androgens. In diabetic patients, the application were reported with AndroGel 1%, but none was post approval use of AndroGel 1%. Because the reactions metabolic effects of androgens may decrease blood glucose severe enough to require treatment or discontinuation of are reported voluntarily from a population of uncertain size, and, therefore, may decrease insulin requirements. drug. 7.2 Oral Anticoagulants it is not always possible to reliably estimate their frequency Six patients (4%) in this trial had adverse events that led to or establish a causal relationship to drug exposure (Table 4). Changes in anticoagulant activity may be seen with andro¬ gens, therefore more frequent monitoring of international discontinuation of AndroGel 1%. These events included: cer¬ Table 4: Adverse Drug Reactions from Postmarketing ebral hemorrhage, convulsion (neither of which were consid¬ normalized ratio (1NR) and prothrombin time are recom¬ Experience of AndroGel 1% by MedDRA System Organ ered related to AndroGel 1% administration), depression, mended in patients taking anticoagulants, especially at the Class initiation and termination of androgen therapy. sadness, memory loss, elevated prostate specific antigen, 7.3 Corticosteroids and hypertension. No AndroGel 1% patient discontinued Blood and the lymphatic Elevated Hgb, Hct due to skin reactions. The concurrent use of testosterone with adrenocorticotropic system disorders: (polycythemia) hormone (ACTH) or corticosteroids may result in increased In a separate uncontrolled pharmacokinetic study of 10 pa¬ fluid retention and requires careful monitoring particularly tients, two had adverse events associated with AndroGel Myocardial infarction, Cardiovascular disorders: in patients with cardiac, renal or hepatic disease. 196; these were asthenia and depression in one patient and stroke increased libido and hyperkinesia in the other. 8 USE IN SPECIFIC POPULATIONS In a 3 year, flexible dose, extension study, the incidence of j Endocrine disorders: Hirsutism 8.1 Pregnancy all adverse events judged by the investigator to be at least Pregnancy Category X /see Contraindications (■#)/: possibly related to treatment with AndroGel 1% and re¬ Gastrointestinal disorders: Nausea j AndroGel 1% is contraindicated during pregnancy or in ported by > 1% of patients is shown in Table 3. women who may become pregnant. Testosterone is terato¬ General disorders and genic and may cause fetal harm. Exposure of a female fetus Table 3: Adverse Events Possibly, Probably or Definitely administration site Asthenia, edema, malaise to androgens may result in varying degrees of virilization. If Related to Use of AndroGel 1% in the 3 Year, Flexible reactions: this drug is used during pregnancy, or if the patient be¬ Dose, Extension Study comes pregnant while taking this drug, the patient should Genitourinary disorders: Impaired urination j be apprised of the potential hazard to a fetus Adverse Event Percent of Subjects •ornr (N = 162)

Lab Tbst Abnormal* Skin drv Application Site Reaction Acne Pruritus Enlarged Prostate Carcinoma of Prostate Urinary Symptoms* Testis Disorder** Gynecomastia Anemia

9.3 1.9 5.6 3.1 1.9 11.7 1.2 3.7 1.9 2.5 2.5

+Lab test abnormal occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/ LDL ratio, elevated triglycerides, elevated HDL. elevated serum creatinine. *Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream. **listis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness. Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVTI and prostate disorder requiring a transurethral resection of the prostate (TURP). Discontinuation for adverse events in this study included: two patients with application site reactions, one with kid¬ ney failure, and five with prostate disorders (including in¬ crease in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient). Increases m Strum PSA Observed in Clinical Trials of Hypagonadal Men During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the

.

Hepatobiliary disorders:

Abnormal liver function tests (e.g. transaminases, elevated GGTP, bilirubin)

Investigations:

Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone concentrations, weight increase

J Neoplasms benign, | malignant and unspecified | (cysts and polyps):

Nervous system

j Psychiatric disorders:

Reproductive system and breast disorders:

Prostate cancer

Headache, dizziness, sleep apnea, insomnia Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety Gynecomastia, mastodynia. prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections)

Respiratory disorders:

Dyspnea

Skin and subcutaneous tissue disorders:

Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating

8.3

Nursing Mothers

I Although it is not known how much testosterone transfers j into human milk. AndroGel 19? is contraindicated in nurs¬ ing women because of the potential for serious adverse re¬ actions in nursing infants. Testosterone and other andro¬ gens mav adversely affect lactation /see Contraindications (4)1. 8.4

Pediatric Use

The safety and efficacy of AndroGel 19? in pediatric patients less than 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses. 8.5

Geriatric Use

There have not been sufficient numbers of geriatric patients J involved in controlled clinical studies utilizing AndroGel 19? ; to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insuffi¬ cient long-term safety data in geriatric patients to assess the potential risks of cardiovascular diseq.se and prostate cancer. | Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH 8.6

Renal Impairment

No studies were conducted in patients with renal impair! ment. 8.7

Hepatic Impairment

No studies were conducted in patients with hepatic impairI ment. 9 9.1

DRUG ABUSE AND DEPENDENCE Controlled Substance

| AndroGel 19? contains testosterone, a Schedule III con¬ trolled substance in the Controlled Substances Act. 9.2

Abuse

Anabolic steroids, such as testosterone, are abused Abuse is | often associated with adverse physical and psychological ef¬ fects.

Information on the AbbVie, Inc products lifted on these pages is from the prescribing informetion in use es of July 31, 2015 For more informetion. please visit rxsbbvie.com or call 1-800-633-9110

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406/ABBVIE • ANDROGEL 1% 9.3 Dependence Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for approved in¬ dications. dependence is observed in some individuals abus¬ ing high doses of anabolic steroids. In general, anabolic ster¬ oid dependence is characterized by any three of the following: • Taking more drug than intended • Continued drug use despite medical and social problems • Significant time spent in obtaining adequate amounts of drug • Desire for anabolic steroids when supplies of the drugs are interrupted • Difficulty in discontinuing use of the drug despite desires and attempts to do so • Experience of a withdrawal syndrome upon discontinua¬ tion of anabolic steroid use 10

steady-state concentration by the end of the first 24 hours and are at steady state by the second or third day of dosing. With single daily applications of AndroGel 1%, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (less than 300 ng/dL) maintained on AndroGel 1% 50 mg or 100 mg for 30 days. The average (± SD) daily testosterone concentration pro¬ duced by AndroGel 1% 100 mg on Day 30 was 792 (± 294) ng/dL and by AndroGel 1% 50 mg 566 (± 262) ng/dL.

Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel 1% Once Daily

OVERDOSAGE

There is one report of acute overdosage with use of an ap¬ proved injectable testosterone product: this subject had serum testosterone concentrations of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of AndroGel 1%, washing the application site with soap and water, and appropriate symptomatic and supportive care. 11

DESCRIPTION

AndroGel (testosterone gel) 1% is a clear, colorless hydroal¬ coholic gel containing testosterone. The active pharmacologic ingredient in AndroGel 1% is testosterone, an androgen. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

Distribution

Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Ap¬ proximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. Metabolism

Pharmacologically inactive ingredients in AndroGel 1% are carbomer 980, ethanol 67.0%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active. 12 CLINICAL PHARMACOLOGY 12.1

Mechanism of Action

Endogenous androgens, including testosterone and dihydro¬ testosterone (DHT), are responsible for the normal growth and development of the male sex organs and for mainte¬ nance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, pe¬ nis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal en¬ largement, vocal chord thickening, alterations in body mus¬ culature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism, a clinical syndrome resulting from in¬ sufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypo¬ thalamus lor pituitary) to produce sufficient gonadotropins (ESH, LH). 12.2

Pharmacodynamics

No specific pharmacodynamic studies were conducted using AndroGel 1%. 12.3

Pharmacokinetics

Absorption

AndroGel 1% delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that ap¬ proximate normal concentrations (298 - 1043 ng/dL) seen in healthy men. AndroGel 1% provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen. AndroGel 1% is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation Approximately 10% of the testosterone dose applied on the skin surface from AndroGel is absorbed into systemic circulation. In a study with AndroGel 1% 100 rag . all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the

Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabo¬ lites of testosterone are estradiol and dihydrotestosterone (DHT). DHT concentrations increased in parallel with testosterone concentrations during AndroGel 1% treatment. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment ranged from 0.23 to 0.29 (50 mg of AndroGel 1%/day) and from 0.27 to 0.33 (100 mg of AndroGel 1%/day).

14

CLINICAL STUDIES

14.1

Clinical Trials in Adult Hypogonadal Males

AndroGel 1% was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hy¬ pogonadal men. The study was conducted in 2 phases. Dur¬ ing the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel 1% 50 mg daily, 78 patients to AndroGel 1% 100 mg daily, and 76 patients to a nonscrotal testosterone transdermal system. The study was double-blind for dose of AndroGel 1% but open-label for ac¬ tive control. Patients who were originally randomized to AndroGel 1% and who had single-sample serum testosterone concentrations above or below the normal range on Day 60 were titrated to 75 mg daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 1% 50 mg daily, 52 patients continued on AndroGel 1% 100 mg daily, 41 patients contin¬ ued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 1% 75 mg daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of AndroGel 1% for an additional period of up to 3 years. Mean peak, trough and average serum testosterone concen¬ trations within the normal range 2 times the baseline value at some time during the study. When a shirt covered the ap¬ plication sitels), the transfer of testosterone from the males to the female partners was completely prevented. 13 NONCI.INK’AL TOXICOLOGY 13.1

Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

TVstosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibil¬ ity to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays. The administration of exogenous testosterone has been reported to suppress sper¬ matogenesis in the rat. dog and non-human primates, which was reversible on cessation of the treatment.

Cm„ c '-'nun

Of 129 hypogonadal men who were appropriately titrated with AndroGel 1% and who had sufficient data for analysis, 87% achieved an average serum testosterone concentration within the normal range on Treatment Day 180. In patients treated with AndroGel 1%, there were no ob¬ served differences in the average daily serum testosterone concentrations at steady-state based on age, cause of hypo¬ gonadism, or body mass index. DHT concentrations increased in parallel with testosterone concentrations at AndroGel 1% doses of 50 mg/day and 100 mg/day, but the DHT/T ratio stayed within the normal range, indicating enhanced availability of the major physi¬ ologically active androgen. Serum estradiol )E2) concentra¬ tions increased significantly within 30 days of starting treatment with AndroGel 1% 50 or 100 mg/day and re¬ mained elevated throughout the treatment period but re¬ mained within the normal range for eugonadal men. Serum levels of SHBG decreased very slightly (1 to 11%) during AndroGel 1% treatment. In men with hypergonadotropic hypogonadism, serum levels of LH and FSH fell in a doeeand time-dependent manner during treatment with AndroGel 1%. 14.2

Phototoxicity in Humans

The phototoxic potential of AndroGel 1% was evaluated in a double-blind, smgle-doee study in 27 subjects with photo-

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ANDROGEL1* • ABB VIE/407

sensitive skin types. The Minimal Erythema Dose (MED) of j soon as possible /see Dosage and Administration 12.2), Your healthcare provider will test your blood before you ultraviolet radiation was determined for each subject. A sin¬ Warnings and Precautions (5.2) and Clinical Pharmacol¬ start and while you are taking ANDROGEL IN. ogy (12.3)]. gle 24 i + l) hour application of duplicate patches containing | It is not known if ANDROGEL IT. is safe or effective to 17.3 Potential Adverse Reactions with Androgens test articles (placebo gel, testosterone gel, or saline) was Patients should be informed that treatment with androgens I treat men who have low testosterone due to aging. made to naive skin sites on Day 1. On Day 2, each subject It is not known if ANDROGEL IT is safe or effective in chil¬ may lead to adverse reactions which include: received five exposure times of ultraviolet radiation, each dren younger than 18 years old Improper use of • Changes in urinary habits such as increased urination at exposure being 25T greater than the previous one. Skin night, trouble starting your urine stream, passing urine ANDROGEL IT may affect bone growth in children. evaluations were made on Days 2 to 5. Exposure of test and many times during the day, having an urge that you have ANDROGEL IT is a controlled substance (CIII) because it control article application sites to ultraviolet light did not to go to the bathroom right away, having a urine accident, contains testosterone that can be a target for people who produce increased inflammation relative to non-irradiated being unable to pass urine and weak urine flow. abuse prescription medicines. Keep your ANDROGEL IT in sites, indicating no phototoxic effect. • Breathing disturbances, including those associated with a safe place to protect it. Never give your ANDROGEL IT to sleep, or excessive daytime sleepiness. 16 HOW SUPPLIED/STORAGE AND HANDLING anyone else, even if they have the same symptoms you have. • fbo frequent or persistent erections of the penis. AndroGel 1% is supplied in non-aerosol, metered-dose Selling or giving away this medicine may harm others and • Nausea, vomiting, changes in skin color, or ankle swelling. pumps that deliver 12.5 mg of testosterone per complete is against the law. 17.4 Patients Should Be Advised of the Following In¬ pump actuation. The pumps are composed of plastic and structions for Use: ! ANDROGEL IT is not meant for use in women. stainless steel and an LDPE/aluminum foil inner liner en¬ • Read the Medication Guide before starting AndroGel 1% Who should not use ANDROGEL IN? cased in rigid plastic with a polypropylene cap. Each 88 g therapy and to reread it each time the prescription is re¬ Do not use ANDROGEL IN if you: metered-dose pump is capable of dispensing 75 g of gel or newed • have breast cancer 60-metered pump actuations; each pump actuation dis¬ • AndroGel 1% should be applied and used appropriately to • have or might have prostate cancer penses 1.25 g of gel. maximize the benefits and to minimize the risk of second¬ • are pregnant or may become pregnant or breast-foeding. ary exposure in children and women AndroGel 1% is also supplied in unit-dose aluminum foil • Keep AndroGel 1% out of the reach of children ANDROGEL IT may harm your unborn or breast-feeding packets in cartons of 30. Each packet of 2.5 g or 5 g gel con¬ • AndroGel 1% is an alcohol based product and is flamma¬ baby. tains 25 mg or 50 mg testosterone, respectively. ble; therefore avoid fire, flame or smoking until the gel Women who are pregnant or who may become pregnant has dried should avoid contact with the area of skin where • It is important to adhere to all recommended monitoring NDC Number Package Size ANDROGEL IT has been applied • Report any changes in their state of health, such as 0051-8488-88 2 x 75 g pump (each pump dispenses Talk to your healthcare provider before taking this medicine changes in urinary habits, breathing, sleep, and mood 60 metered pump actuations with each if you have any of the above conditions. • AndroGel 1% is prescribed to meet the patient’s specific pump actuation containing 12.5 mg of needs; therefore, the patient should never share AndroGel What should I tell my healthcare provider before using testosterone in 1.25 g of gel) 1% with anyone. ANDROGELIN? 0051-8425-30 30 packets (a unit dose packet • Wait 5 hours before swimming or washing following appli¬ Before you use ANDROGEL IN, tell your healthcare pro¬ containing 25 mg of testosterone cation of AndroGel 191. This will ensure that the greatest vider if you: provided in 2.5 g of gel) amount of AndroGel 1% is absorbed into their system. • have breast cancer 0051-8450-30 30 packets (a unit dose packet Medication Guide • have or might have prostate cancer containing 50 mg of testosterone ANDROGEL* * (AN DROW JEL) (m • have urinary problems due to an enlarged prostate (testosterone gel) 1% provided in 5 g of gel) • have heart problems Read this Medication Guide that comes with ANDROGEL IT before you start taking it and each time you get a refill. • have liver or kidney problems Storage There may be new information. This Medication Guide does • have problems breathing while you sleep (sleep apnea1 Store at 25°C (77°F); excursions permitted to 15° to 30°C not take the place of talking to your healthcare provider • have any other medical conditions about your medical condition or your treatment. (59° to 86°F) [see USP Controlled Room Temperaturel. Tell your healthcare provider about all the medicines you What is the most important information I should know Disposal take, including prescription and non-prescription medi¬ about ANDROGEL 1%? Used AndroGel 1% pumps or used AndroGel 1% packets cines, vitamins, and herbal supplements. 1. Early signs and symptoms of puberty have happened in should be discarded in household trash in a manner that Using ANDROGEL IT with certain other medicines can af¬ young children who were accidentally exposed to prevents accidental application or ingestion by children or fect each other. testosterone through contact with men using pets. ANDROGEL1%. Especially, tell your healthcare provider if you take: 17 PATIENT COUNSELING INFORMATION Signs and symptoms of early puberty in a child may in¬ • insulin clude: • corticosteroids See FDA-Approved Patient Labeling (Medication Guide) • enlarged penis or clitoris • medicines that decrease blood clotting Patients should be informed of the following: • early development of pubic hair Know the medicines you take Ask your healthcare provider 17.1 Use in Men with Known or Suspected Prostate or • increased erections or sex drive Breast Cancer or pharmacist for a list of these medicines, if you are nat • aggressive behavior sure. Keep a list of them and show it to your healthcare pro¬ Men with known or suspected prostate or breast cancer ANDROGEL 1% can transfer from your body to others. vider and pharmacist when you get a new medicine. should not use AndroGel 1% /see Contraindications (4) and 2 Women and children should avoid contact with the un¬ Warnings and Precautions (5.1)]. How should I use ANDROGEL IN? washed or unclothed area where ANDROGEL 1% has 17.2 Potential for Secondary Exposure to Testosterone • It is important that you apply ANDROGEL IT exactly as been applied to your skin. and Steps to Prevent Secondary Exposure your healthcare provider tells you to. Stop using ANDROGEL 1% and call your healthcare pro¬ Secondary exposure to testosterone in children and women • Your healthcare provider will tell you how much vider right away if you see any signs and symptoms in a can occur with the use of testosterone gel in men. Cases of ANDROGEL IT to apply and when to apply it child or a woman that may have occurred through acci¬ secondary exposure to testosterone have been reported in • Your healthcare provider may changt your ANDROGEL dental exposure to ANDROGEL IT. children. IT dose. Do not change your ANDROGEL IT dose with¬ Signs and symptoms of exposure to ANDROGEL 1% in Physicians should advise patients of the reported signs and children may include: out talking to your healthcare provider symptoms of secondary exposure which may include the fol¬ • enlarged penis or clitoris • ANDROGEL IN is to be applied to the area of your shoul¬ lowing: • early development of pubic hair ders, upper arms, or abdomen that will be covered by a • In children; unexpected sexual development including in¬ • increased erections or sex drive short sleeve t-shirt. Do not apply ANDROGEL 1 ■ to any appropriate enlargement of the penis or clitoris, prema¬ • aggressive behavior other parts of your body such as your penis, scrotum, ture development of pubic hair, increased erections, and Signs and symptoms of exposure to ANDROGEL 1% in chest, armpits (axillae), knees, or back. aggressive behavior women may include: • Apply AndroGel IT at the same time each morning • In women; changes in hair distribution, increase in acne, • changes in body hair ANDROGEL IT should be applied after showering or or other signs of testosterone effects • a large increase in acne bathing. * • The possibility of secondary exposure to testosterone gel • To lower the risk of transfer of ANDROGEL 1% from your • Wash your hands right away w ith 'o.tp and water after should be brought to the attention of a healthcare provider body to others, you should follow these important in¬ applying ANDROGEL IT. • AndroGel 191 should be promptly discontinued until the structions: • Avoid showering, swimming, or bathing for at least 5 cause of virilization is identified ’ Apply ANDROGEL IT only to areas that will be covered hours after you apply ANDROGEL IT • Strict adherence to the following precautions is advised to by a short sleeve T-shirt. These areas are your shoulders • ANDROGEL IT is flammable until dry. Let AN’DKi >< ,KI minimize the potential for secondary exposure to and upper arms, or stomach area (abdomen), or shoul¬ IT dry before smoking or going near an open flame testosterone from testosterone gel in men /see Medication ders, upper arms and stomach area. • Let the application areas dry completely before putting on Guide/: - Wash your hands right away with soap and water after a t-shirt. • Children and women should avoid contact with un¬ applying ANDROGEL 1%. Applying ANDROGEL 1%: washed or unclothed application site(s) of men using • After the gel has dried, cover the application area with ANDROGEL IN comes in a pump or in packets testosterone gel clothing Keep the area covered until you have washed • Before applying ANDROGEL IN, make sure that your • Patients using AndroGel 1% should apply the product as the application area well or have showered. shoulders, upper arms, and abdomen are clean, dry. and directed and strictly adhere to the following: ■ If you expect to have skin-to-skin contact with another there is no broken skin Wash hands with soap and water after application person, first wash the application area well with soap • The application sites for ANDROGEL tT ire the shoul¬ • Cover the application site(s) with clothing after the gel and water. ders, upper arms, or abdomen that will be revered by a has dried ' H a woman or child makes contact with the ANDROGEL short sleeve t-shirt (See Figure A) • Wash the application site(s) thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated •In th* * event that unwashed or unclothed skin to which AndroGel 155 has been applied comes in contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as

1% application area, that area on the woman or child should be washed well with soap and water right away

What is ANDROGEL IN?

Information on the AbbVie, Inc. products listed on these

ANDROGEL IN is a prescription medicine that contains testosterone. ANDROGEL IT is used to treat adult males who have low or no testosterone due to certain medical con¬ ditions.

pages of

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July

from

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information

2015. For more information, rxabbvie.com or call 1-800-633-9110

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408/ABBVIE • ANDROGEL1%

General information about the safe and effective use of ANDROGEL1%

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ANDROGEL 1% for a condition for which it was not prescribed. Do not give ANDROGEL 1% to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important in¬ formation about ANDROGEL 1%. If you would like more in¬ formation, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about ANDROGEL 1% that is written for health profession¬ als. For more information, go to www.ANDROGEL.com or call 1-800-633-9110.

If you are using the ANDROGEL 1% pump:

• Before using a new bottle of ANDROGEL 1% for the first time, you will need to prime the pump. To prime the ANDROGEL 1% pump, slowly push the pump all the way down 3 times. Do not use any ANDROGEL 1% that came out while priming. Wash it down the sink to avoid acciden¬ tal exposure to others. Your ANDROGEL 1 % pump is ready to use. • Remove the cap from the pump. Then, position the nozzle over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1% to the application site. You may also apply ANDROGEL 1% directly to the application site.

What are the ingredients in ANDROGEL 1%? Active ingredient: testosterone Inactive ingredients: carbomer 980, ethyl alcohol 67.0%,

isopropyl myristate, purified water and sodium hydroxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Marketed by: AbbVie Inc. North Chicago, IL 60064, USA © 2015 AbbVie Inc. Ref. A090630059176-Revised May, 2015 Shown in Product Identification Guide, page 303

• Wash your hands with soap and water right away.

• Your healthcare provider will tell you the number of times to press the pump for each dose. If you are using ANDROGEL 1% packets:

• Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. • Squeeze all of the ANDROGEL 1% out of the packet into the palm of your hand. Apply ANDROGEL 1% to the ap¬ plication site. You may also apply ANDROGEL 1% from the packet directly to the application site. • ANDROGEL 1% should be applied right away. • Wash your hands with soap and water right away.

ANDROGEL® 1.62%

IJ (£

[AN DROW JEL] (testosterone gel) for topical use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ANDROGEL 1.62% safely and effectively. See full prescribing information for ANDROGEL 1.62%. AndroGel® (testosterone gel) 1.62% for topical use CHI Initial U.S. Approval: 1953

What are the possible side effects of ANDROGEL 1%?

See "What is the most important information I should know about ANDROGEL 1%?"

WARNING:

ANDROGEL 1% can cause serious side effects including: • If you already have enlargement of your prostate gland

TESTOSTERONE See full prescribing information for complete boxed

EXPOSURE

TO

your signs and symptoms can get worse while using

warning.

ANDROGEL 1%. This can include:

• Virilization has been reported in children who were

»increased urination at night »trouble starting your urine stream ° having to pass urine many times during the day ° having an urge that you have to go to the bathroom right away • having a urine accident ° being unable to pass urine or weak urine flow • Possible increased risk of prostate cancer. Your health¬ care provider should check you for prostate cancer or any other prostate problems before you start and while you use ANDROGEL 1%. • Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or red¬ ness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain. • Possible increased risk of heart attack or stroke • In large doses ANDROGEL 1% may lower your sperm count. • Swelling of your ankles, feet, or body, with or without heart failure. • Enlarged or painful breasts. • Have problems breathing while you sleep (sleep apnea). Call your healthcare provider right away if you have any of the serious side effects listed above. The most common side effects of ANDROGEL 1% include:

• • • •

SECONDARY

acne skin irritation where ANDROGEL 1% is applied lab tost changes increased prostate specific antigen (a test used to screen for prostate cancer) Other side effects include more erections than are normal for you or erections that last a long time. Ttll your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ANDROGEL IV For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

secondarily exposed to testosterone gel (5.2, 6.2). • Children should avoid contact with unwashed or unclothed application sites testosterone gel (2.2, 5.2).

in

men

using

• Healthcare providers should advise patients to strictly adhere to recommended instructions for use (2.2, 5.2, 17).

• Dose adjustment: AndroGel 1.62% can be dose adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20.25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets). The dose should be titrated based on the predose morning serum testosterone concentration at approx¬ imately 14 days and 28 days after starting treatment or following dose adjustment. Additionally, serum testosterone concentration should be assessed periodically thereafter. (2.1) • Patients should wash hands immediately with soap and water after applying AndroGel 1.62% and cover the appli¬ cation site(s) with clothing after the gel has dried. Wash the application site thoroughly with soap and water priof to any situation where skin-to-skin contact of the applica¬ tion site with another person is anticipated. (2.2) -DOSAGE FORMS AND STRENGTHSAndroGel (testosterone gel) 1.62% for topical use is avail¬ able as follows: • a metered-dose pump that delivers 20.25 mg testosterone per actuation. (3) • packets containing 20.25 mg testosterone. (3) • packets containing 40.5 mg testosterone. (3) -CONTRAINDICATIONS• Men with carcinoma of the breast or known or suspected prostate cancer (4, 5.1) • Pregnant or breast-feeding women. Testosterone may cause fetal harm (4, 8.1, 8.3) -WARNINGS AND PRECAUTIONS• Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH (5.1) • Avoid unintentional exposure of women or children to AndroGel 1.62%. Secondary exposure to testosterone can produce signs of virilization. AndroGel 1.62% should be „ discontinued until the cause of virilization is identified (5.2) • Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. (5.4) • Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. (6.5) • Exogenous administration of androgens may lead to azoo¬ spermia (5.7) • Edema with or without congestive heart failure (CHF) may be a complication in patients with preexisting car¬ diac, renal, or hepatic disease (5.9) • Sleep apnea may occur in those with risk factors (5.11) • Monitor serum testosterone, prostate specific antigen (PSA), hemoglobin, hematocrit, liver function tests and lipid concentrations periodically (5.1, 5.3, 5.8, 5.12) • AndroGel 1.62% is flammable until dry (5.15) -ADVERSE REACTIONS-

RECENT MAJOR CHANGES5/2015 5/2015 11/2014 6/2014 5/2015

The most common adverse reaction (incidence i 5%) is an increase in prostate specific antigen (PSA). (6.1)

-INDICATIONS AND USAGE-

-DRUG INTERACTIONS-

AndroGel 1.62% is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: • Primary hypogonadism (congenital or acquired) (1) • Hypogonadotropic hypogonadism (congenital or acquired)

• Androgens may decrease blood glucose and therefore may decrease insulin requirements in diabetic patients (7.1) • Changes in anticoagulant activity may be seen with an¬ drogens. More frequent monitoring of International Nor¬ malized Ratio (INR) and prothrombin time is recom¬ mended (7.2) • Use of testosterone with adrenocorticotrophic hormone (ACTH) or corticosteroids may result in increased fluid re¬ tention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease (7.3)

Indications and Usage (1) Dosage and Administration (2) Dosage and Administration (2.2) Warnings and Precautions (5.4) Warnings and Precautions (5.5)

(1)

Limitations of use: • Safety and efficacy of AndroGel 1.62% in men with “age-related hypogonadism’ have not been established. (1 > • Safety and efficacy of AndroGel 1.62% in males less than 18 years old have not been established. (1, 8.4) • Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure. (1, 12.3) -DOSAGE AND ADMINISTRATION• Dosage and Administration for AndroGel 1.62% differs

To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-USE IN SPECIFIC POPULATIONSThere are insufficient long-term safety data in geriatric pa¬ tients using AndroGel 1.62% to assess the potential risks of cardiovascular disease and prostate cancer. (8.5) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 6/2015

from AndroGel 1%. For dosage and administration of AndroGel 1% refer to its full prescribing information. (2)

• Prior to initiating AndroGel 1.62%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate How should I store ANDROGEL 1%? days and that these concentrations are below the normal • Store ANDROGEL 1% between 59°F to 86°F because it contains testosterone that can be a target for people who abuse prescription medicines. Keep your ANDROGEL 1.62% in a safe place to protect it. Never give your ANDROGEL 1.62% to anyone else, even if they have the same symptoms you have. Selling or giving away this med¬ icine may harm others and is against the law. ANDROGEL 1.62% is not meant for use in women

If you are using ANDROGEL 1.62% pump:

• Before using a new bottle of ANDROGEL 1.62 % for the first time, you will need to prime the pump. To prune the ANDROGEL 1.62% pump, slowly push the pump all the way down 3 times. Do not use any ANDROGEL 1.62%

Information on the AbbVie, Inc

products lifted on these

Who should not use ANDROGEL 1.62%? Do not use ANDROGEL 1.62% H you:

pages

• have breast cancer • have or might have prostate cancer

rxabbvie com or call 1-800^33-9110

of

is

July

Free mobilePDR app fot fast drug references on Apple or Android devices

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the

2015.

prescribing For

more

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Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

414/ABBVIE • ANDROGEL 1.62% Find Your Dose as Prescribed by Your Healthcare Provider

DESCRIPTION

Application Method

1 PUMP DEPRESSION

20.25 mg

Apply 1 pump depression of ANDROGEL 1.62% to 1 upper arm and shoulder.

2 PUMP DEPRESSIONS

40.5 mg

Apply 1 pump depression of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 1 pump depression of ANDROGEL 1.62% to the opposite upper arm and shoulder.

3 PUMP DEPRESSIONS

60.75 mg

Apply 2 pump depressions of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 1 pump depression of ANDROGEL 1.62% to the opposite upper arm and shoulder.

4 PUMP DEPRESSIONS

81 mg

Apply 2 pump depressions of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply 2 pump depressions of ANDROGEL 1.62% to the opposite upper arm and shoulder.

Find Your Dose as Prescribed by Your Healthcare Provider

One 20 25 mg packet

20.25 mg

One 40.5 mg packet

40.5 mg

One 40.5 mg packet and one 20.25 mg packet

60.75 mg

Two 40.5 mg packets

81 mg

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C^HggNO^, and the molecular weight is 747.96. The structural formula is:

Application Method

Apply 1 packet of ANDROGEL 1.62% to 1 upper arm and shoulder. Apply half of the 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply the remaining packet contents to the opposite upper arm and shoulder. Apply one 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply one 20.25 mg packet of ANDROGEL 1.62%. to the opposite upper arm and shoulder. Apply one 40.5 mg packet of ANDROGEL 1.62% to 1 upper arm and shoulder and then apply one 40.5 mg packet of ANDROGEL 1.62% to the opposite upper arm and shoulder.

that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your ANDROGEL 1.62% pump is now ready to use. • Remove the cap from the pump. Then, position the nozzle over the palm of your hand and slowly push the pump all the way down. Apply ANDROGEL 1.62% to the applica¬ tion site. You may also apply ANDROGEL 1.62% directly to the application site. • Wash your hands with soap and water right away.

Other side effects include more erections than are normal for you or erections that last a long time. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ANDROGEL 1.62%>. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

[See first table above)

How should I store ANDROGEL 1.62%?

If you are using ANDROGEL 1.62% packets:

• Store ANDROGEL 1.62% at 59°F to 86°F (15°C to 30°C). • When it is time to throw away the pump or packets, safely throw away used ANDROGEL 1.62% in household trash. Be careful to prevent accidental exposure of children or pets. • Keep ANDROGEL 1.62% away from fire.

• Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. • Squeeze all of the ANDROGEL 1.62%. out of the packet into the palm of your hand. Apply ANDROGEL 1.62% to the application site. You may also apply ANDROGEL 1.62% directly to the application site. • ANDROGEL 1.62% should be applied right away. • Wash your hands with soap and water right away.

General information about the safe and effective use of ANDROGEL 1.62%

[See second table above) What are the possible side effects of ANDROGEL 1.62%? See "What is the most important information I should know about ANDROGEL 1.62%?" ANDROGEL 1.62% can cause serious side effects including: • If you already have enlargement of your prostate gland your signs and symptoms can get worse while using ANDROGEL 1 62%. This can include:

r° ° ■

increased urination at night trouble starting your urine stream having to pass urine many times during the day having an urge that you have to go to the bathroom right away ° having a urine accident ° being unable to pass urine or weak urine flow • Possible increased risk of prostate cancer. Your health¬ care provider should check you for prostate cancer or any other prostate problems before you start and while you use ANDROGEL 1.62%. • Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling, or red¬ ness. Signs and symptoms of a blood dot in your lungs can include difficulty breathing or chefit pain. • Possible increased risk of heart attack or stroke. • In large doses ANDROGEL 1.62% may lower your sperm

count. • Swelling of your ankles, feet, or body, with or without heart failure. • Enlarged or painful breasts. • Have problems breathing while you sleep (sleep apnea). Call your healthcare provider right away if you have any of the serious side effects listed above. The most common side effects of ANDROGEL 1.62% in¬ clude:

• increased prostate specific antigen (a test used to screen for prostate cancer) • mood swings • hyixTtensi'in

• increased red blood cell count • skin irritation where ANDROGEL 1.62% is applied

Keep ANDROGEL 1.62% and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ANDROGEL 1.62% for a condition for which it was not prescribed. Do not give ANDROGEL 1.62% to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important in¬ formation about ANDROGEL 1.62%. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about ANDROGEL 1.62% that is written for health profes¬ sionals. For more information, go to www.androgel.com or call 1-800-633-9110. What are the ingredients in ANDROGEL 1.62%? Active ingredient: testosterone Inactive ingredients: carbopol 980, ethyl alcohol, isopro¬

pyl myristate, purified water and sodium hydroxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Marketed by: AbbVie Inc. North Chicago, IL 60064, USA © 2015 AbbVie Inc. Ref. A090630059177- Revised May, 2015 Shown in Product Identification Guide, pane 303 BIAXIN® Filmtab® |6i ax an |

[{

(clarithromycin tablets. USP)

BIAXIN® XL Filmtab® (clarithromycin extended-release tablets)

BIAXIN® Granules (clarithromycin for oral suspension, USP)

Tb reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXLN and other antibacte¬ rial drugs, BIAXIN should be used only to treat or prevent infections that are proven or strongly suspected to be : caused by bacteria.

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. BIAXIN is available as immediate-release tablets, extended-release tablets, and granules for oral suspension. Each yellow oval film-coated immediate-release BLAXIN tablet (clarithromycin tablets, USP) contains 250 mg or 500 mg of clarithromycin and the following inactive ingre¬ dients: 250 mg tablets: hypromellose, hydroxypropyl cellulose, croscarmellose sodium, D&C Yellow No. 10. FD&C Blue No. 1, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sor¬ bic acid, sorbitan monooleate, stearic acid, talc, titanium di‘ oxide, and vanillin. 500 mg tablets: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose, po¬ vidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin. Each yellow oval film-coated BIAXIN XL tablet (clarithromycin extended-release tablets) contains 500 mg of clarithromycin and the following inactive ingredi¬ ents: cellulosic polymers, D&C Yellow No. 10, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, and van¬ illin. After constitution, each 5 mL of BIAXIN suspension (clarithromycin for oral suspension, USP) contains 125 mg or 250 mg of clarithromycin. Each bottle of BIAXIN granules contains 1250 mg (50 mL size), 2500 mg (50 and 100 mL sizes) or 5000 mg (100 mL size) of clarithromycin and the following inactive ingredients: carbomer, castor oil, citric acid, hypromellose phthalate, maltodextrin, potas¬ sium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor. CLINICAL PHARMACOLOGY Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointesti¬ nal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, in¬ creasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concen¬ tration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indi¬ cated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, BIAXIN tablets may be given without regard to food. In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimina¬ tion half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state, concentration of 14-OH clarithromycin is slightly higher i up to 1 mcg/mLi, and its elimination half-life is about 7 to 9

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Look for PDR drug information and services in your EHR hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days. After a 250 mg tablet every 12 hours, approximately 2091 of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30'S. In comparison, after an oral dose of 250 mg 0.25 mcg/mL Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentra¬ tion (MIC) of > 256 mcg/ml. by E-test. [See second table at top of previous p.tge| Patients not eradicated of H pylori following omeprazole/ clarithromycin, ranitidine bismuth rilrate/clarithromycin omeprazole/clarithromycifl/nmoxicillin, or lansoprazole/ clarithromycin/ amoxicillin therapy would likely have clanlhrumycin resistant H pylon L-Mat. > Therefore, for patients who fail therapy, clarithromycin sum:< ptibilifv test ing should be done, if ixissible Patients with cfarilh'nimyrin resistant H pylori should not be tn a ted w ilh any of the fol¬ lowing: omeprazoki/clanthromycin dual therapy; ranitidine

bismuth citrate/clarithromycin dual therapy; omeprazole/ clarithromycin/amoxicillin triple therapy; lansoprazole/ clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antimicrobial agent. Amoxicillin Susceptibility Test Results and Clinical/Bacteri¬ ological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 84.9% (157/185) of the patients who had pre¬ treatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed ther¬ apy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had-posttreatment //. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. In the iansoprazole/clarithromycin/amoxicillin triple¬ therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of > 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 12.8% (22/172) of the patients failed the 10- and 14-day triple-therapy regi¬ mens. Post-treatment susceptibility results were not ob¬ tained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple-therapy regimen also had clarithromycin resistant H. pylori isolates. The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most isolates of the following bacteria; how¬ ever, the safety and effectiveness of clarithromycin in treat¬ ing clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-Positive Bacteria

Streptococcus qgalactiae Streptococci (Groups C, F, G) Viridans group streptococci

For testing Haemophilus spp b MIC (mcg/mL)

32.0

Interpretation

Susceptible (S) Intermediated) Resistant l R)

b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus ,-pp using Haemophilus Testing Medium (HTM).1

Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A re¬ port of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which pre¬ vents small uncontrolled technical factors from causing ma¬ jor discrepancies in interpretation. A report of “Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the con¬ centrations usually achievable; other therapy should be se¬ lected. Quality Control

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the ac¬ curacy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test.1' Standard clarithromycin powder should provide the fnllowing MIC ranges.

Gram-Negative Bacteria

Bordetella pertussis Legionella pneumophila Pasteurella multocida Gram-Positive Bacteria

S. aureus S. pneumoniaed Haemophilus influenzae"

Clostridium perfringens Peptococcus niger Propionibacterium acnes Gram-Negative Anaerobic Bacteria

Prevotella melaninogenica (formerly Bacteriodes melaninogenicus) Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter) Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimi¬ crobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria2:

Susceptibility Test Interpretive Criteria for Staphylococcus aureus MIC (mcg/mL)

Interpretation

£ 2.0

Susceptible (S)

4.0

Intermediate (I)

i 8.0

MIC (mcg/mL)

QC Strain

Resistant (R)

ATCC® 29213c ATCC 49619 ATCC 49247

0.12 to 0.5 0.03 to 0.12 4 to 16

c ATCC is a registered trademark of the American Ty pe Culture Collection. d This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood. e This quality control range is applicable only to II. influenzae ATCC 49247 tested by a microdilution procedure using HTM1. Diffusion Techniques

Quantitative methods that require measurement of zone di¬ ameters also provide reproducible estimates of the suscep¬ tibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should he deter¬ mined using a standardized method.21 The procedure uses paper disks impregnated with 15 meg of clarithromycin to test the susceptibility of bacteria. The disk diffusion inter¬ pretive criteria are provided below. Susceptibility Test Interpretive Criteria for Staphylococcus aureus Zone diameter (mm)

Interpretation

;> 18 14 to 17 < 13

Susceptible (S) Intermediate (I) Resistant (R)

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae *

MIC (mcg/mL) £ 0.25 0.5 2 1.0

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae'

Interpretation

Susceptible (S) Intermediate (I) Resistant (R)

* These interpretive standards are applicable only to broth microdilution susceptibility tests using cationadjusted Mueller-Hinton broth with 2-5% lysed horse blood.

Zone diameter (mm)

Interpretation

2: 21 17 to 20 S 16

Susceptible IS) Intermediate II) Resistant lR>

f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% C02.

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Look for PDR drug information and services in your EHR For testing Haemophilus spp.9 Zone diameter (mm)

Interpretation

5 13 11 to 12 S 10

Susceptible (S) Intermediate (I) Resistant (R)

Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin. Quality Control

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the ac¬ curacy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test.2'3 For the diffusion technique using the 15 meg disk, the cri¬ teria in the following table should be achieved. Acceptable Quality Control Ranges for Clarithromycin

S. aureus S. pneumoniaeh Haemophilus influenzae'

Acceptable Quality Control Ranges

Antimicrobial Agent

MIC (mcg/mLI1

H. pylori H. pylori

Clarithromycin Amoxicillin

0.015-0.12 mcg/mL 0.015-0.12 mcg/mL

ATCC 43504 ATCC 43504

1 These are quality control ranges for the agar dilution methodology and should not be used to control test results obtained using alternative methods.

* These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM.

QC Strain

BIAXIN • ABBVIE/417

(1 x 107-1 x 108 CFU/mL for H. pylori) are inoculated di¬ rectly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (> 2-weeks old). The agar dilution plates are in¬ cubated at 35*C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to in¬ hibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria: Susceptibility Test Interpretive Criteria for H. pylori Clarithromycin MIC (mcg/mL)1

Interpretation

S 0.25 0.5 >1.0

Susceptible (S) Intermediate (I) Resistant (R)

Zone diameter (mm)

ATCC 25923 ATCC 49619 ATCC 49247

Susceptibility Test Interpretive Criteria for H. pylori

26 to 32 25 to 31 11 to 17

h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood. ' This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2.

Amoxicillin MIC (mcg/mL) *Jl

Interpretation

0.25 meg/ mL to determine a resistance breakpoint.

In vitro Activity of Clarithromycin against Mycobacteria

Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms iso¬ lated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium spe¬ cies from M. intracellulare, many studies only reported re¬ sults on M. avium complex (MAC) isolates. Various in vitro methodologies employing broth or solid me¬ dia at different pH’s, with and without oleic acid-albumindextrose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of oleic acid-albumindextrose-catalase (OADC) in these assays has been shown to further alter MIC values. Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed an MIC value of S 4.0 mcg/mL in 817i and 8975 of the AIDS and non-AIDS MAC isolates, re¬ spectively. Twelve percent of the non-AIDS isolates had an MIC value i 0.5 mcg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Clarithromycin activity was evaluated against Mycobacte¬ rium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at > 10.0 mcg/mL. Susceptibility Testing for Mycobacterium avium Complex (MAC)

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC val¬ ues against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for de¬ termining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M avium or M intra¬ cellulare are susceptible or resistant to clarithromycin have not been established. Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.4 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the ac¬ curacy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test. Standard clarithromycin or amoxicillin powder should pro¬ vide the following MIC ranges. [See table above]

INDICATIONS AND USAGE BIAXIN Filmtab (clarithromycin tablets, USP) and BLAXIN Granules (clarithromycin for oral suspension, USP) are in¬ dicated for the treatment of mild to moderate infections caused by susceptible isolates of the designated bacteria in the conditions as listed below: Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)

Pharyngitis/Ibnsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fe¬ ver is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the sub¬ sequent prevention of rheumatic fever are not available at present). Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhaJis, or Streptococcus pneumoniae. Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae. Mor¬ axella catarrhalis, or Streptococcus pneumoniae. Community-Acquired Pneumonia due to Haemophilus in¬ fluenzae, Mycoplasma pneumoniae, Streptococcus pneumo¬ niae, or Chlamydophila pneumoniae (TWAR). Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Ab¬ scesses usually require surgical drainage). Disseminated mycobacterial infections due to Mycobacte¬ rium avium, or Mycobacterium intracellulare BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Releasc Capsules, as tri¬ ple therapy, are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (ac¬ tive or five-year history of duodenal ulcer) to eradicate H. pylori. BLAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine bismuth cit¬ rate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated with H pylon in¬ fection. However, regimens which contain clarithromycin as the single antimicrobial agent are more likely to be associ¬ ated with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-containing

regimens should not be used in patients with known or sus¬ pected clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting. In patients who fail therapy, susceptibility testing should be done if possible. If resistance to clarithromycin is demon¬ strated, a non-clarithromycin-containing therapy is recom¬ mended. (For information on development of resistance see Microbiology section.) The eradication of H. pylon has been demonstrated to reduce the risk of duodenal ulcer recur¬ rence. Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)

Pharyngitis/Ibnsillitis due to Streptococcus pyogenes. Community-Acquired Pneumonia due to Mycoplasma pneu¬ moniae, Streptococcus pneumoniae, or Chlamydophila pneu¬ moniae (TWAR) Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae Acute otitis media due to Haemophilus influenzae, Morax¬ ella catarrhalis, or Streptococcus pneumoniae NOTE: For information on otitis media, see CLINICAL STUDIES - Otitis Media Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Ab¬ scesses usually require surgical drainage.) Disseminated mycobacterial infections due to Mycobacte¬ rium avium, or Mycobacterium intracellulare Adults (BIAXIN XL Filmtab Tablets)

BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions listed below: Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Mor¬ axella catarrhalis, or Streptococcus pneumoniae Community-Acquired Pneumonia due to Haemophilus in¬ fluenzae, Haemophilus parainfluenzae, Moraxella catarrha¬ lis, Streptococcus pneumoniae, Chlamydophila pneumoniae (TWAR), or Mycoplasma pneumoniae THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN ESTAB¬ LISHED. Prophylaxis

BIAXIN Filmtab tablets and BLAXIN Granules for oral suspension are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. 1b reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other antibacte¬ rial drugs. BIAXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and suscepti¬ bility information are available, they should be considered in selecting or modifying antibacterial therapy. In the ab¬ sence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CONTRAINDICATIONS Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin or any of its excipients, erythromycin, or any of the macrolide antibiotics. Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin. Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimo¬ zide. astemizole, terfenadine, and ergotamine or dihydroergotamine (see Drug Interactions). There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac ar¬ rhythmias (QT prolongation, ventricular tachycardia, ven¬ tricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.

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418/ABBVIE • BIAXIN Concomitant administration of clarithromycin and colchi¬ cine is contraindicated in patients with renal or hepatic im¬ pairment. Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, in¬ cluding torsades de pointes. Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are exten¬ sively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see WARNINGS) For information about contraindications of other drugs in¬ dicated in combination with BIAXIN, refer to the CON¬ TRAINDICATIONS section of their package inserts. WARNINGS Use In Pregnancy CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREG¬ NANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED AD¬ VERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS - Pregnancy). Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This he¬ patic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with seri¬ ous underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepa¬ titis occur. QT Prolongation Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing prnarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see CONTRAINDICATIONS) and in patients receiving Class 1A (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Drug Interactions Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 sub¬ strates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorva¬ statin; and hypotension and acute kidney injury with cal¬ cium channel blockers metabolized by CYP3A4 (e.g.. verap¬ amil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabo¬ lized by CYP3A4 involved elderly patients 65 years of age or older (see CONTRAINDICATIONS and PRECAUTIONS - Drug Interactions). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see PRE¬ CAUTIONS - Drug Interactions' Colchicine Life-threatening and fatal drug interactions have been re¬ ported in patients treated with clarithromycin and colchi¬ cine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their rec¬ ommended doses. If co-administration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of col¬ chicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICA¬ TIONS and PRECAUTIONS - Drug Interactions) Benzodiazepines Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and tnazolobenzodiazepines, such as triazolam, and mid¬ azolam.

CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended. Oral Anticoagulants There is a risk of serious hemorrhage and significant eleva¬ tions in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently. HMG-CoA Reductase Inhibitors (statins) Concomitant use of clarithromycin with lovastatin or sim¬ vastatin is contraindicated (see CONTRAINDICATIONS) as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of my¬ opathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin con¬ comitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Caution should be exercised when prescribing clarithromycin with statins. In situations where the con¬ comitant use of clarithromycin with atorvastatin or prava¬ statin cannot-be avoided, atorvastatin dose should not ex¬ ceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g.fluvastatin) can be considered. It is recom¬ mended to prescribe the lowest registered dose if concomi¬ tant use cannot be avoided, Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, includ¬ ing BIAXIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. dif¬ ficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all pa¬ tients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein sup¬ plementation, antibiotic treatment of C. difficile, and surgi¬ cal evaluation should be instituted as clinically indicated. Acute Hypersensitivity Reactions. In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epider¬ mal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Hsnoch-Schonlein purpura clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated. Combination Therapy with Other Drugs For information about warnings pf other drugs indicated in combination with BIAXIN, refer to the WARNINGS section of their package inserts.

PRECAUTIONS General Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Clarithromycin is principally excreted via the liver and kid¬ ney. Clarithromycin may lie administered without dosage adjustment to patients with hepatic impairment and nor¬ mal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage-or prolonged dosing intervals may be ap¬ propriate. Clarithromycin in combination with ranitidine bismuth cit¬ rate therapy is not recommended in patients with creatinine clearance less than 25 mL/min (see DOSAGE AND ADMINISTRATION) Clarithromycin in combination with ranitidine bismuth cit¬ rate should not be used in patienjs with a history of acute porphyria. Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syhdrome has been re¬ ported in patients receiving clarithromycin therapy: For information about precautions of other drugs indicated in combination with BIAXIN, refer to the PRECAUTIONS section of their package inserts.

Oral Hypoglycemic Agcnt-s/Insulin

Information to Patients

The concomitant use of clarithromycin and oral hypoglyce¬ mic agents and/or insulin can resoh in significant hypogly¬ cemia With certain hypoglycemic drugs such as nateglinide, pioghtazone, repaglmide and rosightazone, inhibition of

Patients should be counseled that antibacterial drugs in¬ cluding RLAXIN should only be used to treat bacterial infec¬ tions. They do not treat viral infections (eg, the common mid' When BIAXIN is prescribed to treat a bacteria) infec¬

j

; 1 I

i I

tion, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1' decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by BIAXIN or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Some¬ times after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. BIAXIN may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications. BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk; however, BIAXIN XL tablets should be taken with food. Do NOT refrigerate the suspension. Drug Interactions Clarithromycin use in patients who are receiving theophyl¬ line may be associated with an increase of serum theophyl¬ line concentrations. Monitoring of serum theophylline con¬ centrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophyl¬ line was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg ql2b clarithromycin), the steady-state levels of CCmi[„ and the area under the serum concentration time curve (AUC) of theophylline increased about 20(1. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of ter¬ fenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-OHclarithromycin were not significantly affected by coadminis¬ tration of terfenadine once clarithromycin reached steadystate conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated (see CONTRAINDICATIONS) Clarithromycin 500 mg every 8 hours was given in combi¬ nation with omeprazole 40 mg daily to healthy adult sub¬ jects. The steady-state plasma concentrations of omeprazole were increased (CmM, AUCll 24, and tw increases of 30T, 8971, and 34(1, respectively), by the concomitant adminis¬ tration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentra¬ tions (5700, increased plasma bismuth trough concentra¬ tions (48"0, and increased 14-hydroxy-clarithromycin plasma concentrations (3VO. These effects are clinically in¬ significant. Simultaneous oral administration of BIAXIN tablets and zi¬ dovudine to HIV-infected adult patients may result in de¬ creased steady-state zidovudine concentrations Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4 hours, the steady-state zi¬ dovudine AUC decreased 12ri compared to administration of zidovudine alone (n=4L Individual values ranged from a decrease of 3471 to an increase of 14ri When clarithromycin tablets were administered two to four hours prior to zidovu¬ dine, the steady-state zidovudine Cmil, increased 100C whereas the AUC was unaffected (n=24' Administration of clarithromycin and zidovudine should be separated by at least two hourk. The impact of co-administration of clarithromycin extended-release tablets and zidovudine has not been evaluated. Simultaneous administration of BIAXIN cablets and didanosine to 12 HIV-infected adult patients resulted in no sta¬ tistically significant change in didanosine pharmacokinetics.

Following administration of flucunazote 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin C„... and AUC increased 1 33T and 1871, respectively. Steady-state concentrations of , 14-OH clarithromycin were not significantly affected by con¬ comitant administration of fluconazole. No dosage adjust¬ ment of clarithromycin is necessary when ce-administered 1 with fluconazole.

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BIAXIN • ABBVIE/419

Ritonavir administration of clarithromycin with sildenafil, tadalafil, j vasospasm and ischemia of the extremities and other tisConcomitant administration of clarithromycin and ritonavir or vardenafil will result in increased exposure of these phos¬ , sues including the central nervous system. Concomitant (n = 22) resulted in a 77% increase in clarithromycin AUC phodiesterase inhibitors. Co-administration of these phos¬ administration of clarithromycin with ergotamine or dihy¬ and a 100% decrease in the AUC of 14-OH clarithromycin. phodiesterase inhibitors with clarithromycin is not recomdroergotamine is contraindicated isee CONTRAINDICA¬ Clarithromycin may be administered without dosage ad¬ I mended. TIONS). justment to patients with normal renal function taking rito¬ Tolterodine Triazolobenzodiazepines (Such as Triazolam and navir. Since concentrations of 14-OH clarithromycin are sig¬ j The primary route of metabolism for tolterodine is via Alprazolam) and Related Benzodiazepines (Such as Mid¬ nificantly reduced when clarithromycin is co-administered CYP2D6. However, in a subset of the population devoid of azolam) with ritonavir, alternative antibacterial therapy should be CYP2D6, the identified pathway of metabolism is via Erythromycin has been reported to decrease the clearance considered for indications other than infections due to My¬ CYP3A In this population subset, inhibition of CYP3A re¬ of triazolam and midazolam, and thus, may increase the cobacterium avium complex (see PRECAUTIONS - Drug sults in significantly higher serum concentrations of tolt¬ pharmacologic effect of these benzodiazepines. There have Interactions). Doses of clarithromycin greater than 1000 mg erodine. Tolterodine 1 mg twice daily is recommended in pa¬ been post-marketing reports of drug interactions and CNS per day should not be co-administered with protease inhibi¬ tients deficient in CYP2D6 activity (poor metabolizers) effects (e.g., somnolence and confusion) with the concomi¬ tors. when co-administered with clarithromycin. tant use of clarithromycin and triazolam. Spontaneous reports in the post-marketing period suggest Triazolobenzodiazepines (e.g., alprazolam, midazolam, tri¬ Sildenafil (Viagra) that concomitant administration of clarithromycin and oral azolam) Erythromycin has been reported to increase the systemic anticoagulants may potentiate the effects of the oral antico¬ When a single dose of midazolam was co-administered with exposure (AUC) of sildenafil. A similar interaction may oc¬ agulants. Prothrombin times should be carefully monitored clarithromycin tablets (500 mg twice daily for 7 days), mid¬ cur with clarithromycin; reduction of sildenafil dosage while patients are receiving clarithromycin and oral antico¬ azolam AUC increased 174% after intravenous administra¬ should be considered. (See Viagra package insert.) agulants simultaneously. tion of midazolam and 600% after oral administration. There have been spontaneous or published reports of Digoxin is a substrate for P-glycoprotein (Pgp) and When oral midazolam is co-administered with CYP3A based interactions of erythromycin and/or clarithromycin is known to inhibit Pgp. When clarithromycin, dose adjustments may be necessary and clarithromycin with cyclosporine, carbamazepine, tacroli¬ clarithromycin and digoxin are co-administered. inhibition possible prolongation and intensity of effect should be anticmus, alfentanil, disopyramide, rifabutin, quinidine, methylof Pgp by clarithromycin may lead to increased exposure of | ipated. Caution and appropriate dose adjustments should prednisolone, cilostazol, bromocriptine, vinblastine, phenodigoxin. Elevated digoxin serum concentrations in patients | be considered when triazolam or alprazolam is co¬ barbital and St. John’s Wort. receiving clarithromycin and digoxin concomitantly have administered with clarithromycin. For benzodiazepines Concomitant administration of clarithromycin with cisa¬ been reported in post-marketing surveillance. Some pa¬ which are not metabolized by CYP3A(e.g., temazepam, ni¬ pride, pimozide, astemizole, or terfenadine is contraindi¬ tients have shown clinical signs consistent with digoxin tox¬ trazepam, lorazepam), a clinically important interaction cated (see CONTRAINDICATIONS). icity, including potentially fatal arrhythmias. Monitoring of with clarithromycin is unlikely. In addition, there have been reports of interactions of eryth¬ serum digoxin concentrations should be considered, espe¬ There have been post-marketing reports of drug interac¬ romycin or clarithromycin with drugs not thought to be me¬ cially for patients with digoxin concentrations in the upper tions and central nervous system (CNS) effects (e.g., somno¬ tabolized by CYP3A, including hexobarbital. phenvtoin, and therapeutic range. lence and confusion) with the concomitant use of valproate. Co-administration of clarithromycin, known to inhibit clarithromycin and triazolam. Monitoring the patient for in¬ Carcinogenesis, Mutagenesis, Impairment of Fertility CYP3A, and a drug primarily metabolized by CYP3A may creased CNS pharmacological effects is suggested. The following in vitro mutagenicity tests have been con¬ be associated with elevations in drug concentrations that Atazanavir ducted with clarithromycin: could increase or prolong both therapeutic and adverse ef¬ Both clarithromycin and atazanavir are substrates and in¬ Sa/mone//a/Mammalian Microsomes Thst fects of the concomitant drug. hibitors of CYP3A, and there is evidence of a bi-directional Bacterial Induced Mutation Frequency Tbst Clarithromycin should be used with caution in patients re¬ drug interaction. Following administration of In Vitro Chromosome Aberration Test ceiving treatment with other drugs known to be CYP3A en¬ clarithromycin (500 mg twice daily) with atazanavir Rat Hepatocyte DNA Synthesis Assay zyme substrates, especially if the CYP3A substrate has a (400 mg once daily), the clarithromycin AUC increased 94%, Mouse Lymphoma Assay narrow safety margin (e.g., carbamazepinei and/or the sub¬ the 14-OH clarithromycin AUC decreased 70% and the ata¬ Mouse Dominant Lethal Study strate is extensively metabolized by this enzyme. Dosage zanavir AUC increased 28%. When clarithromycin is co¬ Mouse Micronucleus Test adjustments may be considered, and when possible, serum administered with atazanavir, the dose of clarithromycin All tests had negative results except the In Vitro Chromo¬ concentrations of drugs primarily metabolized by CYP3A should be decreased by 50%. Since concentrations of 14-OH some Aberration Test which was weakly positive in one test should be monitored closely in patients concurrently receiv¬ clarithromycin are significantly reduced when and negative in another. ing clarithromycin. clarithromycin is co-administered with atazanavir, alterna¬ In addition, a Bacterial Reverse-Mutation Tbst (Ames Tbst) The following are examples of some clinically significant tive antibacterial therapy should be considered for indica¬ has been performed on clarithromycin metabolites with CYP3A based drug interactions. Interactions with other tions other than infections due to Mycobacterium avium negative results. drugs metabolized by the CYP3A isoform are also possible. complex (see PRECAUTIONS - Drug Interactions). Doses Fertility and reproduction studies have shown that daily Carbamazepine and Terfenadine of clarithromycin greater than 1000 mg per day should not doses of up to 160 mg/kg/day (1.3 times the recommended Increased serum concentrations of carbamazepinp and the be co-administered with protease inhibitors. maximum human dose based on mg/m2) to male and female active acid metabolite of terfenadine were observed in clin¬ Itraconazole rats caused no adverse effects on the estrous cycle, fertility, ical trials with clarithromycin. Both clarithromycin and itraconazole are substrates and in¬ parturition, or number and viability of offspring. Plasma Colchicine hibitors of CYP3A, potentially leading to a bi-directional levels in rats after 150 mg/kg/day were 2 times the human Colchicine is a substrate for both CYP3A and the efflux drug interaction when administered concomitantly. serum levels. transporter, P-glycoprotein (Pgp). Clarithromycin and other Clarithromycin may increase the plasma concentrations of In the 150 mg/kg/day monkey studies, plasma levels were macrolides are known to inhibit CYP3A and Pgp. When a itraconazole, while itraconazole may increase the plasma 3 times the human serum levels. When given orally at single dose of colchicine 0.6 mg was administered with concentrations of clarithromycin. Patients taking itracona150 mg/kg/day (2.4 times the recommended maximum hu¬ clarithromycin 250 mg BID for 7 days, the colchicine Cmnl | zole and clarithromycin concomitantly should be monitored man dose based on mg/m2), clarithromycin was shown to increased 197% and the AUC0_ increased 239% compared closely for signs or symptoms of increased or prolonged adproduce embryonic loss in monkeys. This effect has been at¬ to administration of colchicine alone. The dose of colchicine I verse reactions. tributed to marked maternal toxicity of the drug at this should be reduced when co-administered with Saquinavir high dose. clarithromycin in patients with normal renal and hepatic Both clarithromycin and saquinavir are substrates and in¬ In rabbits, in utero fetal loss occurred at an intravenous function. Concomitant use of clarithromycin and colchicine hibitors of CYP3A and there is evidence of a bi-directional dose of 33 mg/m2, which is 17 times less than the maximum is contraindicated in patients with renal or hepatic impair¬ drug interaction. Following administration of proposed human oral daily dose of 618 mg/m2. ment (see WARNINGS). clarithromycin (500 mg bid) and saquinavir (soft gelatin Long-term studies in animals have not been performed to Efavirenz, Nevirapine. Rifampicin, Rifabutin, and capsules, 1200 mg tid) to 12 healthy volunteers, the steadyevaluate the carcinogenic potential of clarithromycin Rifapentine state saquinavir AUC and Cmis increased 177% and 187% Pregnancy Inducers of CYP3A enzymes, such as efavirenz, nevirapine, respectively compared to administration of saquinavir Teratogenic Effects rifampicin, rifabutin, and rifapentine will increase the me¬ alone. Clarithromycin AUC and Cm,, increased 45% and Pregnancy Category C tabolism of clarithromycin, thus decreasing plasma concen¬ 39% respectively, whereas the 14-OH clarithromycin AUC Four teratogenicity studies in rats (three with oral doses trations of clarithromycin, while increasing those of 14-OHand Cm 3%

% ever gaining

% gaining > 6 weeks

500 1000 2000

33% 26% 26%

14% 17% 12%

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated. Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the group randomized to clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and ane¬ mia. Safety

In AIDS patients treated with clarithromycin over long pe¬ riods of time for prophylaxis against M. avium, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treat¬ ment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group. Treatment-related* Adverse Event Incidence Rates (%) in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex Body System*

Clarithromycin

Placebo

Adverse Event

(n = 339)

(n = 339)

%

%

5.0% 2.7%

3.5% 0.9%

7.7% 3.8% 2.4% 11.2% 5.9%

4.1% 2.7%0.9% 7.1% 3.2%.

3.2%

3.5%

8.0%

0.3%

Body as a Whole

Digestive

Diarrhea Dyspepsia Flatulence Nausea Vomiting Skin & Appendages

Rash Special Senses

Taste Perversion

* Includes those events possibly or probably related to study drug and excludes concurrent conditions. * > 2% Adverse Event Incidence Rates for either treatment group.

Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated group compared to the placebotreated group. Discontinuation due to adverse events was required in 1891 of patients receiving clarithromycin compared to 17% of pa¬ tients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression and taste perver¬ sion. Changes in Laboratory Values of Potential Clinical Impor¬ tance

In immunocompromised patients receiving prophylaxis against M. avium, evaluations of laboratory values were made by analyzing those values outside the seriously abnor¬ mal value (i.e., the extreme high or low limit) for the speci¬ fied test. Percentage of Patients* 1*1 * Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M. avium Complex Clarithromycin 500 mg b.i.d.

Hemoglobin Platelet Count WBO Count

% ever resolving

85% 70% 72%.

% resolving > 6 weeks

Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy) 500 mg b.i.d.

1000 mg

2000 mg

Four Drug

(N = 35)

b.i.d. (N = 32)

b.i.d. (N = 26)

Regimen (N = 24)

1.5

2.3

2.3

1.4

42% 33%. 36%

Although the 1000 mg and 2000 mg b.i.d. doses showed sig¬ nificantly better control of bacteremia during the first four weeks of therapy, no significant differences were seen be¬ b.i.d. % ever %> yond that point. The percent of patients whose blood was dose increasing increasing sterilized as shown by one or more negative cultures at any (mg) > 6 weeks time during acute therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the 1000 500 58% 26% and 2000 mg b.i.d. groups, respectively. The percent of pa¬ 1000 37% 6% tients who had 2 or more negative cultures during acute 2000 18% 62% therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discon¬ SCOT > 5 x ULNlb) 7/196 4% 5/208 2% tinued from the study, and 14% (7/49), 12% (6/49), and 13% SGPT > 5 x ULNtbl 6/217 3% 4/232 2% (6/48) of patients had relapsed in the 500, 1000, and Aik. Phos. >5xULNlb) 5/220 2% 5/218 2% 2000 mg b.i.d. dose groups, respectively. All of the isolates had an MIC < 8 mcg/mL at pre-treatment. Relapse was al¬ Includes only patients with baseline values within the most always accompanied by an increase in MIC. The me¬ normal range or borderline high (hematology variables) dian time to first negative culture was 54, 41, and 29 days and within the normal range or borderline low (chemistry for the 500, 1000, and 2000 mg b.i.d. groups, respectively. variables). The time to first decrease of at least 1 log in CFU count was Ibl ULN = Upper Limit of Normal significantly shorter with the 1000 and 2000 mg b.i.d. doses (median equal to 16 and 15 days, respectively) in compari¬ son to the 500 mg b.i.d. group (median equal to 29 days). Treatment The median time to first positive culture or study discon¬ Three randomized studies (500, 577, and 521) compared dif¬ tinuation following the first negative culture was 43, 59 and ferent dosages of clarithromycin in patients with CDC43 days for the 500,1000, and 2000 mg b.i.d. groups, respecdefined AIDS and CD4 counts < 100 cells/pL. These studies . tively. Clinically Significant Disseminated MAC Disease accrued patients from May 1991 to March 1992. Study 500 Among patients experiencing night sweats prior to therapy, was randomized, double-blind; Study 577 was open-label 84% showed resolution or improvement at some point dur¬ compassionate use. Both studies used 500 and 1000 mg ing the 12 weeks of clarithromycin at 500 to 2000 mg b.i.d. b.i.d. doses; Study 500 also had a 2000 mg b.i.d. group. doses. Similarly, 77% of patients reported resolution or im¬ Study 521 was a pediatric study at 3.75, 7.5, and 15 mg/kg provement in fevers at some point. Response rates for clin¬ b.i.d. Study 500 enrolled 154 adult patients, Study 577 en¬ ical signs of MAC are given below: rolled 469 adult patients, and Study 521 enrolled 25 pa¬ [See first table above] [See second table above] tients between the ages of 1 to 20. The majority of patients The median duration of response, defined as improvement had CD4 cell counts < 50/pL at study entry. The studies or resolution of clinical signs and symptoms, was 2 to were designed to evaluate the following end points: 6 weeks. 1. Change in MAC bacteremia or blood cultures negative for Since the study was not designed to determine the benefit of M. avium. monotherapy beyond 12 weeks, the duration of response 2. Change in clinical signs and symptoms of MAC infection may be underestimated for the 25 to 33% of patients who including one or more of the following: fever, night sweats, continued to show clinical response after 12 weeks. weight loss, diarrhea, splenomegaly, and hepatomegaly. Survival The results for the 500 study are described below. The 577 Median survival time from study entry (Study 500) was study results were similar to the results of the 500 study. 249 days at the 500 mg b.i.d. dose compared to 215 days Results with the 7.5 mg/kg b.i.d. dose in the pediatric study with the 1000 mg b.i.d. dose. However, during the first were comparable to those for the 500 mg b.i.d. regimen in 12 weeks of therapy, there were 2 deaths in 53 patients in the adult studies. the 500 mg b.i.d. group versus 13 deaths in 51 patients in Study 069 compared the safety and efficacy of the 1000 mg b.i.d. group. The reason for this apparent mor¬ clarithromycin in combination with ethambutol versus tality difference is not known. Survival in the two groups clarithromycin in combination with ethambutol and clofaz¬ was similar beyond 12 weeks. The median survival times for imine for the treatment of, disseminated MAC IdMAC) in¬ these dosages were similar to recent historical controls with fection.4 ’ This 24-week study enrolled 106 patients with MAC when treated with combination therapies.* AIDS and dMAC, with 55 patients randomized to receive Median survival time from study entry in Study 577 was clarithromycin and ethambutol, and 51 patients random¬ 199 days for the 500 mg b.i.d. dose and 179 days for the ized to receive clarithromycin, ethambutol, and clofazimine. 1000 mg b.i.d. dose. During the first four weeks of therapy, Baseline characteristics between study arms.were similar while patients were maintained on their originally assigned with the exception of median CFU counts being at least dose, there were 11 deaths in 255 patients taking 500 mg 1 log higher in the clarithromycin, ethambutol, and clofaz¬ b.i.d. and 18 deaths in 214 patients taking 1000 mg b.i.d. imine arm. Safety Compared to prior experience with clarithromycin mono¬ The adverse event profiles showed that both the 500 and therapy, the two-drug regimen of clarithromycin and etham¬ 1000 mg b.i.d. doses were well tolerated. The 2000 mg b i d butol was well tolerated and extended the time to microbi¬ dose was poorly tolerated and resulted in a higher propor¬ ologic relapse, largely through suppressing the emergence tion of premature discontinuations. of clarithromycin resistant strains. However, the addition of In AIDS patients and other immunocompromised patients clofazimine to the regimen added no additional microbio¬ treated with the higher doses of clarithromycin over long logic or clinical benefit. Tblerability of both multidrug regi¬ periods of time for mycobacterial infections, it was often dif¬ mens was comparable with the most common adverse ficult to distinguish adverse events possibly associated with events being gastrointestinal in nature. Patients receiving clarithromycin administration from underlying signs of HIV the clofazimine-containing regimen had reduced survival disease or intercurrent illness. rates; however, their baseline mycobacterial colony counts The following analyses summarize experience during the were higher. The results of this trial support the addition of first 12 weeks of therapy with clarithromycin. Data are re¬ ethambutol to clarithromycin for the treatment of initial ported separately for Study 500 (randomized, double-blind) dMAC infections but do not support adding clofazimine as a and Study 577 (open-label, compassionate use) and also third agent. combined. Adverse events were reported less frequently in MAC Bacteremia Study 577, which may be due in part to differences in mon¬ Decrease's in MAC bacteremia or negative blood cultures itoring between the two studies. In adult patients receiving were seen in the majority of patients in all dose groups. clarithromycin 500 mg b.i.d , the most frequently reported Mean reductions in colony forming units iCFU) are shown adverse events, considered possibly or probably related to below. Included in the table are results from a separate study drug, with an incidence of 5% or greater, are listed study with a four drug regimen* (ciprofloxacin, ethambutol. below . Most of these events were mild to moderate in sever¬ rifampicin, and clofazimine t Since patient populations and ity, although 5% (Study 500: 8%; Study 577: 4%) of patients study procedures may vary between these two studies, com¬ receiving 500 mg b.i.d and 5% (Study 500: 4%; Study 577: parisons between the clarithromycin results and the combi¬ 6% ) of patients receiving 1000 mg b.i.d. reported severe adnation therapy results should be interpreted cautiously. I verse events. Excluding those patients who discontinued Hemoglobin Increase > 1 gm

b.i.d. dose (mg)

Abdominal pain Headache

bid. dose (mg)

Placebo

< 8 g/dL < 50 x 10S/L

4/118 3% 11/249 4%

5/103 5% 12/250 5%

< 1 x 10*/L

2/103 4%

0/95 0%

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BIAXIN • ABBVIE/423

therapy or died due to complications of their underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study 577: 790 of the patients who received 500 mg b i d. and 12% (Study 500: 14%; Study 577: 1290 of the pa¬ tients who received 1000 mg b.i.d. discontinued therapy due to drug-related events during the first 12 weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had similar ad¬ verse event profiles.

M93-131

14 days

Treatment-related* Adverse Event Incidence Rates (%) in

M95-392

14 days

Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg b.i.d. Clarithromycin Dose

M95-399f

14 days

Adverse Event

Abdominal Pain Diarrhea Flatulence Headache Nausea Rash Taste Perversion Vomiting

Study 500

Study 577 (n = 2551

Combined

(n = 53)

7.5 9.4 7.5 7.5 28.3 9.4 18.9 24.5

2.4 1.6 0.0 0.4 9.0 2.0 0.4 3.9

3.2 2.9 1.3 1.6 12.3 3.2 3.6 7.5

H. pylori Eradication Rates-Triple Therapy (BIAXIN/lansoprazole/amoxicillin) Percent of Patients Cured |96N> Confidence Interval) (number of patients) Study

Duration

Triple Therapy Evaluable Analysis*

Intent-to-Treat Analysis'

92 180.0-97.7] (n = 48) 86 (75.7-93.61 (n = 66) 85 [77.0-91.0] (N = 113) 84 176.0-89.8] (N = 123)

86* [73.3-93.5] (n = 55) 83: 172.0-90.81 (n = 70) 82 173.9-88.11 (N = 126) 81 [73.9-87.6] (N = 135)

10 days

(n = 308)

* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients were dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as evaluable failures of therapy. * Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. (p < 0.05) versus BIAXIN/lansoprazole and lansoprazole/amoxicillin dual therapy. (p < 0.05) versus BLAXIN/amoxicillin dual therapy. 1 The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day. is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

* Includes those events possibly or probably related to study drug and excludes concurrent conditions. A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse events, ex¬ cluding those due to the patient’s concurrent condition, were consistent with those observed in adult patients.

Safety

j The incidence of adverse events in all patients treated, pri¬ marily diarrhea and vomiting, did not differ clinically or statistically for the two agents. In two other controlled clinical trials of acute otitis media Changes in Laboratory Values performed in the United States, where significant rates of In immunocompromised patients treated with beta-lactamase producing organisms were found, clarithromycin for mycobacterial infections, evaluations of laboratory values were made by analyzing those values out¬ j clarithromycin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these side the seriously abnormal level (i.e., the extreme high or studies, very strict evaluability criteria were used to deter¬ low limit) for the specified test. mine the clinical responses. In the 233 patients who were Percentage of Patients1*1 Exceeding Extreme Laboratory evaluated for clinical efficacy, the combined clinical success Value Limits During First 12 Weeks of Treatment 500 mg rate (i.e., cure and improvement) at the post-therapy visit b.i.d. Doselbl j was 91% for both clarithromycin and the control. For the patients who had microbiologic determinations at Study Study the pre-treatment visit, the following presumptive bacterial 500 577 Combined j eradication/clinical cure outcomes (i.e., clinical success) were obtained: BUN > 50 mg/dL < 1% < 1% 0% < 50 x 109/L Two U.S. Acute Otitis Media Studies Clarithromycin vs. Platelet Count < 1% 0% < 1% SCOT > 5 x ULN,C> Antimicrobial/Beta-lactamase Inhibitor EFFICACY 0% 3% 2% > 5 x ULN"’ SGPT RESULTS 0% 2% 1% < 1 x 10b/L WBC 0% 1%> 1% PATHOGEN

'*' Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables) bl Includes all values w ithin the first 12 weeks for patients who start on 500 mg b.i.d. cl ULN = Upper Limit of Normal

1 S. pneumoniae j H. influenzae* M. catarrhalis S. pyogenes

Otitis Media

In a controlled clinical study of acute otitis media performed in the United States, where significant rates of betalactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In this study, very strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clin¬ ical efficacy, the clinical success rate (i.e., cure plus improve¬ ment) at the post-therapy visit was 88% for clarithromycin and 91% for the cephalosporin. In a smaller number of patients, microbiologic determina¬ tions were made at the pre-treatment visit. The following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:

J Overall

H. influenzae’ M. catarrhal is S. pyogenes Overall

clarithromycin success rate, 43/51 (84%), control 55/56 (98%) clarithromycin success rate, 36/45 (80%), control 31/33 (94%) clarithromycin success rate, 9/10 (90%)" control 6/6 clarithromycin success rate, 3/3, control 5/5 clarithromycin success rate. 91/109 (83%), control 97/100 (97%)

Safety

i The incidence of adverse events in all patients treated, pri¬ marily diarrhea (15% vs. 38%) and diaper rash (3% vs. 11%) in young children, was clinically and statistically lower in ] the clarithromycin arm versus the control arm. Duodenal Ulcer Associated with H pylori Infection Clarithromycin + Lansoprazole and Amoxicillin H. pylori Eradication for Reducing the Risk of Duodenal Ul¬ cer Recurrence

OUTCOME

clarithromycin success rate, 13/15 (87%). control 4/5 clarithromycin success rate, 10/14 (71%), control 3/4 clarithromycin success rate, 4/5.contro! 1/1 clarithromycin success rate, 3/3, control 0/1 clarithromycin success rate, 30/37 evaluated clarithromycin 500 mg t.i.d plus omeprazole 40 mg q.d. for 14 days, followed by omepra¬ zole 20 mg q.d. (067, 100, and 058) or by omeprazole 40 mg q.d. (812b> for an additional 14 days in patients with active duodenal ulcer associated with H pylon. Studies 067 and 100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylon infection and duodenal ulcer were confirmed in 219 patients in Study 067 and 228 patients in Study 100 These studies compared the

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424/ABBVIE • BIAXIN Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval!

Omeprazole

0% (0/3)

55% (39/71)

5% (2/42)

0% (0/7)

0% (0/1)

54% (32/59)

3% (1/40)

0% (0/6)

0% (0/1)

67% (29/43)

Study 812b* Clarithromycin + omeprazole + amoxicillin

Study 126 Study 127 Study M96-446

Clarithromycin + amoxicillin

Per-Protocol ’

Intent-to-Treat *

Per-Protocol *

Intent-to-Treat *

*77 [64, 86] (n = 64) *78 [67, 88) (n = 65) *90 180, 96] (n = 69)

69 |57, 79] (n = 80) 73 [61, 82] (n = 77) 83 [74, 91] (n = 84)

43 [31, 56] (n = 67) 41 [29, 54] (n = 68) 33 [24, 441 (n = 93)

37 [27, 48] (n = 84) 36 [26, 47] (n = 84) 32 [23, 42] (n = 99)

Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127; history of ulcer within 5 years, study M96-446) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer. Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. * p < 0.05 versus clarithromycin plus amoxicillin.

Clarithromycin + Omeprazole Omeprazole *12-month recurrence rates:

Clarithromycin + Omeprazole Omeprazole

Thus, in patients with duodenal ulcer associated with H. pylori infection, eradication of 11. pylori reduced ulcer re¬ currence. Safety

The adverse event profiles for the four studies showed that the combination of clarithromycin 500 mg t.i.d. and omepra¬ zole 40 mg q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or 40 mg q.d. (812b) for an addi¬ tional 14 days was well tolerated. Of the 346 patients who received the combination, 12 (3.5%) patients discontinued study drug due to adverse events. Adverse Events with an Incidence of 3% or Greater

End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N) Study

Clarithromycin +

Omeprazole

Clarithromycin

Adverse Event

Omeprazole

Omeprazole (N = 346)

U.S. Studies

Study 100 Study 067

94% (58/62)' 88% (56/64/

88% (60/68) 85% (55/65)

71% (49/69) 64% (44/691

99% (84/85) 100% (64/64)

95% (82/86) 99% (71/72)

N/A N/A

Non-U.S. Studies

Study 058 Study 812b1 2 * 4

Clarithromycin +

% of Patients

Taste Perversion Nausea • Headache Diarrhea Vomiting Abdominal Pain Infection

p < 0.05 for clarithromycin + omeprazole versus clarithromycin monotherapy. 1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28.

H. pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (n/N)

Omeprazole Clarithromycin (N = 355) IN = 166) % of % of Patients

Patients*

1% 1% 6% 3% < 1%

16% 3% 9% 7% 1%

2% 4%

1% 2%

15% 5% 5% 4% 4% 3% 3%

* Studies 067 and 100, only. Clarithromycin + Study

Omeprazole

Omeprazole

Clarithromycin

64% (39/61 )n 74% (39/53 )n

0% (0/59) 0% (0/54)

39% (17/44) 31% (13/42)

74% (64/86/ 83% (50/60/

1% (1/90) 1% (1/74)

N/A N/A

U.S. Studies

Study 100 Study 067 Non-U.S. Studies

Study 058 Study 812b

Statistically significantly higher than clarithromycin monotherapy (p < 0.05). • Statistically significantly higher than omeprazole monotherapy (p < 0.05).

RBC 400 mg + Clarithromycin 500 mg b.i.d.

RBC 400 mg + Clarithromycin 500 mg t.i.d.

95% Cl Rate Difference

65% (122/188) [58%, 72%) 72% (117/162) [65%, 79% ]

63% (122/195) [55%, 69%] 71% (120/170) [63%, 77%i]

(-8%, 12%)

ITT Per-Protocol

combination regimen to omeprazole and clarithromycin monotherapies. Studies 812b and 058 were conducted in Europe and enrolled 154 and 215 patients, respectively. II pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b and 208 patients in Study 058. These studies compared the combination regimen to omeprazole monotherapy. The results for the efficacy anal¬ yses for these studies are described below.

Eradication of H. pylori Associated with Duodenal Ulcer

The combination of clarithromycin and omeprazole was ef¬ fective in eradicating H. pylori. ISee third table above) II. pylon eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradi¬ cated. In the* per-protocol analysis, the following patients were excluded: dropouts, patients with major protocol viola¬ tions. patients with missing H. pylon tests post-treatment, and patients that were not assessed for H. pylon eradica¬ tion at 4 weeks after the end of treatment because they were found to have an unhealed ulcer at the end of treatment.

(-9%, 12%)

Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were healed posttreatment. Ulcer Recurrence at 6 months by H. pylori Status at 4-6 Weeks

Duodenal Ulcer Healing

The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal ulcer. ISee second table abovel

H. pylori

H. pylori

Negative

Positive

6% (2/34)

56% (9/161

- (0/0) 12% (2/17)

71% (35/49) 32% (7/22)

38% (11/29)

50% (6/12)

-• (0/0) 18% (2/11)

67% (31/46) 52% (14/27)

6% (3/53)

24% (4/17)

U.S. Studies Study 100

Clarithromycin + Omeprazole Omeprazole Clarithromycin Study 067

Clarithromycin + Omeprazole Omeprazole Clarithromycin Non-U.S Studies Study 058

Clarithromycin + Omeprazole

Changes in Laboratory Values

Changes in laboratory values with possible clinical signifi¬ cance in patients taking clarithromycin and omeprazole were as follows: Hepatic - elevated direct bilirubin < 1%; GGT < 1%; SGOT (AST) < 1%; SGPT (ALT) < 1%. Renal - elevated serum creatinine < 1%. For information on omeprazole, refer to the ADVERSE RE¬ ACTIONS section of the PRILOSEC package insert. Clarithromycin + Ranitidine Bismuth Citrate Therapy

H. pylori Eradication Rates in Study H2BA-3001 Analysis

Most of these events were mild to moderate in severity.

In a U.S. double-blind, randomized, multicenter, dosecomparison trial, ranitidine bismuth citrate 400 mg b i d. for 4 weeks plus clarithromycin 500 mg b i d. for the first 2 weeks was found to have an equivalent H pylori eradica¬ tion rate (based on culture and histology) when compared to ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg t.i.d. for the first 2 weeks. The intent-to-treat H. pylori eradication rates are shown below: [See fourth table above) H. pylori eradication was defined as no positive test at 4 weeks following the end of treatment. Patients must have had two tests performed, and these must have been nega¬ tive to be considered eradicated of H. pylori. The following patients were excluded from the per-protocol analysis: pa¬ tients not infected with H. pylori prestudy, dropouts, pa¬ tients with major protocol violations, patients with missing H. pylori tests. Patients excluded from the intent-to-treat analysis included those not infected with II pylon prestudy and those with missing H pylori tests prestudy. Patients were assessed for H. pylori eradication i4 weeks following treatment) regardless of their healing status (at the end of treatment). The relationship between H. pylori eradication and duode¬ nal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebocontrolled trials using ranitidine bismuth citrate with or without antibiotics. The results from approximately 650 U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylon infection was eradicated compared to patients in whom H. pylori infection was not eradicated. Safety

In clinical trials using combination therapy with clarithromycin plus ranitidine bismuth citrate, no adverse reactions peculiar to the combination of these drugs (using clarithromycin twice daily or three times a day) were ob¬ served. Adverse reactions that have occurred have been lim¬ ited to those reported with clarithromycin or ranitidine bis-

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Look for PDR drug information and services in your EHR muth citrate. (See ADVERSE REACTIONS section of the Tritec package insert.) The most frequent adverse experi¬ ences observed in clinical trials using combination therapy with clarithromycin (500 mg three times a day) with raniti¬ dine bismuth citrate (n = 329) were taste disturbance Ill'S), diarrhea (5%), nausea and vomiting . The most fre¬ quent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg twice daily) with ranitidine bismuth citrate (n = 196) were taste disturbance (8%), nausea and vomiting (5%), and diarrhea (4%). ANIMAL PHARMACOLOGY AND TOXICOLOGY Clarithromycin is rapidly and well-absorbed with doselinear kinetics, low protein binding, and a high volume of distribution Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all spe¬ cies tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maxi¬ mum human daily dose, based on mg/m2). Renal tubular de¬ generation (calculated on a mg/m2 basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Thsticular atrophy (on a mg/m2 basis) occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose. Corneal opacity (on a mg/m2 basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m2 basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - 9th edition. Approved Standard. CLSI Document M07-A9, CLSI. 950 West Val¬ ley Rd, Suite 2500, Wayne, PA 19087, 2012. 2. CLSI. Performance Standards for Antimicrobial Suscep¬ tibility Testing, 23rd Informational Supplement, CLSI Document M100-S23, 2013. 3. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests, 11th edition. Approved Standard CLSI Document M02-A11, 2012. 4. CLSI. Methods for Antimicrobial Dilution and Disk Dif¬ fusion Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria - 2nd edition. CLSI document M45A2, 2010. 5. Chaisson RE, et al. Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection. AIDS. 1997;11:311-317. 6. Kemper CA. et al. Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral Reg¬ imen. Ann Intern Med. 1992:116:466-472. Filmtab* - Film-sealed tablets, AbbVie Inc. Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg Mfd. by AbbVie LTD, Barceloneta, PR 00617 Biaxin Granules for Oral Suspension, 125 mg/5 mL and 250 mg/5 mL Mfd. by AbbVie Inc., North Chicago, 1L 60064 For AbbVie Inc., North Chicago, IL 60064, U.S.A. 03-B069 January, 2015 Shown in Product Identification Guide, pane 303

CREON • ABBVIE/425 (2.1) Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consen¬ sus Conferences Guidelines. (2.2) Infants tup to 12 months) • Prior to each feeding, infants may be given 3,000 lipase units (one capsule) per 120 ml, of formula or per breast¬ feeding. (2.1) • Do not mix CREON capsule contents directly into formula or breast milk prior to administration. (2.1) Children Older than 12 Months and Younger than 4 Years • Begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or lass than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. (2.2) Children 4 Years and Older and Adults • Begin with 500 lipase units/kg of body weight |«*r meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. (2.2) Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Puncreatectonic • Individualize dosage based on clinical symptoms, the de gree of steatorrhea present and the fat content of the diet. (2.2) -DOSAGE FORMS AND STRENGTHS• Delayed-Release Capsules: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase (3) • Delayed-Release Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amy¬ lase (3) • Delayed-Rulease Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amy¬ lase (3) • Delayed-Release Capsules: 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amy¬ lase (3) • Delayed-Release Capsules: 36,000 USP units of lipase; 114,000 USP units of protease; 180,000 USP units of am¬ ylase (3) -CONTRAINDICATIONSNone (4) -WARNINGS AND PRECAUTIONS• Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement in the treatment of cystic fibrosis patients. Exercise caution when doses of CREON exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day). (5.11 • TV) avoid irritation of oral mucosa, do not chew CREON or retain in the mouth. (5.2) • Exercise caution when prescribing CREON to patients with gout, renal impairment, or hyperuricemia. (5.3) • There is theoretical risk of viral transmission with all pan¬ creatic enzyme products including CREON. (5.4) • Exercise caution when administering pancrelipase to a pa¬ tient with a known allergy to proteins of porcine origin

(5.5) -ADVERSE REACTIONS• Adverse reactions occurring in at least 2 cystic fibrosis pa¬ tients (greater than or equal to 4r4 I receiving CREON are vomiting, dizziness, and cough. (6.11 • Adverse reactions that occurred in at least 1 chronic pan¬ creatitis or pancreatectomy patient (greater than or equal

CREON* I Are'On |

to 4**) receiving CREON are hyperglycemia, hypoglyce¬

1J

(pancrelipase)

mia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, and nasopharyngitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact

-delayed-release capsules for oral use

Abb Via Inc at 1-800-633-9110 or FDA at 1-800-FDA-1088 or wwwfda.gov/medwatch.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CREON safety and effectively. See full prescribing in¬ formation for CREON

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 3/2015

CREON (pancrelipase) delayed-release capsules for oral use Initial U S. Approval: 2009

FULL PRESCRIBING INFORMATION CONTENTS*

-INDICATIONS AND USAGE-

1 2

CREON is a combination of porcine-derived lipases, pro¬ teases, and amylases indicated for the trealmunt of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pan¬ creatitis, pancreatectomy, or other conditions. (1) -DOSAGE AND ADMINISTRATIONCREON is not interchangeable with any other pancrelipase product. (2.1) Do not crush or chew capsules and capsule contents. For in¬ fants or patients unable to swallow intact capsules, the cuntents may be sprinkled on soft acidic food, e.g., applesauce.

3 4 5

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Administration 2.2 Dosage DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Fibmsing Colonopathy 5.2 Potential for Irritation to Oral Mucosa 5.3 Potential for Risk of Hyperuricemia 5.4 Potential Viral Exposure from the Product Source 5.5 Allergic Reactions

6

ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE . 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLIN1CAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Cystic Fibrosis 14.2 Chronic Pancreatitis or Pancreatectomy 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Dosing and Administration 17.2 Fibrosing Colonopathy 17.3 Allergic Reactions 17.4 Pregnancy and Breast Feeding * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

CREON® (pancrelipase) is indicated for the treatment of ex¬ ocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions. 2

DOSAGE AND ADMINISTRATION

CREON is not interchangeable with other pancrelipase products. CREON is orally administered. Therapy should bo initiated at the lowest recommended dose and gradually increased. The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below /see Dosage and Administration (2.2) and Warnings and Precautions (5.1)f. 2.1

Administration

Infants (up to 12 months) CREON should be administered to infants immediately prior to each feeding, using a dosage of 3,000 lipase units per 120 mL of formula or prior to breast-feeding. Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce. Administration should be followed by breast milk or formula. Contents of the cap¬ sule should not be mixed directly into formula or breast milk as this may diminish efficacy. Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa. Children and Adults CREON should be taken during meals or snacks, with suf¬ ficient fluid. CREON capsules and^ capsule contents should not he crushed or chewed. Capsules should be swallowed whole. For patients w'ho are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with watef or juice to en¬ sure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth 2.2 Dosage Dosage recommendations for pancreatic enzyme replace¬ ment therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.1 • *•1 CREON should be administered in a manner consistent with the recommenda¬ tions of the Cystic Fibrosis Foundation Consensus Confer¬ ences (also known as Conferences) provided in the following paragraphs, except for infants. Although the Conferences recommend doses of2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule. Then-fore, the recommended dose of CREON in in¬ fants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

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Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clin¬ ical triai conducted in these populations. Infants (up to 12 months) CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one cap¬ sule) per 120 mL of formula or per breast-feeding. Do not mix CREON capsule contents directly into formula or breast milk prior to administration Isee Administration

30 mm Hg decrease) occurred in 73% of DUOPA-treated patients compared to 68% of patients treated with oral immediate-release carbidopa-levodopa in the controlled clinical study. Orthostatic diastolic hypotension (>20mm Hg decrease) occurred in 70% of DUOPA-treated patients compared to 62% of patients treated with oral immediaterelease carbidopa-levodopa. Inform patients about the risk for hypotension and syncope. Monitor patients for ortho¬ static hypotension, especially after starting DUOPA or in¬ creasing the dose.

existing neuropathy and in patients taking medications or those who have medical conditions that are also associated with neuropathy.

5.4

Epidemiological studies have shown that patients with Par¬ kinson’s disease have a higher risk (2 to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factore, such as drugs used to treat Parkinson's disease, is unclear. In the clinical studies, 2 of 416 (0.5%) DUOPA-treated patients developed mela¬ noma. Appropriately qualified health care provide™ (e.g., derma¬ tologists) should perform periodic skin examinations to monitor for melanoma in patients receiving DUOPA.

Hallucinations/Psychosis/Confusion

There is an increased risk for hallucinations and psychosis in patients taking DUOPA. In the controlled clinical trial, hallucinations occurred in 5% of DUOPA-treated patients compared to 3% of patients treated with oral immediaterelease carbidopa-levodopa. Confusion occurred in 8% of DUOPA-treated patients compared to 3% of patients treated with oral immediate-release carbidopa-levodopa, and psy¬ chotic disorder occurred in 5% of DUOPA-treated patients compared to 3% of patients treated with oral immediaterelease carbidopa-levodopa. Hallucinations associated with levodopa may present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Confusion, insomnia, and ex¬ cessive dreaming may accompany hallucinations. Abnormal thinking and behavior may present with one or more symp¬ toms, including paranoid ideation, delusions, hallucina¬ tions, confusion, psychosis, disorientation, aggressive be¬ havior, agitation, and delirium. Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with DUOPA. In addition, medications that antagonize the ef¬ fects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of DUOPA [see Drug Interactions (7.3)]. 5.5

Impulse Control/Compulsive Behaviors

Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or com¬ pulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medi¬ cations, including DUOPA, that increase central dopamin¬ ergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was re¬ duced or the medication was discontinued. Because patients may not recognize these behaviors as ab¬ normal, it is important for prescribe™ to ask patients or their caregivere specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with DUOPA. Consider reducing the dose or discontinuing DUOPA if a patient develops such urges. 5.6

Depression and Suicidality

In the controlled clinical trial, 11% of DUOPA-treated pa¬ tients developed depression compared to 3% of oral immediate-release carbidopa-levodopa-treated patients. Monitor patients for the development of depression and con¬ comitant suicidal tendencies. 5.7

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscu¬ lar rigidity, altered consciousness, and autonomic instabil¬ ity), with no other obvious etiology, has been reported in as¬ sociation with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinu¬ ation or rapid dose reduction in patients taking DUOPA. If DUOPA is discontinued, the dose should be tapered to re¬ duce the risk of hyperpyrexia and confusion I see Dosage and Administration (2.4)]. 5.8

Dyskinesia

DUOPA may cause or exacerbate dyskinesias. In the con¬ trolled clinical trial, dyskinesia occurred in 14% of DUOPAtreated patients compared to 12% of patients treated with oral immediate-release carbidopa-levodopa. The occurrence of dyskinesias may require a dosage reduction of DUOPA or other medications used to treat Parkinson's disease. 5.9

Neuropathy

In clinical studies, 19 of 412 (5%) patients treated with DUOPA developed a generalized polyneuropathy. The onset of neuropathy could be determined in 13 of 19 patients. Most cases (12/19) were classified as subacute or chronic in onset. The neuropathy was most often characterized as sen¬ sory or sensorimotor. Electrodiagnostic testing performed in 16 patients was most often (15/16) consistent with an axo¬ nal polyneuropathy, and one patient was classified as hav¬ ing a demyelinating neuropathy. There was insufficient in¬ formation to determine the potential role of vitamin deficiencies in the etiology of neuropathy associated with DUOPA. Patients should have clinical assessments for the signs and symptoms of peripheral neuropathy before starting DUOPA. Monitor patients periodically for signs of neuropa¬ thy after starting DUOPA, especially in patients with pre¬

5.10

Cardiovascular Ischemic Events

In clinical studies, myocardial infarction and arrhythmia were reported in patients taking carbidopa-levodopa. Ask patients about symptoms of ischemic heart disease and ar¬ rhythmia, especially those with a history of myocardial in¬ farction or cardiac arrhythmias. 5.11

5.12

Melanoma

Laboratory Test Abnormalities

DUOPA may increase the risk for elevated (above the upper limit of normal for the reference range) blood urea nitrogen (BUN) and creatine phosphokinase (CPK). In the controlled clinical trial, the shift from a low or normal value at base¬ line to an increased BUN value was greater for DUOPAtreated patients (13%) than for patients treated with oral immediate-release carbidopa-levodopa (4%). The shift from a low or normal value at baseline to an increased CPK value was greater for DUOPA-treated patients (17%) than for pa¬ tients treated with oral immediate-release carbidopalevodopa (7%). The incidence of patients with a markedly increased BUN (210 mmol/L; >28 mg/dL) was greater for patients treated with DUOPA (11%) than that for patients treated with oral immediate-release carbidopa-levodopa (0%). The incidence of patients with an increased CPK (>3 times the upper limit of normal) was greater for patients treated with DUOPA (9%) than that for patients treated with oral immediate-release carbidopa-levodopa (0%). Patients taking levodopa or carbidopa-levodopa may have increased levels of catecholamines and their metabolites in plasma and urine giving false positive results suggesting the diagnosis of pheochromocytoma in patients on levodopa and carbidopa-levodopa. 5.13

Glaucoma

Carbidopa-levodopa may cause increased intraocular pres¬ sure in patients with glaucoma. Monitor intraocular pres¬ sure in patients with glaucoma after starting DUOPA. 6

ADVERSE REACTIONS

The following serious adverse reactions are discussed below and elsewhere in labeling: • Gastrointestinal and Gastrointestinal Procedure-Related Risks [see Warnings and Precautions (5.1)] • Falling Asleep During Activities of Daily Living and Som¬ nolence /see Warnings and Precautions (5.2)] • Orthostatic Hypotension /see Warnings and Precautions (5.3)1 • Hallucinations/Psychosis/Confusion /see Warnings and Precautions (5.4)1 • Impulse Control/Compulsive Behavio™ [see Warnings and Precautions (5.5)] • Depression and Suicidality I see Warnings and Precautions (5.6) I • Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7)1 • Dyskinesia [see Warnings and Precautions (5.8)] • Neuropathy [see Warnings and Precautions (5.9)1 • Cardiovascular Ischemic Events /see Warnings and Pre cautions (5.10)] • • Melanoma /see Warnings and Precautions (5.11)] • Laboratory TVst Abnormalities [see Warnings and Precau¬ tions (5.12)] • Glaucoma /see Warnings and Precautions (5.13)1 6.1

Clinical Trials Experience

Because clinical studies are run under widely varying con¬ ditions. the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies, 416 patients with advanced Parkinson’s disease received DUOPA. 338 patients were treated with DUOPA for more than 1 year, 233 patients were treated with DUOPA for more than 2 years, and 162 patients were treated with DUOPA for more than 3 years. In a 12-week, active-controlled clinical trial (Study 1), a to¬ tal of 71 patients with advanced Parkinson's disease were

Information on tha AbbVie. Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie com or call 1-800-633-9110.

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enrolled and had a PEG-J procedure. Of these, 37 patients received DUOPA and 34 received oral immediate-release carbidopa-levodopa. The most common adverse reactions for DUOPA (incidence at least 791 greater than oral immediate-release carbidopalevodopa) were: complication of device insertion, nausea, de¬ pression, peripheral edema, hypertension, upper respira¬ tory tract infection, oropharyngeal pain, atelectasis, and incision site erythema. Table 3 lists the incidence of adverse reactions occurring in the DUOPA-treated group (requiring at least 2 patients in this group) in Study 1 when the incidence was numerically greater than that for oral immediate-release carbidopalevodopa. Table 3. Adverse Reactions in Study 1 for DUOPA in Patients with Advanced Parkinson's disease Preferred Term

DUOPA (n = 37) %

Oral immediate-release carbidopa-levodopa* (n = 34) %

Complication of device insertion

57

44

Nausea

30

21

Constipation

22

21

Incision site erythema

19

12

Dyskinesia

14

12

Depression

11

3

Post procedural discharge

11

9

Peripheral edema

8

0

Hypertension

8

0

Upper respiratory tract infection

8

0

Oropharyngeal pain

8

0

Atelectasis

8

0

Confusional state

8

3

Anxiety

8

3

Dizziness

8

6

Hiatal hernia

8

6

Postoperative ileus

5

0

Sleep disorder

5

0

Pyrexia

5

0

Excessive granulation tissue

5

0

Rash

5

0

Bacteriuria

5

0

White blood cells urine positive

5

0

Hallucination

5

3

Psychotic disorder

5

3

Diarrhea

5

3

Dyspepsia

5

3

Additional adverse reactions that were co-reported with complication of naso-jejunal and PEG-J insertion included upper abdominal pain, duodenal ulcer, duodenal ulcer hem¬ orrhage, erosive duodenitis, erosive gastritis, gastrointesti¬ nal hemorrhage, peritonitis, post-operative abscess, and small intestine ulcer. 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase (MAO) Inhibitors The use of nonselective MAO inhibitors with DUOPA is con¬ traindicated [see Contraindications (4)]. Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating DUOPA. The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with DUOPA may be associated with orthostatic hypotension. Monitor patients who are taking these drugs. 7.2 Antihypertensive Drugs The concurrent use of DUOPA with antihypertensive medi¬ cations can cause symptomatic postural hypotension. A dose reduction of the antihypertensive medication may be needed after starting or increasing the dose of DUOPA. 7.3 Dopamine D2 Receptor Antagonists and Isoniazid Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide, papaverine) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson’s symptoms. 7.4 Iron Salts Iron salts or multi-vitamins containing iron salts can form chelates with levodopa, carbidopa, and can cause a reduc¬ tion in the bioavailability of DUOPA. If iron salts or multi¬ vitamins containing iron salts are co-administered with DUOPA, monitor patients for worsening Parkinson’s symp¬ toms. 7.5 High-Protein Diet Because levodopa competes with certain amino acids for transport across the gut wall, the absorption of levodopa may be decreased in patients on a high-protein diet. Advise patients that a high-protein diet may reduce the effective¬ ness of DUOPA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate or well-controlled studies in preg¬ nant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. In animal studies, carbidopalevodopa has been shown to be developmentally toxic (in¬ cluding teratogenic effects) at clinically relevant doses. DUOPA should be used during pregnancy only if the poten¬ tial benefit justifies the potential risk to the fetus. When administered to pregnant rabbits throughout organ¬ ogenesis, carbidopa-levodopa caused both visceral and skel¬ etal malformations in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were ob¬ served when carbidopa-levodopa was administered to preg¬ nant mice throughout organogenesis. There was a decrease in the number of live pups delivered by rats receiving carbidopa-levodopa during organogenesis. 8.3 Nursing Mothers

droxybenzene) propanoic arid monohydrate. Its empirical formula is CfoHuNjOjeHjO, and its structural formula is:

OH The content of carbidopa in DUOPA is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3. The 4.63 mg/mL of anhydrous carbidopa is equiva¬ lent to 5.0 mg/mL of carbidopa. Levodopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-LL-a-amino-fl-l3,4-dihydroxybenzenei pro¬ panoic acid. Its empirical formula is C9H,,N04, and its structural formula is:

O

The inactive ingredients in DUOPA are carmellose sodium and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Carbidopa When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decar¬ boxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Levodopa Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to do¬ pamine in the brain. This is thought to be the mechanism whereby levodopa treats the symptoms of Parkinson’s dis¬ ease. 12.2 Pharmacodynamics Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available to the brain. The addition of carbidopa to levodopa reduces the peripheral ef¬ fects (e.g., nausea and vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. 12.3 Pharmacokinetics The pharmacokinetics of carbidopa and levodopa with 16-hour intrajejunal infusion of DUOPA was evaluated in 18 patients with advanced Parkinson’s disease who had been on DUOPA therapy for 30 days or longer. Patients re¬ mained on their individualized DUOPA doses. The plasma concentrations versus time profile for levodopa with DUOPA 16-hour intrajejunal infusion is presented in Figure 1.

Carbidopa is excreted in rat milk. In a study of one nursing mother with Parkinson's disease, excretion of levodopa in human milk was reported. Caution should be exercised when DUOPA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the controlled clinical trial, 49% of patients were 65 years and older, and 8% were 75 years and older. In patients 65 years and older, there was an increased risk for elevation of BUN and CPK (above the upper limit of the normal refer¬ ence range for these laboratory analytes) during treatment with DUOPA compared to the risk for patients less than 65 years. 10

,

"All patients in the clinical trial regardless of treatment arm received a PEG-J. Procedure and Device- Related Adverse Reactions The most common adverse reactions associated with compli¬ cations due to naso-jejunal (NJ) insertion were: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, esophageal hemorrhage, anxiety, dysphagia, and vomiting The most common adverse reactions associated with compli¬ cations due to PEG-J insertion were: abdominal pain, ab¬ dominal discomfort, abdominal distension, flatulence, or pneumoperitoneum.

OVERDOSAGE

Management of acute overdosage with DUOPA is the same as management of acute overdosage with levodopa. Pyridoxine is not effective in reversing the actions of oral immediate-release carbidopa-levodopa. In the event of an overdosage with DUOPA, the infusion should be stopped and the pump disconnected immediately. Administer intravenous fluids and maintain an adequate airway. Patients should receive electrocardiographic moni¬ toring for arrhythmias and hypotension.

Time (hr) Figure 1. Plasma Concentrations (mean t standard deviation) versus Time Profile of Levodopa with DUOPA (levodopa, 1580 ± 403 mg; carbidopa. 366 i 92 mg) 16-Hour Infusion

Absorption and Bioavailability Following initiation of1 the 16-hour intrajejunal infusion of DUOPA, peak plasma levels of levodopa is reached at 2.5 hours. The absorption of levodopa may be decreased in pa¬ 1 tients on a high-protein diet because levodopa competes 11 DESCRIPTION with certain amino acids for transport across the gut walL DUOPA is a combination of carbidopa, an inhibitor of aro- * The gastnc emptying rate does not influence the absorption matic amino acid decarboxylation, and levodopa. an aro¬ of DUOPA since it is administered by continuous intestinal matic amino arid. infusion. In a cross-study population pharmacokinetic anal¬ Carbidopa is a white, crystalline compound, slightly soluble ysis, DUOPA had comparable bioavailahility to the oral in water, with a molecular weight of 244.3. It is designated immediate-release carbidopa-levodopa (25/100 mg) tablets chemically as (-)-L-'u-hydrazino-(a-methyl-JJ-(3,4-dihy- I (over-encapsulated tablets). The estimated bioavailability

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Look for PDR drug information and services in your EHR for levodopa from DUOPA relative to oral immediaterelease carbidopa-levodopa tablets was 97% (95% confi¬ dence interval; 95% to 98%). In the controlled clinical trial, the intra-suhject variability in carbidopa and levodopa plasma concentrations were lower for patients treated with DUOPA (N=33, 25% and 21%, respectively) than in patients treated with oral immediate-release carbidopa-levodopa (25/100 mg) tablets (N=28, 39% and 67%, respectively). Distribution Carbidopa is approximately 36% bound to plasma proteins. Levodopa is approximately 10-30% bound to plasma pro¬ teins. Metabolism and Elimination Carbidopa Carbidopa is metabolized to two main metabolites (a-methyl-3-methoxy-4-hydroxyphenylpropionic acid and a-methyl-3,4-dihydroxyphenylpropionic acid). These 2 me¬ tabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa ac¬ counts for 30% of the total urinary excretion. The elimina¬ tion half-life of carbidopa is approximately 2 hours. Levodopa Levodopa is mainly eliminated via metabolism by the aro¬ matic amino acid decarboxylase (AAAD) and the catecholO-methyl-transferase (COMT) enzymes. Other routes of me¬ tabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co¬ administered. O-methylation of levodopa by COMT forms 3-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours (see Figure 1). Drug Interaction Studies COMT Inhibitors Systemic exposure of levodopa is expected to increase in the presence of entacapone. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis. Mutagenesis, Impairment of Fer¬ tility Carcinogenesis In rat, oral administration of carbidopa-levodopa for two years resulted in no evidence of carcinogenicity. DUOPA contains hydrazine, a degradation product of carbidopa. In published studies, hydrazine has been demonstrated to be carcinogenic in multiple animal species. Increases in liver (adenoma, carcinoma) and lung (adenoma, adenocarcinoma) tumors have been reported with oral administration of hy¬ drazine in mouse, rat, and hamster. Mutagenesis Carbidopa was positive in the in vitro Ames test, in the presence and absence of metabolic activation, and the in vi¬ tro mouse lymphoma tk assay in the absence of metabolic activation but was negative in the in vivo mouse micronu¬ cleus assay. In published studies, hydrazine was reported to be positive in in vitro genotoxicity (Ames, chromosomal aberration in mammalian cells, and mouse lymphoma tk) assays and in the in vivo mouse micronucleus assay. Impairment of Fertility In reproduction studies, no effects on fertility were observed in rats receiving carbidopa -levodopa. 14

DUOPA • ABBVIE/443

Baseline

Week 2

Week 3

Week 4

Patients were eligible for participation in the studies if they .were experiencing 3 hours or more of “Off” time on their cur¬ rent Parkinson's disease drug treatment and they demon¬ strated a clear responsiveness to treatment with levodopa. Seventy-one (71) patients enrolled in the study and 66 pa¬ tients completed the treatment (3 patients discontinued treatment because of adverse reactions, 1 patient for lack of effect, and 1 patient for non-compliance). Patients enrolled in this study had a mean age of 64 years and disease* duration of 11 years. Most patients (89%) were taking at least one concomitant medication for Parkinson’s disease (e.g., dopaminergic agonist. COMT-inhibitor, MAO-B inhibitor) in addition to oral immediate-release carbidopa-levodopa. Thirty nine percent of patients were taking two or more of such concomitant medications. Patients were randomized to either DUOPA and placebo capsules or placebo suspension and oral immediate-release carbidopa-levodopa 25/100 mg capsules. Patients in both treatment arms had a PEG-J device placement. DUOPA or placebo-suspension was infused over 16 hours daily through a PEG-J tube via the CADD*-Legacy 1400 model ambula¬

Week 8

Week 10

Week 12

DUOPA

(N)

35

33

34

35

35

35

33

35

Oral Immediaterelease carbidopalevodopa

(N)

31

27

29

31

30

29

30

31

Figure 2. Change in “Off" Time Over 12 Weeks.

tory infusion pump. The mean daily levodopa dose was 1117 mg/day in the DUOPA group and 1351 mg/day in the oral immediate-release carbidopa-levodopa group. The clinical outcome measure in Study 1 was the mean change from baseline to Week 12 in the total daily mean “Off" time, based on a Parkinson’s disease diary. The “Off" time was normalized to a 16-hour awake period, based on a typical person's waking day and the daily infusion duration of 16 hours. The mean score decrease (i.e., improvement) in “Off” time from baseline to Week 12 for DUOPA was signif¬ icantly greater (p=0.0015) than for oral immediate-release carbidopa-levodopa. Additionally, the mean score increase (i.e., improvement) in “On” time without troublesome dyski¬ nesia from baseline to Week 12 was significantly greater (p=0.0059) for DUOPA than for oral immediate-release carbidopa-levodopa. The treatment difference (DUOPA oral immediate release carbidopa-levodopa) for decrease in “Off” time was approximately 1.9 hours and the treatment difference for the increase in “On” time without troublesome dyskinesia was approximately 1.9 hours. Results of Study 1 are shown in Table 4. Table 4. Change from Baseline to Week 12 in “Off" Time and in "On" Time Without Troublesome Dyskinesia in Patients with Advanced Parkinson's Disease Treatment Group

Baseline (hours)

LS Mean Change from Baseline at Week 12 (hours)

6.9

-2.1

6.3

-4.0*

"Off" time Oral immediate-release carbidopa-levodopa DUOPA

CLINICAL STUDIES

The efficacy of DUOPA was established in a randomized, double-blind, double-dummy, active-controlled, parallel group, 12-week study (Study 1) in patients with advanced Parkinson’s disease w ho were levodopa-rcsponsive and had persistent motor fluctuations while on treatment with oral immediate-release carhidopa-levodopa and other Parkin¬ son’s disease medications.

Week 6

Visit

"On" time without troublesome dyskinesia Oral immediate- relpase carbidopa-levodopa DUOPA

8.0

2.2

8.7

4.1*

j LS Mean Change from Baseline based on Analysis of | Covariance (ANCOVA). I *=Statistically Significant. ! Figure 2 shows results over time according to treatment for i the efficacy variable (change from baseline in “Off” time) j that served as the clinical outcome measure at the end of the trial at 12 weeks. [See figure 2 above) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied I Single-use cassettes containing 4.63 mg carbidopa las 5 mg of the monohydrate) and 20 mg levodopa per mL of enteral suspension. Each cassette contains approximately 100 mL of suspension. Carton of 7 DUOPA cassettes: NDC 0074-3012-07 16.2 Storage and Handling Store in freezer at -20“C 1-4’F). Thaw in refrigerator at 2*C to 8*C )36*F to 46'F) prior to dispensing. Cassettes should I be protected from light and kept in the carton prior to use

Thawing instructions for pharmacies • Assign a 12 week “Use By” date based on the time the car¬ tons are put into the refrigerator to thaw. • Fully thaw DUOPA in the refrigerator prior to dispensing. • In order to ensure controlled thawing of DUOPA, take the cartons containing the seven individual cassettes out of the transport box and separate the cartons from each other. • Thawing may take up to 96 hours when the cartons are taken out of the transport box. • Once the product has thawed, the individual cartons may be packed in a closer configuration within the refrigerator. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Medication Guide and Instructions for Use). Administration Information Ask patients if they have had any previous surgery in the upper part of their abdomen that may lead to difficulty in performing the gastrostomy or jejunostomy [see Dosage and Administration (2.3)1. Advise patients that foods that are high in protein may re¬ duce the effectiveness of DUOPA/see Drug Interactions (7.5) and Clinical Pharmacology (12.3)1. Interruption of DUOPA Infusion If the patient anticipates disconnecting the pump for a short period of time (less than 2 hours such as to swim, shower, or short medical procedure), no supplemental oral medication is needed, but the patient may be advised to take an extradose of DUOPA before disconnecting. Instruct the patient to stop the continuous rate, turn off the pump, clamp the cas¬ sette tube, disconnect the tubing, and replace the red cap on the cassette tube. The DUOPA cassette can remain attached to the pump until the tubing is reconnected. Refer the pa¬ tient to the Patient Instructions for Use for additional infor¬ mation (i.e., changing the DUOPA Cassette: disconnecting Steps 1-5 and reconnecting Steps 10-16). Advise the patient to contact their healthcare provider and to take oral carbidopa-levodopa until the patient is able to resume DUOPA infusion, if the patient will have prolonged interruption of therapy lasting more than 2 hours [see Dos¬ age and Administration (2.4)1. Gastrointestinal and Gastrointestinal Procedure-Related Risks , Inform patients of the gastrointestinal procedure-related risks including bezoar, ileus, implant site erosion/ulcer, in¬ testinal hemorrhage, intestinal ischemia, intestinal ob¬ struction. intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum, post-operative wound infection and sepsis. Advise patients of the symptoms of the above listed complications and instruct them to contact their healthcare provider if they experience any of these symptoms [see Warnings and Precautions (5.1)1 . Falling Asleep during Activities of Daily Living and Somnono

Alert patients to the potential sedating effects caused by DUOPA, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a common adverse reaction with potentially serious consequences, patients should not drive a car, oper¬ ate machinery, or engage in other potentially dangerous ac-

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31. 2015. For more information, please visit rxabbvie com or call 1-800-633-9110

Free mobile?DR app for fast drug references on Apple or Android devices

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444/ABBVIE • DUOPA tivities until they have gained sufficient experience with DUOPA to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other cen¬ tral nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with DUOPA or when taking a concomitant medication that in¬ creases plasma levels of levodopa /see Warnings and Precau¬ tions (5.2)1. Orthostatic Hypotension Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as diz¬ ziness, nausea, syncope, and sometimes sweating while tak¬ ing DUOPA. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the ini¬ tiation of treatment with DUOPA/see Warnings and Precau¬ tions (5.3)J. Hallucinations/Psychosis/Confusion Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations) and other symptoms of psychosis can occur while taking DUOPA. Tell patients to report hallucinations, abnormal thinking, psychotic behav¬ ior or confusion to their healthcare provider promptly should they develop /see Warnings and Precautions (5.4)1. Impulse Control/Compulsive Behaviors Advise patients that they may experience impulse control and/or compulsive behaviors while taking DUOPA. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with DUOPA/see Warnings and Precautions (5.5)). Depression and Suicidality Inform patients that they may develop depression or expe¬ rience worsening of depression while taking DUOPA. In¬ struct patients to contact their healthcare provider if they experience depression, worsening of depression, or suicidal thoughts [see Warnings and Precautions (5.6)]. Withdrawal-Emergent Hyperpyrexia and Confusion Advise patients to contact their healthcare provider before stopping DUOPA. Ttell patients to inform their healthcare provider if they develop withdrawal symptoms such as fe¬ ver, confusion, or severe muscle stiffness /see Warnings and Precautions (5.7)]. Dyskinesia Inform patients that DUOPA may cause or exacerbate pre¬ existing dyskinesias [see Warnings and Precautions (5.8)). Neuropathy Inform patients that neuropathy may develop or they may experience worsening neuropathy on DUOPA, and to contact their healthcare provider if they develop any symptoms or features suggesting neuropathy /see Warnings and Pre¬ cautions (5.9)1. Melanoma Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to have their skin examined on a regular basis by a qualified health¬ care provider (e.g., dermatologist) when using DUOPA/see Warnings and Precautions (5.11)1■ Nursing Mothers Because of the possibility that carbidopa or levodopa may be excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother /see Use in Specific Populations (8.3)1. Abb Vic Inc. North Chicago, IL 60064, USA 03-B168 May 2015

!

■ j j i j

»stopping movement through intestines (ileus) "drainage, redness, swelling, pain, feeling of warmth around the small hole in your stomach wall (stoma) ° bleeding from stomach ulcers or your intestines »inflammation of your pancreas (pancreatitis) °air or gas in your abdominal cavity « skin infection around the intestinal tube, infection in your blood or abdominal cavity may occur, after surgery o stomach pain, nausea or vomiting • Tell your healthcare provider right away if you have any of the following symptoms of stomach and intestine problems and gastrointestinal procedure-related prob¬ lems:

“stomach (abdominal) pain «constipation that does not go away ° nausea or vomiting «fever ° blood in your stool or a dark tarry stool (melanotic stool) You will need to have a procedure to make a small hole (called a “stoma”) in your stomach wall to place a gastro¬ jejunostomy tube (called a PEG-J tube) in an area of your small intestine called the jejunum. DUOPA is delivered di¬ rectly to your small intestine through this tube. Your healthcare provider will talk to you about the stoma proce¬ dure. Before the stoma procedure, tell your healthcare pro¬ vider if you have ever had a surgery or problems with your stomach. Talk to your healthcare provider about what you need to do to care for your stoma. After the procedure, you and your healthcare provider will need to regularly check the stoma for any signs of infection. If your PEG-J tube becomes kinked, knotted, or blocked this may cause you to have worsening of your Parkinson’s symp¬ toms or recurring movement problems (motor fluctuations). Call your healthcare provider if your Parkinson’s symptoms get worse or you have slow movement while you are treated | with DUOPA. What is DUOPA?

DUOPA is a prescription medicine used for treatment of ad¬ vanced Parkinson’s disease. DUOPA contains 2 medicines, carbidopa and levodopa. DUOPA should not be given to children (younger than 18 years). Who should not use DUOPA? Do not use DUOPA if you:

• take a medicine called a nonselective Monoamine Oxidase (MAO) Inhibitor (such as phenelzine or tranylcypromine) or have taken a nonselective MAO Inhibitor within the last 14 days. Ask your healthcare provider or pharmacist if you are not sure if you take an MAO Inhibitor. What should I tell my healthcare provider before using DUOPA? Before you use DUOPA, tell your healthcare provider if you:

• have or have had stomach ulcers or stomach surgery • have low blood pressure (hypotension) or if you feel dizzy or faint, especially when getting up from sitting or lying | down • have had problems with fainting (syncope) • feel sleepy or have fallen asleep suddenly during the day • have or have had depression (feelings of hopelessness or sadness) or any mental problems • drink alcohol. Alcohol can increase the chance that DUOPA will make you feel sleepy or fall asleep when you should be awake • have trouble controlling your muscles (dyskinesia) • have nerve problems (peripheral neuropathy) • have or have had heart problems, an abnormal heart rate or have had a heart attack in the past j • have or have had a type of skin cancer called melanoma • have or have had high blood pressure (hypertension) • have eye problems that cause increased pressure in your eye (glaucoma) • have a history of attacks of suddenly falling asleep and without warning • have any other medical conditions MEDICATION GUIDE • are pregnant or planning to become pregnant. It is not DUOPA (Do-oh-pa) known if DUOPA will harm your unborn baby (carbidopa and levodopa) enteral suspension • are breastfeeding or plan to breastfeed. DUOPA can pass Read this Medication Guide before you start using DUOPA into your milk and may harm your baby. Talk to your and each time you get a refill. There may be new informa- 1 healthcare provider about the best way to feed your baby if tion. This information does not take the place of talking to you take DUOPA your healthcare provider about your medical condition or Tell your healthcare provider about all the medicines you treatment. take, including prescription and over-the-counter medi¬ What is the most important information I should know cines, vitamins, herbal supplements. about DUOPA? DUOPA can cause serious side effects, including: Using DUOPA with certain other medicines may affect each other and cause serious side effects • Stomach and intestine (gastrointestinal) problems and problems from the procedure you will need ta-have to re¬ Especially tell your healthcare provider if you take: ceive DUOPA (gastrointestinal procedure-related prob¬ • medicines used to treat high blood pressure (hypertension! lems). • medicines used to treat depression called nonselective Some of these problems may require surgery and may lead Monuamine Oxidase be/oar > davs

• dopamine D2 receptor antagonists (antipsychotics or metoclopramide), and isoniazid • iron or multivitamins with iron Eating high protein foods may affect how DUOPA works. Tfell your healthcare provider if you change your diet. Ask your healthcare provider or pharmacist for a list of these medicines or foods if you are not sure. Know the medicines you take. Keep a list of them to show

your healthcare provider and pharmacist when you get a new medicine. How should I use DUOPA?

• Use DUOPA exactly as your healthcare provider tells you to use it. • Your healthcare provider should show you how to use DUOPA before you use it for the first time. Ask your healthcare provider or pharmacist if you have any ques¬ tions. • Your prescribed dose of DUOPA will be programmed into your pump by a healthcare provider and should only be changed by your healthcare provider or while you are with your healthcare provider. • Do not stop using DUOPA or change your dose unless you are told to do so by your healthcare provider. Tell your healthcare provider if you develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness. • Keep a supply of oral carbidopa-levodopa immediate re¬ lease (IR) tablets with you in case you are unable to give your DUOPA infusion. • DUOPA is given continuously over 16 hours through a tube that is put into your stomach called a PEG-J. A small pump (CADD-Legacy 1400) is used to move DUOPA from the medication cassette through your PEG-J tube. • Your DUOPA dose has three parts: »a morning dose ° a continuous dose ° extra doses • DUOPA can also be given for a short time (short-term) through a tube put into your nose called a naso-jejunal (NJ) tube. • The CADD-Legacy 1400 portable infusion pump should be used to give DUOPA through your PEG-J tube. See the Instructions for Use that comes with your CADD-Legacy 1400 portable infusion pump for complete instructions on how to use the pump. • DUOPA comes in a small plastic container (cassette) that you connect to the pump to get your medicine. ° Each cassette can only be used 1 time. An opened cas¬ sette should not be reused. ° The cassette should not be used for longer than 16 hours. 0 The cassette should be thrown away at the end of the infusion, even if there is some medicine still in the cas¬ sette. • Disconnect the pump from your PEG-J tube after the 16 hour dosing time is finished. Use a syringe filled with room temperature water to flush your PEG-J tube. See the "Instructions for Use" for more information about how to flush your PEG-J tube with a syringe. • After your daily DUOPA infusion, you should take your usual night-time dose of oral carbidopa-levodopa tablets as prescribed. • If you stop your DUOPA infusion for more than 2 hours during your 16 hour dosing time for any reason, call your healthcare provider and take oral carbidopa-levodopa as prescribed until you are able to restart your DUOPA infu¬ sion. ■ • If you stop your DUOPA infusion for less than 2 hours, you do not need to take oral carbidopa-levodopa, but your healthcare provider may tell you to take an extra dose of DUOPA. What should I avoid while using DUOPA?

• Do not drive, operate machinery, or do other activities un¬ til you know how DUOPA affects you. Sleepiness and fall¬ ing asleep suddenly caused by DUOPA can happen as late as 1 year after you start your treatment. What are the possible side effects of DUOPA? DUOPA may cause serious side effects, including: • See "What is the most important information I should know about DUOPA?"

• Falling asleep during normal daily activities. DUOPA may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating. ° You could fall asleep without any warning 0 Some people using DUOPA have had car accidents be¬ cause they fell asleep while driving. Do not drive or operate machinery until you are sure how DUOPA affects you. TY1I your healthcare provider if you take other medicines that can make you sleepy such as sleep medicines, anti¬ depressants, or antipsychotics. • Low blood pressure when you sit or stand up quickly. Af¬ ter you have been sitting or lying down, stand up slowly until you know how DUOPA affects you. This may help re¬ duce the following symptoms while you are using DUOPA; ° dizziness

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Look for PDR drug information and services in your EHR • nausea • sweating - fainting

DUOPA • ABBVIE/445 DUOPA (carbidopa and levodopa) enteral suspension

• Seeing things that are not there, hearing sounds or feel¬ ing sensations that are not real (hallucinations). Halluci¬

nations can happen in people who use DUOPA. Tell your healthcare provider if you have hallucinations. • Unusual urges. Some people taking certain medicines to treat Parkinson’s disease, including DUOPA, have re¬ ported problems, such as gambling, compulsive eating, compulsive shopping, and increased sex drive. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare pro¬ vider. • Depression and suicide. DUOPA can cause depression or make your depression worse. Pay close attention to sud¬ den changes in your m0.5 kg Graft swelling and tenderness Decrease in daily urine volume >500 mL (or 50%) CyA serum trough level 0.3 mg/dL/day)“ Cr >25% above baseline BUN/Cr 200 ng/mL Gradual rise in Cr (20% of sediment Intracapsular pressure >40 mm Hg*’ Increase in graft cross sectional area AP diameter > Transverse diameter Loss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid Responds to increased steroids or antilymphocyte globulin

“p . Sirolimus Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration. Nifedipine Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine. Methylprednisolone Convulsions when high dose methylprednisolone is given concurrently with cyclosporine have been reported. Other Immunosuppressive Drugs and Agents Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression. C. Effect of Cyclosporine on the Efficacy of Live Vaccines During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided. For additional information on Cyclosporine Drug Interac¬ tions please contact AbbVie Inc. Medical Information De¬ partment at 1-800-633-9110. Carcinogenesis. Mutagenesis, and Impairment of Fertility Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and pancreatic is¬ let cell adenomas were not dose related. Published reports indicate that co-treatment of hairless mice with UV irradi¬ ation and cyclosporine or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone. Cyclosporine was not mutagenic in appropriate test sys¬ tems. Cyclosporine has not been found to be mutagenic/ genotoxic in the Ames Tbst, the V79-HGPRT Tbst, the mi¬ cronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bonemarrow, the mouse dominant lethal assay, and the DNArepair test in sperm from treated mice. A recent study ana¬ lyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indica¬ tion of a positive effect ti.e., induction of SCE', at high con¬ centrations in this system. In two published research stud¬ ies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously! demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Preg¬ nant rats which received 12 mg/kg/day of cyclosporine intra¬ venously (twice the recommended human intravenous dose' had fetuses with an increased incidence of ventricular sep¬ tal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown. No impairment io fertility was demonstrated in studies in male and female rats. Widely distributed papillumatoeia of the skin was observed after chronic treatment of dogs with cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg.

Information on the AbbVie. Ine products fisted on these pages is from the prescribing information in use es of July 31, 2015. For more informetion, please visit rxabbvie.com or call 1-800-633-9110.

Free moMePDR app for fast drug references on Apple or Android devices

456/ABBVIE • GENGRAF

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

Cyclosporine (MODIFIEDl/Sandimmune® Rheumatoid Arthritis Percentage of Patients with Adverse Events £3% in any Cyclosporine Treated Group

Body System

Preferred Term

Autonomic Nervous System Disorders Flushing Body As A Whole-General Disorders Accidental Trauma Edema NOS* Fatigue Fever Influenza-like symptoms Pain Rigors Cardiovascular Disorders Arrhythmia Chest Pain Hypertension Central and Peripheral Nervous System Disorders Dizziness Headache Migraine Paresthesia Tremor Gastrointestinal System Disorders Abdominal Pain Anorexia Diarrhea Dyspepsia Flatulence Gastrointestinal Disorder NOS* Gingivitis Gum Hyperplasia Nausea Rectal Hemorrhage Stomatitis Vomiting Hearing and Vestibular Disorders Ear Disorder NOS* Metabolic and Nutritional Disorders Hypomagnesemia Musculoskeletal System Disorders Arthropathy Leg Cramps / Involuntary Muscle Contractions Psychiatric Disorders Depression Insomnia Renal Creatinine elevations >30% Creatinine elevations >50% Reproductive Disorders, Female Leukorrhea Menstrual Disorder Respiratory System Disorders Bronchitis Coughing Dyspnea Infection NOS* Pharyngitis Pneumonia Rhinitis Sinusitis Upper Respiratory Tract Skin and Appendages Disorders Alopecia Bullous Eruption Hypertrichosis Rash Skin Ulceration Urinary System Disorders Dysuria Micturition Frequency NPN. Increased Urinary Tract Infection Vascular (Extracardiac) Disorders Purpura

Studies 651+652+2008

Study 302

Study 654

Study 654

Study 302

Sandimmune®’ (N=269)

Sandimmune® |N=155)

Methotrexate & Sandimmune® IN=74)

Methotrexate & Placebo IN=73)

Cyclosporine (MODIFIED) |N=143)

Placebo (N=201)

2%

2%

3%

0%

5%

2%

0% 5% 6% 2% losing spondylitis showed similar results.

Patients treated w ith HUMIRA achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Ques¬ tionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated pa¬ tients at Week 24. 14.5

Adult Crohn's Disease

The safety and efficacy of multiple doses of HUMIRA were assessed in adult patients with moderately to severely ac¬ tive Crohn's disease, CD, (Crohn's Disease Activity Index (CDAI) > 220 and £450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of ami¬ nosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to re¬ ceive at least one of these medications. Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naive patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg HUMIRA at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2 Clinical results were assessed at Week 4. In the second induction study, Study CD-II, 325 patients who had lost response to. or were intolerant to, previous in¬ fliximab therapy were randomized to receivo.eilher 160 mg HUMIRA at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4 Maintenance of clinical remission was evaluated in Study CD-III. In this study. 854 patients with active disease re¬ ceived open-label HUMIRA. 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg HUMIRA every other week, 40 mg HUMIRA every week, or placebo The total study duration was 56 weeks Patients in clinical response (decrease in CDAI >70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4. Induction of Clinical Remission A greater percentage of the patients treated with 1BO/80 mg HlTMIRA achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were

Information on the AbbVis, Inc. products listed on thsss pages is from ths prescribing information in usa as of July 31. 2015 For mors information, plassa visit rxabbvia.com or call 1-800-633-9110.

Free mobile PDR app for fast drug references on Apple or Android devices

468/ABBVIE • HUMIRA

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard Table 10. Components of Ankylosing Spondylitis Disease Activity

Placebo N=107 Baseline mean Week 24 mean ASAS 20 Response Criteria* Patient's Global Assessment of Disease Activity"* Total back pain* Inflammation1’BASFF* BASDAI'1 score* BASMI1’ score* Tragus to wall (cm) Lumbar flexion (cm) Cervical rotation (degrees) Lumbar side flexion (cm) Intermalleolar distance (cm) CRP'*

HUMIRA N=208 Baseline mean Week 24 mean

65

60

63

38

67 6.7 56 6.3 4.2 15.9 4.1 42.2 8.9 92.9 2.2

58 5.6 51 5.5 4.1 15.8 4.0 42.1 9.0 94.0 2.0

65 6.7 52 6.3 3.8 15.8 4.2 48.4 9.7 93.5 1.8

37 3.6 34 3.7 3.3 15.4 4.4 51.6 11.7 100.8 0.6

Percent of subjects with at least a 20% and 10-unit improvement measured on a Visual Analog Scale (VAS) with 0 = “none" and 100 = “severe” b mean of questions 5 and 6 of BASDAI (defined in ‘d’) 1 Bath Ankylosing Spondylitis Functional Index d Bath Ankylosing Spondylitis Disease Activity Index * Bath Ankylosing Spondylitis Metrology Index r C-Reactive Protein (mg/dL) * statistically significant for comparisons between HUMIRA and placebo at Week 24

Table 11. Induction of Clinical Remission in Studies CD-I and CD-II (Percent of Patients) CD-I Placebo N=74

CD-II

HUMIRA 160/80 mg N=76

Placebo

HUMIRA 160/80 mg

N=166

N=159

At both Weeks 26 and 52, the proportion of patients in clin¬ ical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Ta¬ ble 13). The recommended maintenance regimen is 20 mg every other week for patients weighing < 40 kg and 40 mg every other week for patients weighing > 40 kg. Every week dosing is not the recommended maintenance dosing regi¬ men /see Dosage and Administration (2.4)]. Table 13. Clinical Remission and Clinical Response in Study PCD-I Low Maintenance Dose' (20 or 10 mg every other week)

12% 34%

36%* 58%“

"

7% 34%

21%* 52%“

Clinical remission is CDAI score < 150; clinical response is decrease in CDAI of at least 70 points. pcO.OOl for HUMIRA vs. placebo pairwise comparison of proportions p10'? body surface area * BSA> involvement. Physician's Global Assessment (PGA) of at least moderate disease se¬ verity, and Psoriasis Area and Severity Index (PASI) 212 within three treatment periods. In period A, patients re¬ ceived placebo or HUMIRA at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week start¬ ing at Week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75*4 relative to base¬ line. entered period B and received open-label 40 mg HUMIRA every other week. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 re¬ sponse at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to re¬ ceive 40 mg HUMIRA every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe" (41% l to “very severe’ (6%), Study Ps-II evaluated 99 patients randomized to HUMIRA and 48 patients randomized to placebo with chronic plaque psoriasis with >10' < BSA involvement and PASI >12. Pa¬ tients received placebo, or an initial dose of 80 mg HUMIRA at Week 0 follow'ed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score rangid from “moderate” (4191) to “severe" (51%) to “very se¬ vere” (8%). Studies Ps-I and II evaluated the proportion of patients who achieved “clear" or “minimal” disease on the 6-point PGA scale and the proportion of patients who achieved a reduc¬ tion in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 15 and 16). Additionally. Study Ps-I evaluated the proportion of sub¬ jects who maintained a PGA of “clear" or “minimal" disease or a PASI 75 response after Week 33 and on or before Week 52.

Table 14. Induction of Clinical Remission in Studies UC-I and UC-II and Sustained Clinical Remission in Study UC-II (Percent of Patients) Study UC-I

PGA: Clear or minimal" PASI 75

N = 398

506 (62%) 578(71%)

17(4%) 26 (7% )

HUMIRA

N=130

160/80 mg

Treatment Difference

N=130

195% Cl)

9.2%

18.5%

9.3%* (0.9%, 17.6%)

9.3%

16.5%

N/A

N/A

N/A

4.1%

8.5%

randomized to placebo based on maintenance of PGA of “clear” or “minimal" disease (68% vs. 28%) or a PASI 75 (79% ns. 43%). A total of 347 stable responders participated in a with¬ drawal and retreatment evaluation in an open-label exten¬ sion study. Median time to relapse (decline to PGA “moder¬ ate” or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of HUMIRA, then 40 mg eow beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal". 15

REFERENCES

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Inci¬ dence Crude Rates, 11 Registries, 1993-2001. 2. Hyams JS, Ferry GD. Mandel FS, et al. Development and validation of a pediatric Crohn’s disease activity index. J Pediatr Gastroenterol Nutr. 1991:12:439-447. 16

HOW SUPPLIED/STORAGE AND HANDLING

HUMIRA' (adalimumab) is supplied as a preservative-free, sterile solution for subcutaneous administration. The fol¬ lowing packaging configurations are available. • HUMIRA Pen Carton

HUMIRA is dispensed in a carton containing two alcohol preps and two dose trays Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge V4 inch needle, providing 40 mg/0.8 mL of HUMIRA. The NDC number is 00744339-02. • HUMIRA Pen - Crohn's Disease/Ulcerative Colitis Starter Package

* Clear = no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some w hite coloration, plus or minus up to red coloration

HUMIRA is dispensed in a carton containing 6 alcohol preps and 6 dose trays (Crohn's Disease/Ulcerative Colitis Starter Package). Each dose tray consists of a single-use pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge Vi inch needle, providing 40 mg/0.8 mL of HUMIRA. The NDC number is 0074-4339-06. •

HUMIRA Prefilled Syringe - Pediatric Crohn's Disease Starter Package (6 count)

HUMIRA is dispensed in a carton containing 6 alcohol preps and 6 dose trays (Pediatric Starter Package). Each dose tray consists of a single-use, 1 mL prefilled glass sy¬ ringe with a fixed 27 gauge Vi inch needle, providing 40 mg/0.8 mL of HUMIRA The NDC number is 00743799-06.

Table 16. Efficacy Results at 16 Weeks in Study Ps-II Number of Patients 1%)

•

HUMIRA Prefilled Syringe - Pediatric Crohn's Disease Starter Package (3 count)

PGA: Clear or minimal*. , PASI 75

HUMIRA 40 mg every other week N = 99

Placebo

70(71%) 77 (78%)

5(10%) 9(19%)

N = 48

* Clear = no plaque elevation, no scale, plus or minus hyperpigmenlation or diffuse pink or red coloration Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration

Placebo N=246

HUMIRA

Treatment Difference (95% Cl)

160/80 mg N=248

7.2%* (1.2%, 12 9%) 4.4% * (0.1%, 8.6%)

Clinical remission is defined as Mayo score < 2 with no individual subscores > 1. CI=Confidence interval * p 15 kg to 40 kg is 10/2.5 mg/kg given twice daily. Table 5 summarizes the recommended daily dosing regimen for pediatric pa¬ tients 6 months to 18 years.

of 100/25 mg Tablets Twice Daily

15 to 20

>0.6 to < 0.8

2

>20 to 30

>0.8 to < 1.2

3

>30 to 45

>1.2 to 1.7

5 /see Dosage and Administration (2.2)1

>45 Given twice daily

Recommended number

Area (m2)*

Frequency

* KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet. F’lease refer to the individual product labels for appropriate dosing in children. 2.4

Dosage Recommendations in Pregnancy

Administer 400/100 mg of KALETRA twice daily in preg¬ nant patients with no documented lopmavir-associated re¬ sistance substitutions. Once daily KALETRA dosing is not recommended in pregnancy /see Use in Specific Populations (8.1) and Clinical Pharmacology 112.3)1. • There are insufficient data to recommend dosing in preg¬ nant women with any documented lopinavir-associated re¬ sistance substitutions. • No dosage adjustment of KALETRA is required for pa¬ tients during the postpartum period. • Avoid use of KALETRA oral solution in pregnant women /see Use in Specific Populations 250 mg/dL

Uric Acid

> 12 mg/dL

SCOT/ AST2

> 180 U/L

SGPT/ ALT2

>215 U/L

4%

4%

11%

1%

1%

GGT

>300 U/L

N/A

N/A

10%

N/A

N/A

Tbtal Cholesterol

>300 mg/dL

9%

5%

27%

4%

3%

Triglycerides

>750 mg/dL

9%

1%

29%

3%

6%

Amylase

>2 x ULN

3%

2%

4%

N/A

N/A

Lipase

>2 x ULN

N/A

N/A

N/A

3%

5%

Chemistry

Low

Calculated Creatinine Clearance

, anemia (N=2i, high potassium (N=2), and low Laboratory Abnormalities in Adults sodium (N=2). The percentages of adult patients treated with combination KALETRA oral solution and soft gelatin capsules dosed at •therapy with Grade 3-4 laboratory abnormalities are pre¬ higher than recommended doses including 400/100 mg/m3 sented in Table 10 l treatment-naive patients) and Table 11 (without concomitant NNRTI) and 480/120 mg/mJ iwith (treatment-experienced patients). concomitant NNRTI) have been studied in 26 pediatric pa¬ (See table 10 at top of previous page] tients 7 to 18 years of age in Study 1038. Patients also had lSee table 11 abovoi saquinavir mesylate added to their regimen at Week 4. Adverse Reactions in Pediatric Patients Rash (12**), blood cholesterol abnormal (12*4) and blood tri¬ KALETRA oral solution dosed up to 900/75 mg/m2 has been glycerides abnormal (1241) were the only adverse reactions studied in 100 pediatric patients 6 months to 12 years of reported in greater than 10% of subjects. Adverse drug re¬ age. The adverse reaction profile seen during Study 940 was actions of moderate to severe intensity occurring in 2 or similar to that for adult patients. more subjects included rash (N=8>, blood triglycerides ab¬ Dysgeusia (22% 1, vomiting (21%), and diarrhea (12*41 were normal (N=3), and electrocardiogram QT prolonged (Nz2). the most common adverse reactions of any severity reported Both subjects with QT prolongation had additional predis¬ in pediatric patients treated with combination therapy for posing conditions such as electrolyte abnormalities, concom¬ up to 48 weeks in Study 940. A total of 8 patients experi¬ itant medications, or pre-existing cardiac abnormalities. enced adverse reactions of moderate to severe intensity. The Laboratory Abnormalities m Pediatric Patients adverse reactions meeting these criteria and reported for The percentages of pediatric patients treated with combina¬ the 8 subjects include: hypersensitivity /characterized by fe¬ tion therapy including KALETRA with Grade 3-4 laboratory ver. rash and jaundice), pyrexia, viral infection, constipa¬ tion. hepatomegaly, pancreatitis, vomiting, alanine amino- 1 abnormalities are presented in Table 12. hypertension*

47

1.8

Table 12. Grade 3-4 Laboratory Abnormalities Reported in > 2% Pediatric Patients in Study 940 Variable

Limit1

KALETRA Twice Daily + RTIs (N s 100)

Chemistry

High

•

3%

Sodium

> 149 mEq/L

Tbtal Bilirubin

> 3.0 x ULN

3%

SGOT/AST

> 180 U/L

8%

SGPT/ALT

> 215 U/L

7%

Tbtal Cholesterol

> 300 mg/dL

3%

Amylase

> 2.5 x ULN

7%*

Chemistry

Sodium

Low

< 130 mEq/L

3%

Information on the AbbVie. Inc products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, pleasa visit rxabbvie com or call 1 800-633 9110

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480/ABBVIE • KALETRA Table 13. Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name

Platelet Count

Clinical Comments

Effect on Concentration of Lopinavir or Concomitant Drug

Neutrophils

HIV-1 Antiviral Agents HIV-1 Protease Inhibitor: fosamprenavir/ritonavir

Hematology

An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

X amprenavir i lopinavir

HIV-1 Protease Inhibitor: indinavir*

T ipdinavir

Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)1. KALETRA once daily has not been studied in combination with indinavir.

HIV-1 Protease Inhibitor: nelfinavir*

T nelfinavir t M8 metabolite of nelfinavir 1 lopinavir

KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

HIV-1 Protease Inhibitor: ritonavir*

T lopinavir

Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor: saquinavir*

T saquinavir

The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).

HTV-1 Protease Inhibitor: tipranavir

1 lopinavir AUC and Cmin

HIV CCR5 - Antagonist: maraviroc

T maraviroc

Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).

Non-nucleoside Reverse Transcriptase Inhibitor: etravirine

l etravirine

Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, no dose adjustment is required.

Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine*

1 lopinavir

KALETRA dose increase is recommended in all patients [see Dosage and Administration (2) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2) and Clinical Pharmacology (12.3)1.

Low

< 50 x 109/L

4%

< 0.40 x 109/L

2%

1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase. 6.2

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of KALETRA. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or es¬ tablish a causal relationship to KALETRA exposure. Body as a Whole Redistribution/accumulation of body fat has been reported [see Warnings and Precautions (5.10)]. Cardiovascular Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, tor¬ sades (torsade) de pointes [see Warnings and Precautions (5.5, 5.6)]. Skin and Appendages Toxic epidermal necrolysis (TEN), Stevens-Johnson syn¬ drome and erythema multiforme. 7

DRUG INTERACTIONS

See also Contraindications (4), Warnings and Precautions (5.1), Clinical Pharmacology (12.3) 7.1

Potential for KALETRA to Affect Other Drugs

Lopinavir/ritonavir is an inhibitor of CYP3A and may in¬ crease plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metab¬ olized by CYP3A and have high first pass metabolism ap¬ pear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co¬ administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma con¬ centrations are associated with serious and/or lifethreatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjust¬ ment or additional monitoring as shown in Table 13. Additionally, KALETRA induces glucuronidation. 7.2

Potential for Other Drugs to Affect Lopinavir

Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concen¬ trations and reduce KALETRA’s therapeutic effect. Al¬ though not observed in the KALETRA/ketoconazole drug in¬ teraction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. 7.3 Established and Other Potentially Significant Drug Interactions

Table 13 provides a listing of established or potentially clin¬ ically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction /see Clinical Pharmacology (12.3) for magnitude of interaction). (See table 13 on this page and pages 481 through 4831 7.4

Drugs with No Observed or Predicted Interactions

with KALETRA

Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine

T lopinavir

Appropriate doses of the combination with respect to safety and efficacy have not been established.

Non-nucleoside Reverse Transcriptase Inhibitor: rilpivirine

T rilpivirine

No dose adjustment is required.

Nucleoside Reverse Transcriptase Inhibitor: didanosine

KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).

Nucleoside Reverse Transcriptase Inhibitor: tenofovir

T tenofovir

KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.

Nucleoside Reverse Transcriptase Inhibitors: abaca vir zidovudine

l abacavir i zidovudine

KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. 1Table continued on next page)

Drug interaction or clinical studies reveal no clinically sig¬ nificant interaction between KALETRA and desipramine (CYP2D6 probe), pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, or ranitidine. Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole. 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors preg¬ nancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.791 in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program 'MACDP). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal de¬ velopmental toxicities occurred in rats administered mater¬ nally toxic doses.

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KALETRA • ABBVIE/481

Table 13 tcont.) Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name

Effect on Concentration of Lopinavir or Concomitant Drug

Clinical Comments

Other Agents Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine

T antiarrhythmics

Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.

Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib

T anticancer agents

Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently wdth vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulants: warfarin, rivaroxaban

T rivaroxaban

Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.

Anticonvulsants: carbamazepine, phenubarbital, phenytoin

i lopinavir -1 phenytoin

KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital. or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.

Anticonvulsants: lamotrigine, valproate

l lamotrigine i or - * valproate

Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.

Antidepressant: bupropion

A bupropion -l active metabolite, hydroxybupropion

Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant: trazodone

T trazodone

Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Anti-infective: clarithromycin

T clarithromycin

For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL,-K 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL,-r < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. (Thble continued on next page)

Clinical Considerations Aw Adjustments During Pregnancy and the Postpartum Period Administer 400/100 mg of KALETRA twice daily in preg¬ nant patients with no documented lopinavir-associated re¬ sistance substitutions /see Dosage and Administration 12.4) and Clinical Pharmacology 112.3)1. TTiere are insufficient data to recommend KALETRA dosing for pregnant patients

with any documented lopinavir-associated resistance sub¬ stitutions. No dose adjustment of KALETRA is required fur patients during the postpartum period. Once daily KALETRA dosing is not recommended in preg¬ nancy. Avoid use of KALETRA oral solution dunng pregnancy due to the alcohol content. KALETRA oral solution contains the

excipients alcohol (42.4% vA) and propylene glycol (15.3% w/v>. Data Human Data KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial Isee Clinical Pharmacology (12.31J. No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data. Antiretroviral Pregnancy Registry Data: Based on pro¬ spective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regi¬ mens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. back¬ ground rate (MACDP). For both lopinavir and ritonavir, suf¬ ficient numbers of first trimester exposures have been mon¬ itored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. Animal Data Embryonic and fetal developmental toxicities (early resorp¬ tion, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossi¬ fication delays) occurred in rats at a maternally toxic dos¬ age. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended ther¬ apeutic dose (400/100 mg twice daily). In a peri- and post¬ natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred. No embryonic and fetal developmental toxicities were ob¬ served in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fo)d for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infante to avoid risking postnatal transmission of HIV-1. Because of the potential for HIV-1 transmission in breastfed infante, advise women not to breastfeed. 8.4

Pediatric Use

The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be admin¬ istered once daily in pediatric patients. An open-label, multi-center, dose-finding trial was per¬ formed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m* twice daily plus two NRTIs in HIV-infected infante £14 days and < 6 months of age. Results revealed that infante younger than 6 months of age generally had lower lopinavir AUC|2 than older children (6 months to 12 years of age), however, des|iite the lower lopinavir drug ex¬ posure observed, antiviral activity was demonstrated as re¬ flected in the proportion of subjects who achieved HIV-1 RNA -pynmidineacetamide. Its mo¬ lecular formula is C^H^N^Oj, and its molecular weight is 628.80. Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Lopinavir has the following structural formula: (See first figure at top of third column on next page] Ritonavir is chemically designated as 10-hydroxy-2-methyl5-< 1-melhylethyl i-l- l2-< 1-methy lethyl >-4-thiazolyl|-3,6-di-

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KAIETRA • AB8V1E/483

Table 13 (cont.l Established and Other Potentially Significant Drug Interactions Concomitant Drug Class:

Effect on Concentration

Drug Name

of Lopinavir or

Clinical Comments

Concomitant Drug

Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone

1 lopinavir T glucocorticoids

Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Dihydropyridine Calcium Channel Blockers: e g. felodipine, nifedipine, nicardipine

T dihydropyridine calcium channel blockers

Caution is warranted and clinical monitoring of patients is recommended.

Disulfiram/metronidazole

KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Endothelin Receptor Antagonists: bosentan

T bosentan

Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

HCV-Protease Inhibitor boceprevir

i lopinavir I boceprevir l ritonavir

It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures lsee Clinical Pharmacology (12.3)].

HCV-Protease Inhibitor: simeprevir

t simeprevir

It is not recommended to co-administer KALETRA and simeprevir.

HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin

T atorvastatin T rosuvastatin

Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.

Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus

T immunosuppressants

Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide

T glucocorticoids

Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered w'ith fluticasone propionate or budesonide.

Long-acting beta-adrenoceptor Agonist: salmeterol

T salmeterol

Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol. including QT prolongation, palpitations and sinus tachycardia.

Narcotic Analgesics: methadone,* fentanyl

i methadone * fentanyl

Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression i is recommended when fentanyl is concomitantly administered with KALETRA.

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA

(Table continued on next page)

oxo-8, ll-bis( phenvlmethyD-2,4,7,12-tetraazatridecan-l 3-oic arid, 5-thiazolylmethyl ester. |5S-|. Its molecular formula is CnH^N^OjS.,, and its molecular weight is 720.95. Ritonavir is a white to light tan powder It

is freely soluble in methanol and ethanol, soluble in isopro¬ panol and practically insoluble in water Ritonavir has the following structural formula: [See second figure at top of next columnl

KALETRA tablets are available for oral administration in two strengths: • Yellow tablets containing 200 mg of lopmavir and 50 mg of ritonavir • Pale yellow tablets containing 100 mg of lopinavir and 25 mg of ritonavir. The yellow, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate. colloidal silicon dioxide, and sodium stearyl fiimarate. The following are the ingredients in the film coating: hypromellosc, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon di¬ oxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80. The pale yellow, 100 mg lopinavir and 25 mg ritonavir, tab¬ lets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, poly¬ ethylene glycol 3350, and yellow ferric oxide E172. KALETRA oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup. Magnaswcet-110 flavor, menthol, natural & artificial vanilla flavor, peppermint oil, polvoxyl 40 hydrogenated castor oil, povidone, propylene glycol, sac¬ charin sodium, sodium chloride, sodium citrate, and water. KALETRA oral solution contains 42.4alcohol 400 copiea/mL at Week 24, 32. 40 and/or 48 were analyzed. No evidence of resistance to KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). Evidence of genotypic re¬ sistance to nelfinavir, defined as the presence of the D30N and/or L90M substitution in HIV-1 protease, was observed

Dose of KALETRA

Pitavastatin6

Ranitidine

1.03

*

0.90 (0.85, 0.95)

0.82 (0.74, 0.91)

fTable continued on next page)

in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral treat¬ ment naive pediatric patients (Study 9401 appears to be con¬ sistent with that seen in adult patients (Study 863). Resistance to KALETRA has been noted to emerge in pa¬ tients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treat¬ ment naive and protease inhibitor experienced patients, iso¬ lates from 4 of 23 patients with quantifiable (> 400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly re¬ duced susceptibility to lopinavir compared to the corre¬

sponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhib¬ itor iindinavir, nelfinavir. or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavtri. All four of these pa-

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486/ABBVIE • KALETRA tients had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA ther¬ apy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resis¬ tance. However, there are insufficient data at this time to identify patterns of lopinavir resistance-associated substitu¬ tions in isolates from patients on KALETRA therapy. The assessment of these patterns is under study. Cross-resistance - Preclinical Studies Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA ther¬ apyThe antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a sin¬ gle protease inhibitor was determined. Isolates that dis¬ played > 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed < 4-fold reduced suscepti¬ bility to lopinavir. Isolates with > 4-fold reduced susceptibil¬ ity to indinavir (n = 16) and ritonavir (n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph. Clinical Studies - Antiviral Activity of KALETRA in Pa¬ tients with Previous Protease Inhibitor Therapies The clinical relevance of reduced susceptibility in cell cul¬ ture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatmentexperienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study. Virologic response to KALETRA has been shown to be af¬ fected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/ R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 16 shows the 48-week viro¬ logic response (HIV-1 RNA cell which help fight off other infections. Reducing the amount of HIV and increas¬ ing the CD4 (T) cell count may improve your immune sys¬ tem. This may reduce your risk of death or infections that can happen when your immune system is weak lopportunistic infections). It is not known if KALETRA is safe and effective in children under 14 days old

KALETRA does not cure HIV infection or AIDS. People tak¬ ing KALETRA may develop infections or other conditions associated with HIV infection, including opportunistic infec¬ tions (for example, pneumonia and herpes virus infections). Avoid doing things that can spread HIV-1 infection to oth¬ ers: • Do not share needles or other injection equipment. • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Ask your doctor if you have any questions on how to prevent passing HIV to other people. Who should not take KALETRA? Do not take KALETRA if you take any of the following medicines: • alfuzosin (Uroxatral®) • cisapride (Propulsid®, Quicksolv®) • ergot containing medicines including » ergotamine tartrate (Cafergot®, Migergot®, Ergomar®, Ergostat®, Medihaler®, Ergotamine, Wigraine®, Wigrettes®) 0 dihydroergotamine mesylate (D.H.E. 45®, Migranal®) ° methylergonovine (Methergine®) • lovastatin (Advicor®, Altoprev®, Mevacor®) • midazolam oral syrup • pimozide (Orap®) • rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) • sildenafil (Revatio®), when used for the treatment of pul¬ monary arterial hypertension • simvastatin (Zocoi , Vytorin®, Simcor®) • St. John’s Wort (Hypericum perforatum) • triazolam (Halcion®) Serious problems can happen if you or your child take any1 of, the medicines listed above with KALETRA. • Do not take KALETRA if you are allergic to lopinavir, ritonavir or any of the ingredients in KALETRA. See the end of this Medication Guide for a complete list of ingre¬ dients in KALETRA. What should I tell my doctor before taking KALETRA? KALETRA may not be right for you. Tell your doctor about all your medical conditions, including if you: • have any heart problems, including if you have a condition called Congenital Long QT Syndrome. • have or had pancreas problems. • have liver problems, including Hepatitis B or Hepatitis C. • have diabetes. • have hemophilia. People who take KALETRA may have increased bleeding. • have low potassium in your blood. • are pregnant or plan to become pregnant. Taking KALETRA during pregnancy has not been associated with an increased risk of birth defects. You and your doctor should decide if KALETRA is right for you. Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during preg¬ nancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to • your doctor about how you can take part in this registry. • are breastfeeding or plan to breastfeed. Do not breastfeed if you take KALETRA • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. • Talk to your doctor about the best way to feed your baby. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Many medicines interact with KALETRA. Do not start taking a new medicine without tell¬ ing your doctor or pharmacist. Your doctor can tell you if it is safe to take KALETRA with other medicines. Your doctor may need to change the dose of other medicines while you take KALETRA. Especially tell your doctor if you take: • medicine to treat HIV • estrogen-based contraceptives (birth control pills and patches). KALETRA may reduce the effectiveness of estrogen-based contraceptives. During treatment with KALETRA, you should use a different type or an extra form of birth control. Talk to your doctor about what types of birth control you can use to prevent pregnancy while taking KALETRA. • medicines to prevent organ transplant rejection • medicines to treat cancer • amiodarone (Cordarone* Pacerone®) • atorvastatin (Lipitor®) • atovaquone (Marlarone®, Mepron®) • avanafil (Stendra®), sildenafil (Viagra®), tadalafil j (Cialis®), or vardenafil (Levitra®) for the treatment of erec- j | tile dysfunction (ED). If you get dizzy or faint (low blood pressure), have vision changes or have an erection that j last longer than 4 hours, call your doctor or get medical help right away.

• • • •

bepridil (Bepadin®, Vascor®) boceprevir (Victrelis®) bosentan (Tracleer®) budesonide (Rhinocort®, Symbicort®, Pulmicort®, Entocort EC®) • bupropion (Aplenzin®, Forfivo XL®, Wellbutrin®, Zyban®) • carbamazepine (Carbatrol®, Epitol®, Equetro®, Tbgretol®) • clarithromycin (Biaxin®, Prevpac®) • colchicine (Colcrys®) • dexamethasone (Maxidex®, Ozurdex®) • disulfiram • felodipine • fentanvl (Abstral®, Actio®, Duragesic®, Fentora®, Lazanda , Onsolis®, Subsys®) • fluticasone (Cutivate®, Flonase®, Flovent®, Flovent Diskus®, Flovent HFA®, Veramyst®) • itraconazole (Onmel® Sporanox®) • ketoconazole (Extina®, Ketozole®, Nizoral®, Xolegel®) • lamotrigine (Lamictal®) • lidocaine • methadone hydrochloride (Dolphine hydrochloride, Methadose®) • metronidazole • nicardipine (Cardene®) • nifedipine (Adalat CC®, Afeditab CR®, Procardia®) • phenobarbital • phenytoin (Dilantin®, Phenytek®) • prednisone • quinidine (Quinidex®) • quetiapine (Seroquel®) • rifabutin (Mycobutin®) • rivaroxaban (Xarelto®) • rosuvastatin (Crestor®) • salmeterol (Serevent®) or salmeterol when taken in com¬ bination with fluticasone (Advair Diskus®, Advair HFA®i • simeprevir (Olysio®) • tadalafil (Adcirca®) for the treatment of pulmonary arte¬ rial hypertension • trazodone (Oleptro®) • valproate (Depakote®, Depakene®, Depacon*) • voriconazole (Vfend®) , • warfarin (Coumadin®, Jantoven®! KALETRA should not be administered once daily in combi¬ nation with carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®), phenobarbital, or phenytoin (Dilantin®, Phenytek®) Ask your doctor or pharmacist if you are not sure if your medicine is one that is listed above. Know all the medicines that you take. Keep a list of them with you to show doctors and pharmacists when you get a new medicine. If you are not sure if you are taking a medicine above, ask your doctor. How should I take KALETRA? • Take KALETRA every day exactly as prescribed by your doctor. • It is very important to set up a dosing schedule and follow it every day. • Do not change your treatment or stop treatment without first talking with your doctor. • KALETRA tablets should not be taken 1 time each day if you are pregnant. You should not take KALETRA oral so¬ lution if you are pregnant. • Swallow KALETRA tablets whole. Do not chew, break, or crush KALETRA tablets. • KALETRA tablets can be taken with or without food. • If you are taking both didanosine (Videx* i and KALETRA: c didanosine can be taken at the same time as KALETRA tablets, without food. ° take didanosine either one hour before or two hours after taking KALETRA oral solution. • Do not miss a dose of KALETRA. This could make the vi¬ rus harder to treat. If you forget to take KALETRA, take the missed dose right away. If it is almost time for your next dose, do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time. Do not take more than one dose of KALETRA at one time. • If you take more than the prescribed dose of KALETRA. call your doctor or go to the nearest emergency room right away. • Take KALETRA oral solution with food to help it work bet ter. • If your child is prescribed KALETRA, tell your doctor if your child's weight changes. • KALETRA should not be given one time each day in chil¬ dren When giving KALETRA to your child, give KALETRA exactly as prescribed. • KALETRA oral solution contains propylene glycol and a large amount of alcohol. KALETRA oral solution should not be given to babies younger than 14 days of age unless your doctor thinks it is right for your baby. ° If a young child drinks more than the recommended dose, it could make them sick. Contact your local poison control center or emergency room right away.

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Look for PDR drug information and services in your EHR 0 Talk with your doctor if you take or plan to take metro¬ nidazole or di.sulfiram. You can have severe nausea and vomiting if you take these medicines with KALETRA. • When your KALETRA supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of KALETRA. The amount of HIV-1 virus in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to KALETRA and become harder to treat. What are the possible side effects of KALETRA? KALETRA can cause serious side effects, including: • See "What is the most important information I should know about KALETRA?" • Inflammation of the pancreas (pancreatitis). Some people who take KALETRA get inflammation of the pancreas which may be serious and cause death. You have a higher chance of getting pancreatitis if you have had it before. Ttoll your doctor if you have nausea, vomiting, or abdomi¬ nal pain while taking KALETRA. These may be signs of pancreatitis. • Liver problems. Liver problems, including death, can hap¬ pen in people who take KALETRA Your doctor should do blood tests before and during your treatment with KALETRA to check your liver function. Some people with liver disease such as Hepatitis B and Hepatitis C who take KALETRA may have worsening liver disease. Tell your doctor right away if you have any of these signs and symp¬ toms of liver problems: ° loss of appetite “yellow skin and whites of eyes (jaundice) °dark-colored urine »pale colored stools °itchy skin • stomach area (abdominal) pain. • Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including KALETRA get new or more serious diabetes, or high blood sugar. Tell your doctor if you notice an increase in thirst or urinate often while taking KALETRA. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medi¬ cines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your doctor right away if you start having new symptoms after starting your HIV medicine. • Increases in certain fat (triglycerides and cholesterol) lev¬ els in your blood Large increases of triglycerides and cho¬ lesterol can be seen in blood test results of some people who take KALETRA. Your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking KALETRA and during your treatment. • Changes in body fat. Changes in body fat in some people who take antiretroviral therapy. These changes may in¬ clude increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the trunk. Loss of fat from the legs, arms and face may also happen. The cause and long-term health effects of these conditions are not known at this time. • Increased bleeding for hemophiliacs Some people with hemophilia have increased bleeding with protease inhibi¬ tors including KALETRA. • Allergic reactions. Skin rashes, some of them severe, can occur in people who take KALETRA. Tell your doctor if you had a rash when you took another medicine for your HIV-1 infection or if you notice any skin rash when you take KALETRA. • Babies taking KALETRA oral solution may have side ef¬ fects. KALETRA oral solution contains alcohol and propyl¬ ene glycol. Call your doctor right away if your baby ap¬ pears too sleepy or their breathing has changed. Common side effects of KALETRA include: • diarrhea • nausea • increased fats in blood (triglycerides or cholesterol) • vomiting Ibll your doctor about any side effect that bothers you or that does not go away. These are not all of the possible side effects of KALETRA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store KALETRA? KALETRA tablets: • Store KALETRA tablets at room temperature, between 59*F to 86*F (15*C to 30'C). • Do not keep KALETRA tablets out of the container it comes in for longer than 2 weeks, especially in areas where there is a lot of humidity. Keep the container closed tightly. KALETRA oral solution: • Store KALETRA oral solution in a rotrigrrator. between 36°F to 46*F (2*C to 8*0. KALETRA oral solution that is kept refrigerated may be used until the expiration date printed on the label.

LUPANETA PACK 3.75 MG • ABBVIE/491 • KALETRA oral solution that is stored it room tempera¬ ture (less than 77 “F or 25*C) should be used within 2 months. • Keep KALETRA away from high heat. Throw away any medicine that is out of date or that you no longer need. Keep KALETRA and all medicines out of the reach of chil¬ dren. General information about KALETRA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KALETRA for a condition for which it was not prescribed. Do not give KALETRA to other people, even if they have the same con¬ dition you have. It may harm them. This Medication Guide summarizes the most important in¬ formation about KALETRA. If you would like more informa¬ tion, talk with your doctor. You can ask your pharmacist or doctor for information about KALETRA that is written for health professionals. For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.com. What are the ingredients in KALETRA?

Active ingredients: lopinavir and ritonavir Inactive ingredients: KALETRA 200 mg

lopinavir and 50 mg

ritonavir

tab¬

copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating con¬ tains: hypromello.se, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide 172, and polysorbate 80. lets:

KALETRA

100 mg

lopinavir

and 25 mg

ritonavir tab¬

copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating con¬ tains: polyvinyl alcohol, titanium dioxide, talc, polytheylene glycol 3350, and yellow ferric oxide El72. KALETRA oral solution: acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fruc¬ tose corn syrup, Magnasweet 110 flavor, menthol, natural and artificial vanilla flavor, peppermint oil, polyoxyl 40 hy¬ drogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water. lets:

KALETRA oral solution contains 42 4% alcohol (v/v). "See How should I take KALETRA?".

This Medication Guide has been approved by the U.S. Food and Drug Administration. KALETRA Tablets. 200 mg lopinavir and 50 mg ritonavir Manufactured by AbbVie LTD, Barceloneta, PR 00617 for AbbVie Inc., North Chicago, IL 60064 USA KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and KALETRA Oral Solution AbbVie Inc., North Chicago, IL 60064 USA Revised: June 2015 The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. © 2015 AbbVie Inc. All rights reserved. 03-B159 Shown in Product Identification Guide, page 303

LUPANETA PACK

It

(leuprolide acetate for depot suspension; norethindrone acetate tablets) co-packaged for intramuscular use and for oral use,

-DOSAGE AND ADMINISTRATION• Leuprolide acetate for depot suspension 3.75 mg given by a healthcare provider as a single intramuscular injection every month for up to six injections (6 months of therapy) (2.1) • Norethindrone acetate 5 mg tablets taken orally by the patient once per day for up to 6 months (2.1) • If endometriosis symptoms recur after initial course of therapy, consider retreatment for up to another six months (2.1) • Assess bone density before retreatment begins 12.1, 5.1) • Reconstitute leuprolide acetate prior to use, see important administration instructions (2.3) -DOSAGE FORMS AND STRENGTHS• Leuprolide acetate for depot suspension 3.75 mg svringe (3) • Norethindrone acetate 5 mg tablets, 30 count bottle (3) -CONTRAINDICATIONS| • Hypersensitivity to GnRH, GnRH agonist or any of the ex¬ cipients in leuprolide acetate for depot suspension or norethindrone acetate (4) • Undiagnosed abnormal uterine bleeding (4) • Pregnancy or suspected pregnancy (4. 8.1) • Women who are breast-feeding (4) • Known, suspected or history of breast or other hormonesensitive cancer(4) • Thrombotic or thromboembolic disorders i4) • Liver tumors or liver disease (4) -WARNINGS AND PRECAUTIONS• Loss of bone mineral density: do not use for more than two six-month treatment courses. (1, 2.1, 5.1) • Exclude pregnancy before starting treatment and discon¬ tinue use if pregnancy occurs; use non-hormonal methods of contraception only. (5.2) • Discontinue in case of sudden loss of vision or onset of proptosis, diplopia or migraine. (5.3) • Carefully observe patients with history of depression and discontinue the drug if the depression recurs to a serious degree. (5.4) • Assess and manage risk factors for cardiovascular disease before starting LUPANETA PACK. (5.6) -ADVERSE REACTIONSLeuprolide acetate for depot suspension: Most common re¬ lated adverse reactions (>10%) were hot flashes/sweats, headache/migraine, depression/emotional lability, nausea/ vomiting, nervousness/anxiety, insomnia, pain. acne, asthe¬ nia. vaginitis, weight gain, constipation/diarrhea (6.1) Progestins: breakthrough bleeding, spotting (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.f da. gov/med watch -USE IN SPECIFIC POPULATIONSPediatric; Safety and effectiveness of LUPANETA PACK has not been established in pediatric patients. (.8.4) Geriatric: LUPANETA PACK has not been studied in women over 65 years of age and is not indicated in this pop¬ ulation. (8.5) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised 10/2013 FULL PRESCRIBING INFORMATION: CONTENTS*

1 2

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Different Formulations of Leuprolide Acetate 2.3 Reconstitution and Administration fur Injec¬ tion of Leuprolide Acetate DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Loss of Bone Mineral Density 5.2 Pregnancy Risk 5.3 Visual Abnormalities Clinical Depression 5.4 5.5 Serious Allergic Reactions Cardiovascular and Metabolic Disorders 5.6 5.7 Initial Flare of Symptoms 5.8 Fluid Retention Convulsions 5.9 ADVERSE REACTIONS Clinical Trials Experience 6.1 6.2 Postmarketing Experience

respectively HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LUPANETA PACK safely and effectively. See full pre¬ scribing information for LUPANETA PACK. LUPANETA PACK (leuprolide acetate for depot suspension;

3 4 5

norethindrone acetate tablets), co-packaged for intramus¬ cular use and for oral use, respectively Initial U.S. Approval: 2012

-RECENT MAJOR CHANGESWarnings and Precautions, Convulsions (5.9) 10/2013 -INDICATIONS AND USAGE-

LUPANETA PACK contains leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist and norethindrone acetate, a progestin, indicated for • Initial management of the painful symptoms of endome¬ triosis (1) • Management of recurrence of symptoms (I) Limitation.- of Use: Initial treatment course is limited to 6 months and use is not recommended longer than a total of 12 months due to concerns about adverse impact on bone mineral density (1, 2.1, 5.1)

6

Information on the AbbVie, Inc. products hsted on these pages is from the prescribing information in use as of

July

31,

2015.

For

more

information,

rxabbvie com or call 1-800-633-9110

Free mobile PDR app for fast drug references on Apple or Android devices

please

visit

Help patients save on Rx drugs: PDR.net/PharmaCYDiscountCard

492/ABBVIE • LUPANETA PACK 3.75 MG DRUG INTERACTIONS 7.1 Drug-Drug Interactions 7.2 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

Figure 1:

7

End

Front

Middle

NOTE: If a blood vessel is accidentally penetrated, as¬ pirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 2:

Figure 6: FULL PRESCRIBING INFORMATION

1

If a blood vessel is injured, blood will be visible in this section of the syringe.

INDICATIONS AND USAGE

LUPANETA PACK (leuprolide acetate for depot suspension and norethindrone acetate tablets) is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. Limitation of Use: Duration of use is limited due to con¬ cerns about adverse impact on bone mineral density [see Warnings and Precautions (5.1)]. The initial treatment course of LUPANETA PACK is limited to six months. A sin¬ gle retreatment course of not more than six months may be administered after the initial course of treatment if symp¬ toms recur. Use of LUPANETA PACK for longer than a total of 12 months is not recommended. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows: • 3.75 mg of leuprolide acetate by intramuscular injection once a month for up to six injections (6 months of therapy); to be administered by a healthcare provider • 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy The initial course of treatment with leuprolide acetate for depot suspension 3.75 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months. If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions (5.1)1. Treatment beyond two six-month courses has not been stud¬ ied and is not recommended due to concerns about adverse impact on bone mineral density. 2.2 Different Formulations of Leuprolide Acetate Due to the specific release characteristics of the 1-month depot formulation, IICPs should not administer 3 doses of the 3.75 mg 1-month formulation simultaneously to mimic the pharmacological profile of the 11.25 mg 3-month formu¬ lation. 2.3 Reconstitution and Administration for Injection of

8. Inject the entire contents of the syringe intramuscu¬ larly. 9. Withdraw the needle. Once the syringe has been with¬ drawn, immediately activate the LuproLoc® safety de¬ vice by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the nee¬ dle is fully extended and a CLICK is heard or felt (see Figure 7).

Figure 3:

Figure 7:

or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).

Figure 4:

Leuprolide Acetate

• Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. • Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative. 5. Keep the syringe UPRIGHT. With the opposite hand 1. Visually inspect the leuprolide acetate for depot pull the needle cap upward without twisting. suspension powder. DO NOT USE the syringe if clump¬ 6. Keep the syringe UPRIGHT. Advance the plunger to ex¬ ing or caking is evident. A thin layer of powder on the pel the air from the syringe. Now the syringe is ready wall of the syringe is considered normal prior to mixing for injection. with the diluent. The diluent should appear clear. 7. After cleaning the injection site with an alcohol swab, 2. lb prepare for injection, screw the white plunger into administer the intramuscular injection by inserting the the end stopper until the stopper begins to turn (see needle at a 90 degree angle into the gluteal area, ante¬ Figure 1 and Figure 2). rior thigh, or deltoid (see Figure 5). Alternate injection ISee figure 1 above) sites. (See figure 2 at top of next columnl 3. Hold the syringe UPRIGHT. Release the diluent by Figure 5: SLOWLY PUSHING thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension , w ill appear milky. If the powder adheres to the stopper

• 10. Dispose of the syringe according to local regulations/ procedures /see References (15)]. 3

DOSAGE FORMS AND STRENGTHS

LUPANETA PACK 1-month copackaged kit contains two separate components: • Leuprolide acetate for depot suspension 3.75 mg for 1-month administration: Leuprolide acetate lyophilized powder for reconstitution with supplied diluent in a pre¬ filled dual chamber syringe • Norethindrone acetate 5 mg tablets: White to off-white oval, flat-faced beveled edged, uncoated debossed with ‘G with breakline' on one side and 304 on other side 4

CONTRAINDICATIONS

LUPANETA PACK is contraindicated in women with the following: • Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist analogs, any of the excipients in leuprolide acetate for depot suspension, or norethindrone acetate • Undiagnosed abnormal uterine bleeding • Known, suspected or planned pregnancy during the course of therapy [see Use in Specific Populations (8.1)] • Lactating women /see Use in Specific Populations (8.3)] • Known, suspected or history of breast cancer or other hormone-sensitive cancer • Current or history of thrombotic or thromboembolic disorder • Liver tumors or liver disease 5 WARNLNGS AND PRECAUTIONS 5.1 Loss of Bone Mineral Density Leuprolide acetate for depot suspension induces a hypoestregenic state that results in loss of bone mineral density (BMD), some of which may not be reversible. Concurrent

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Look for PDR drug information and services in your EHR use of norethindrone acetate is effective in reducing the loss of BMD that occurs with leuprolide acetate /see Clinical Studies U4>l. Nonetheless, duration of use of LUPANETA PACK is limited to two six-month courses of treatment due to concerns about the adverse impact on BMD. It is recom¬ mended that BMD be assessed before retreatment Retreat¬ ment with leuprolide acetate for depot suspension alone is not recommended. In women with major risk factors for decreased BMD such as chronic alcohol (> 3 units per day) or tobaccu use, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD, such as anticonvulsants or corticoster¬ oids, use of LUPANETA PACK may pose an additional risk, and the risks and benefits should be weighed carefully. 5.2

Pregnancy Risk

Visual Abnormalities

Discontinue norethindrone acetate tablets in the LUPANETA PACK pending examination if there is a sud¬ den partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. Discontinue LUPANETA PACK if examination reveals papilledema or retinal vascular lesions. 5.4

Clinical Depression

Serious Allergic Reactions

In clinical trials of LUPANETA PACK, adverse events of asthma were reported in women with pre-existing histories of asthma, sinusitis and environmental or drug allergies. Symptoms consistent with an anaphylactoid or asthmatic process have been reported postmarketing. 5.6

Controlled Study LA/Nt

N=51

N=55

%

N

%

.N

%

Any Adverse Reaction Body as a Whole

50

98

53

96

126

93

Asthenia Headache/Migraine Injection Site Reaction Pain

18 65 2 24

18 51 9 29

11 46 3 21

98

87

57

14

15

10

4 4 25

0 7 29

6 4 13

0 12

9 13

7 4

31 16 31 10 6 8 2

27 11 13 4 2 4 9

34 7 15 7 4 11 3

4 4

5 9

18 11

6 2 20

13 0 15

8 5 8

Cardiovascular System Digestive System

Altered Bowel Function (constipation. diarrhea) Changes in Appetite GI Disturbance (dyspepsia, flatulence) Nausea/Vomiting Metabolic and Nutritional Disorders

Edema Weight Gain Nervous System

Depression/Emotional Lability Dizziness/Vertigo Insomnia/Sleep Disorder Decreased Libido Memory Disorder Nervousness/Anxiety Neuromuscular Disorder ( leg cramps. paresthesia) Skin and Appendages

Androgen-Like Effects (acne, alopecia) Skin/Mucous Membrane Reaction

Cardiovascular and Metabolic Disorders

Breast Changes/Pain/Ifendemess Menstrual Disorders Vaginitis

* LA-Only = leuprolide acetate 3.75 mg + LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg

Table 2. Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study) Assessment

Treatment Group

Number of Patients

Number of Days with Hot

Maximum Number of Hot

Reporting Hot Flashes

Flashes

Flashes in 24 Hours

5.7

* LA-Only = leuprolide acetate 3.75 mg + LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg 'Statistically significantly less than the LA-Only group (p191) Leading to Study Discontinuation: In the controlled study, 18% of patients treated monthly with leuprolide acetate and 18% of patients treated monthly with leuprolide acetate plus norethindrone acetate discon¬ tinued therapy due to adverse reactions, most commonly hot flashes and insomnia (4%) in the leuprolide acetate alone group and hot flashes and emotional lability (4% each < in the leuprolide acetate and norethindrone group. In the open label study, 13% of patients treated monthly with leuprolide acetate plus norethindrone acetate discon¬ tinued therapy due to adverse reactions, most commonly de¬ pression (4%) and acne (2% I. Common Adverse Reactions: Table 1 lists the adverse reactions observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the add-back clinical studies, in which pa¬ tients were treated with monthly leuprolide acetate for depot suspension 3.75 mg with or without norethindrone acetate co-treatment. The most frequently-occurring ad¬ verse reactions observed in these studies were hot flashes | and headaches, j (See table 1 abovel In the controlled clinical trial. 50 of 51 '98% > patients in the leuprolide acetate alone group and 48 of 55 SGPT and 2 of 136 devel¬ oped an elevated GGT. Five of the 6 increases were observed beyond 6 months of treatment. None was associated with an elevated bilirubin concentration. Lipid*

Percent changes from baseline for serum lipids and percent¬ ages of patients with serum lipid values outside of the nor ; mal range in the two studies of leuprolide acetate and norethindrone acetate are summarized in the tables below The major impact of adding norethindrone acetate to treat¬ ment with leuprolide acetate for depot suspension was a de| crease in serum HDL cholesterol and an increase in the LDL/HDI. ratio

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494/ABBVIE • LUPANETA PACK 3.75 MG Table 3. Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24

leuprolide acetate for depot suspension 3.75 mg plus norethindrone

leuprolide acetate 3.75 mg

acetate 5 mg daily

Baseline

Wk 24% Change

Value*

Open Label Study (n=117)

Controlled Study (n=41)

Controlled Study (n=39)

Baseline

Baseline

Wk 24% Change

Value*

Value*

Wk 24% Change

Total Cholesterol

170.5

9.2%

179.3

0.2%

181.2

2.8%

HDL Cholesterol

52.4

7.4%

51.8

-18.8%

51.0

-14.6%.

LDL Cholesterol

96.6

10.9%

101.5

14.1%

109.1

13.1%

LDL/HDL Ratio

2.0+

5.0%

2. It

43.4%

2.3+

39.4%

Triglycerides

107.8

17.5%

130.2

9.5%

105.4

13.8%

* mg/dL t ratio

Table 4. Percent of Patients with Serum Lipid Values Outside of the Normal Range leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg daily Controlled Study

Open Label Study (n=117)

(n=41)

Wk 24*

Baseline

Baseline

Wk 24*

6%

7%

Total Cholesterol (>240 mg/dL)

15%

, 20%

HDL Cholesterol (160 mg/dL)

5%

7%

9%

11%

LDL/HDL Ratio (>4.0)

2%

15%

7%

21%

Triglycerides (>200 mg/dL)

12%

10%

5%

9%

Includes all patients regardless of baseline value.

-CH2CH3-).2CH3COOH CHj

(7^ N-H

CHj

CHj

CHj

CRj-CH

OH

N=J

a

CH,

kJJ

ch3

CH3-CH 6b

CH2 CH, C)b N-H

OH

li

C =NH NHj

H

(See table 3 abovel Changes from baseline tended to be greater at Week 52. Af¬ ter treatment, mean serum lipid levels from patients with follow up data (105 of 158 patients) returned to pretreat¬ ment values. ISee table 4 above) 6.2

CH,

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of leuprolide acetate for depot suspension or norethindrone acetate. Because these reactions arc re¬ ported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Leuprolide Acetate for Depot Suspension

During postmarketing surveillance with other dosage forms and in the same or different populations, the following ad¬ verse reactions wen1 reported: • Allergic reactions (anaphylactic, rash, urticaria, and pho¬ tosensitivity reactions) • Mood swings, including depression • Suicidal ideation and attempt • Symptoms consistent with an anaphylactoid or asthmatic process • Localized reactions including induration and abscess at the site of uyection • Symptoms consistent with fibromyalgia le.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath), individually and collec¬ tively

Other adverse reactions reported are:

Hepato-biliary disorder - Serious liver injury Injury, poisoning and procedural complications - Spinal fracture Investigations - Decreased white blood count Musculoskeletal and connective tissue disorder Tenosynovitis-like symptoms Nervous System disorder - Convulsion, peripheral neuropa¬ thy, paralysis Vascular disorder - Hypotension, Hypertension Serious venous and arterial thrombotic and thromboembolic events, including deep vein thrombosis, pulmonary embo¬ lism, myocardial infarction, stroke, and transient ischemic attack Pituitary apoplexy

During post-marketing surveillance, cases of pituitary apo¬ plexy (a clinical syndrome secondary to infarction uf the pi¬ tuitary gland) have been reported after the administration of leuprolide acetate and other GnRH agonists. In a major¬ ity of these cases, a pituitary adenoma was diagnosed, with a minority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, al¬ tered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Leuprolide Acetate for Depot Suspension No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate for depot suspension. However, drug interactions associated with cy¬ tochrome P-450 enzymes or protein binding would not be expected to occur [see Clinical Pharmacology (12.3)1. Norethindrone Acetate No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate have been conducted. Drugs or herbal products that induce or in¬ hibit certain enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone. 7.2 Drug/Laboratory Test Interactions Leuprolide Acetate for Depot Suspension Administration of leuprolide acetate for depot suspension in therapeutic doses results in suppression of the pituitarygonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, di¬ agnostic tests of pituitary gonadotropic and gonadal func¬ tions conducted during treatment and for up to. three months after discontinuation of leuprolide acetate for depot suspension may be affected. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X - [See Contraindications (4)1 Teratogenic Effects LUPANETA PACK is contraindicated in women who are or may become pregnant while receiving the drug [see Contra¬ indications (4)]. Before starting and during treatment with leuprolide acetate for depot suspension, establish whether the patient is pregnant. Leuprolide acetate for depot suspension is not a contraceptive. In reproductively capable women, a non-hormonal method of contraception should be used [see Warnings and Precautions (5.4)]. Leuprolide acetate for depot suspension may cause fetal harm when administered to a pregnant woman. When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate for depot suspension pro¬ duced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprolide acetate for depot suspension in rabbits and with the highest dose (0.024 mg/kg) in rats. 8.3 Nursing Mothers Do not use LUPANETA PACK in nursing mothers because the effects of leuprolide acetate for depot suspension on lac¬ tation and/or the breast-fed child have not been determined. It is not known whether leuprolide acetate for depot suspension is excreted in human milk. Detectable amounts of progestins have been identified in the milk of mothers receiving them /see Contraindications (4)]. 8.4 Pediatric Use LUPANETA PACK is not indicated in premenarcheal ado¬ lescents. Safety and effectiveness of LUPANETA PACK have not been established in pediatric patients. Experience with LUPANETA PACK for treatment of endometriosis has been limited to women 18 years of age and older. 8.5 Geriatric Use LUPANETA PACK is not indicated in postmenopausal women and has not been studied in women over 65 years of age. 11

DESCRIPTION

LUPANETA PACK (leuprolide acetate for depot suspension; norethindrone acetate tablets) 1-month contains one dual chamber syringe with leuprolide acetate for depot suspension 3.75 mg and norethindrone acetate tablets USP: 5 mg (bottle of 30 tablets). Leuprolide Acetate for Depot Suspension Leuprolide acetate for depot suspension is a synthetic nonapeptide analog of gonadotropin-releasing hormone (GnRH or LH-RH), a GnRH agonist. The chemical name is 5- oxoL-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucylL-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: |See chemical structure abovel Leuprolide acetate for depot suspension 3.75 mg is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, be¬ come a suspension intended as an intramuscular injection. The front chamber of leuprolide acetate for depot suspension 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate for depot suspension (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer • 33.1 mgi, and D-mannitol 16.6 mg'. The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (60 mg), polysorbate 80 (1 mg), water for injec¬ tion. USP, and glacial acetic acid, USP to control pH. During the manufacture of leuprolide acetate for depot suspension, acetic acid is lost, leaving the peptide.

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LUPANETA PACK 3.75 MG • ABBVIE/495

Norethindrone Acetate

Norethindrone acetate tablets USP - 5 mg oral tablets Norethindrone acetate USP. (17-hydroxy-19-nor-17a-pregn4-en-20-yn-3-one acetate), a synthetic, orally active proges¬ tin, is the acetic acid ester of norethindrone. It is a white, or creamy white, crystalline powder.

Figure 8. Mean Norethindrone Plasma Concentration Profile after a Single Dose of 5 mg Norethindrone Acetate Administered to 29 Healthy Female Volunteers under Fasting Conditions

O

Time(h) Norethindrone acetate tablets USP, 5 mg contain the follow¬ ing inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellu¬ lose and talc. Excretion 12 12.1

CLINICAL PHARMACOLOGY

Leuprolide Acetate for Depot Suspension Table 5. Pharmacokinetic Parameters after a Single Dose

Mechanism of Action

of Norethindrone Acetate in Healthy Women

Leuprolide Acetate for Depot Suspension

Leuprolide acetate for depot suspension is a long-acting GnRH analog. A single injection of leuprolide acetate for depot suspension results in an initial elevation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at quarterly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Norethindrone Acetate

Norethindrone acetate induces secretory changes in an estrogen-primed endometrium. 12.2

Pharmacodynamics

In a pharmacokinetic/pharmacodynamic study of leuprolide acetate 11.25 mg for 3-month administration in healthy fe¬ male subjects (N=20 >, the onset of estradiol suppression was observed for individual subjects between day 4 and week 4 after dosing. By the third week following the injection, the mean estradiol concentration (8 pg/mLi was in the meno¬ pausal range. Throughout the remainder of the dosing pe¬ riod, mean serum estradiol levels ranged from the meno¬ pausal to the early follicular range. Serum estradiol was suppressed to 520 pg/mL in all sub¬ jects within four weeks and remained suppressed (540 pg/ mL) in 80% of subjects until the end of the 12-week dosing interval, at which time two of these subjects had a value between 40 and 50 pg/mL. Four additional subjects had at least two consecutive elevations of estradiol (range 43-240 pg/mL) levels during the 12-week dosing interval, but there was no indication of luteal function for any of the subjects during this period. 12.3

Pharmacokinetics

Norethindrone Acetate (n= 29) Arithmetic Mean ± SD

Following administration of leuprolide acetate for depot suspension 3.75 mg for 1-month administration to 3 pa¬ tients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Norethindrone Acetate

Norethindrone AUC (0-inf) (ng/ml*h)

166.90 ± 56.28

Cra„„ (ng/ml)

26.19 ± 6.19

11/2 (hi)

Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg. Norethindrone is excreted in both urine and fe¬ ces, primarily as metabolites. The mean terminal elimina¬ tion half-life of norethindrone following a single dose ad¬ ministration of norethindrone acetate is approximately 9 hours.

1.83 ± 0.58

Specific Populations Hepatic Impairment

8.51 ± 2.19

The effect of hepatic disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. However, norethindrone acetate is contraindicated in markedly impaired liver function or liver disease /see Contraindications (4)J. The pharmacokinetics of the leuprolide acetate for depot suspension in hepatically impaired patients has not been determined.

AUC = area under the curve, Cmax = maximum plasma concentration, tmax = time at maximum plasma concentration, tw = half-life, SD = standard deviation

Renal Impairment

[See figure 8 above] Effect of Food: The effect of food administration on the pharmacokinetics of norethindrone acetate has not been studied. Distribution Leuprolide Acetate for Depot Suspension

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma pro¬ teins ranged from 43/?: to 49%. Norethindrone Acetate

Norethindrone is 36% bound to sex hormone-binding globu¬ lin (SHBG) and 61% bound to albumin. Volume of distribu¬ tion of norethindrone is about 4 LAg. Metabolism Leuprolide Acetate for Depot Suspension

The effect of renal disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. In pre-menopausal women with chronic renal failure undergoing peritoneal dialysis who re¬ ceived multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma norethindrone concentration was unchanged compared to concentrations in pre-menopausal women with normal renal function. The pharmacokinetics of the leuprolide acetate for depot suspension in renally impaired patients has not been deter> mined. Race

The effect of race on the disposition of norethindrone after norethindrone acetate administration has not been evalu¬ ated. Drug Interactions Leuprolide Acetate for Depot Suspension

In healthy male volunteers, a 1 mg bolus of leuprolide ad¬ Absorption Leuprolide acetate for depot suspension is a peptide that is ministered intravenously revealed that the mean systemic Leuprolide Acetate for Depot Suspension primarily degraded by peptidase and not by cytochrome clearance was 7.6 L/h, with a terminal elimination half-life P-450 enzymes as noted in specific studies, and the drug is Following a single injection of the three month formulation of approximately 3 hours based on a two compartment only about 46% bound to plasma proteins, drug interactions of leuprolide acetate for depot suspension 10%) were hot flashes/sweats, headache/migraine, depression/emotional lability, nausea/ vomiting, nervousness/anxiety, insomnia, pain, acne, asthe¬ nia, vaginitis, weight gain, constipation/diarrhea (6.1) Progestins: breakthrough bleeding, spotting (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda gov/medwatch -USE IN SPECIFIC POPULATIONSPediatric: Safety and effectiveness of LUPANETA PACK has not been established in pediatric patients. (8.4) Geriatric: LUPANETA PACK has not been studied in women over 65 years of age and is not indicated in this pop¬ ulation. (8.5) See 17 tor PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2013

FULL PRESCRIBING INFORMATION: CONTENTS*

1 2

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION Dosing Information 2.1 Different Formulations of Leuprolide Acetate 2.2 Reconstitution and Administration for Injec2.3 tion of Leuprolide Acetate DOSAGE FORMS AND STRENGTHS 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 Loss of Bone Mineral Density 5.1 5.2 Pregnancy Risk Visual Abnormalities 5.3 5.4 Clinical Depression Serious Allergic Reactions 5.5 Cardiovascular and Metabolic Disorders 5.6 Initial Flare of Symptoms 5.7 Fluid Retention 5.8 Convulsions 5.9 ADVERSE REACTIONS 6 Clinical Trials Experience 6.1 Postmarketing Experience 6.2 DRUG INTERACTIONS 7 Drug-Drug Interactions 7.1 Drug/Laboratory Test Interactions 7.2 USE IN SPECIFIC POPULATIONS 8 Pregnancy 8.1 8.3 Nursing Mothers 8.4 Pediatric Use Geriatric Use 8.5 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins /see Warnings and Precautions (5.1)]. Treatment beyond two six-month courses has not been stud¬ ied and is not recommended due to concerns about adverse impact on bone mineral density. 2.2

Different Formulations of Leuprolide Acetate

Due to different release characteristics, a fractional dose of the leuprolide acetate for depot suspension 3-month depot formulation is not equivalent to the same dose of the monthly formulation and should not be given. 2.3 Reconstitution and Administration for Injection of Leuprolide Acetate

• Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. • Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot sus¬ pension does not contain a preservative. 1. Visually inspect the leuprolide acetate for depot sus¬ pension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. Tb prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2). [See figure 1 above]

Figure 2;

FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

LUPANETA PACK (leuprolide acetate for depot suspension and norethindrone acetate tablets) is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. Limitation of Use: Duration of use is limited due to con¬ cerns about adverse impact on bone mineral density /see Warnings and Precautions (5.1)1. The initial treatment course of LUPANETA PACK is limited to six months. A sin¬ gle retreatment course of not more than six months may be administered after the initial course of treatment if symp¬ toms recur. Use of LUPANETA PACK for longer than a total of 12 months is not recommended. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows: • 11.25 mg of leuprolide acetate by intramuscular injection once every three months for up to two injections (6 months of therapy); to be administered by a healthcare provider • 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy The initial course of treatment with leuprolide acetate for depot suspension 11.25 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds' the plunger until the first middle stopper is at the blue line in the mid¬ dle of the barrel (see Figure 3).

Figure 3:

4.

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Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly bv gently shaking the syringe un¬ til the powder forms a uniform suspension. The sus¬ pension will appear milky. If the powder adhere* * to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).

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LUPANETA PACK 11.25 MG • ABBVIE/499

Figure 4:

Table 1. Adverse Reactions Occurring in the First Six Months of Treatment in > 5% ot Patients with Endometriosis Controlled Study

Open Label Study

LA-Only*

LA/Nt

LA/Nt

NaSI

N=55

N=136

Adverse Reactions

N

%

N

X

Any Adverse Reaction Body as a Whole

50

98

53

96

Asthenia Headache/M igraine Injection Site Reaction Pain

•

N

%

126

93

18 65 2 24

18 51 9 29

11 46 3 21

98

87

57

14 4 4 25

15 0 7 29

10 6 4 13

0 12

9 13

7 4

31 16 31 10 6 8 2

27 11 13 4 2 4 9

34 7 15 7 4 11 3

4 4

5 9

18 11

6 2 20

13 0 15

8 5 8

Cardiovascular System

Hot flashes/Sweats Digestive System

5. Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection. 7. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5).

Altered Bowel Function (constipation, diarrhea) Changes in Appetite GI Disturbance (dyspepsia, flatulence) Nausea/Vomiting Metabolic and Nutritional Disorders

Edema Weight Gain Nervous System

Depression/Emotional Lability Dizziness/Vertigo Insomnia/Sleep Disorder Decreased Libido Memory Disorder Nervousness/Anxiety Neuromuscular Disorder (leg cramps, paresthesia)

Figure 5:

Skin and Appendages

Androgen-Like Effects (acne, alopecia) Skin/Mucous Membrane Reaction Urogenital System

NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Breast Changes/Pain/ftsndemess Menstrual Disorders Vaginitis * LA-Only = leuprolide acetate 3.75 mg t LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg

Figure 6:

Table 2. Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study) If a blood vessel is injured, blood will be visible in this section of the syringe.

Assessment

Treatment

Visit

Group

Week 24

Number of Patients Reporting Hot Flashes

Number of Days with Hot

Maximum Number Hot

Flashes

Flashes in 24 Hours

N

(%)

N2

Mean

N2

Mean

LA-Only*

32/37

86

37

19

36

5.8

LA/Nt

22/38

58'

38

7*

38

1.9’

* LA-Only = leuprolide acetate 3.75 mg t LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg 'Statistically significantly less than the LA-Onlv group (p240 mg/dL) HDL Cholesterol (1 Teratogenic Effects

LUPANETA PACK is contraindicated in women who are or may become pregnant while receiving the drug (see Contra¬ indications i4)]. Before starting and during treatment with leuprolide acetate for depot suspension, establish whether the patient is pregnant Leuprolide acetate for depot sus-

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR pension is not a contraceptive. In reproductively capable women, a non-hormonal method of contraception should be used [see Warnings and Precautions (5.4)1. Leuprolide acetate for depot suspension may cause fetal harm when administered to a pregnant woman. When administered on day 6 of pregnancy at test dosages of 0.00024,0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate for depot suspension pro¬ duced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprolide acetate for depot suspension in rabbits and with the highest dose (0.024 mg/kg) in rats. 8.3

0 H O

uN

O H

OH

OH

OH

OH

II I

II I

II I

II I

II I

0

N-CH-C-N-CH-C-N-

1.83 ± 0.58

it/s CW

8.51 ± 2.19

AUC = area under the curve. Cm„„ = maximum plasma concentration. tm„x = time at maximum plasma concentration, t|/y = half-life, SD = standard deviation [See figure 8 abovel Effect of Food: The effect of food administration on the pharmacokinetics of norethindrone acetate has not been studied. Distribution Leuprolide Acetate for Depot Suspension

The mean steady-state volume of distribution of leuprolide following intravenous bolus administration loju-alihy male volunteers was 27 L. In vitro binding to human plasma pro¬ teins ranged from 43°r to 49'$. Norethindrone Acetate

Norethindrone is 36') bound to sex hormone-binding globu¬ lin (SHBG) and 61'/ bound to albumin. Volume of distribu¬ tion of norethindrone is about 4 LAg. Metabolism Leuprolide Acetate for Depot Suspension

In healthy male volunteers, a 1 mg bolus of leuprolide ad¬ ministered intravenously revealed that the mean systemic clearance was 7.6 L/h. with a terminal elimination Half-lift* of approximately 3 hours based on a two compartment model. In rats and dogs, administration of MC-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a

Information on the AbbVie, Inc products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633 9110

Free mobile?DR app for fast drug references on Apple or Android devices

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

502/ABBVIE • LUPANETA PACK 11.25 MG Table 6. Percentages of Patients with Symptoms of Endometriosis and Mean Clinical Severity Scores Percent of Patients with Symptom

Final

Baseline

Final

Baseline

Variable

Clinical Pain Severity Score

Change

Value3

Group

N’

(%l*

252 days after the first day of treatment. # 95T Cl: 95V Confidence Interval

NONCLINICAL TOXICOLOGY Carcinogenesis. Mutagenesis. Impairment of Fer¬

tility Leuprolide Acetate for Depot Suspension

A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hy¬ perplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell ad¬ enomas in females and of testicular interstitial cell ad¬ enomas in males (highest incidence in the low dose groupi. In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/ day and for two years with doses as high as 20 mg/dav with¬ out demonstrable pituitary abnormalities. Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems. These studies provided no evidence of a mutagenic potential. Clinical and pharmacologic studies in adults 18 years) with leuprolide acetate and similar analogs have shown re¬ versibility of fertility suppression when the drug is discon¬ tinued after continuous administration for periods of up to 24 weeks Although no clinical studies have been completed in children to assess the full reversibility of fertility sup¬ pression. animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. 14

CLINICAL STUDIES

Leuprolide Acetate for Depot Suspension

Initial endometriosis efficacy data for leuprolide acetate for depot suspension were based on the 3.75 mg dose adminis¬ tered once monthly. A pharmacokinetic/pharmacodynamic study in 41 women that included both the 3.75 mg dose administered once monthly and the 11.25 mg dose administered once every three months did not reveal clinically significant differences in terms of efficacy in reducing painful symptoms of endo¬ metriosis or magnitude of the decrease in bone mineral den¬ sity (BMD) associated with use of leuprolide acetate. Leuprolide

pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. In a pharmacokinetic/pharmacodynamic study of endome¬ triosis patients, intramuscular 11.25 mg leuprolide acetate for depot suspension (n=i9) every 12 weeks or intramuscu¬ lar 3.75 mg leuprolide acetate for depot suspension (n=15) every 4 weeks was administered for 24 weeks. There was no statistically significant difference in changes of serum estra¬ diol concentration from baseline between the 2 treatment groups. M-l plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6V of the peak parent drug concentration, tine week after dosing, mean plasma M-I concentrations were approximately 20'* of mean leuprolide concentrations.

conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. Excretion Leuprolide Acetate for Depot Suspension

Following administration of leuprolide acetate for depot suspension 3.75 mg for 1-month administration to 3 pa¬ tients, less than 5V of the dose was recovered as parent and M-I metabolite in the urine. Norethindrone Acetate

Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg. Norethindrone is excreted in both urine and fe¬ ces. primarily as metabolites. The mean terminal elimina¬ tion half-life of norethindrone following a single dose ad¬ ministration of norethindrone acetate is approximately 9 hours.

Norethindrone Acetate

Specific Populations Hepatic Impairment

Norethindrone undergoes extensive biotransformation, pri¬ marily via reduction, followed by sulfate and glucuronide

The effect of hepatic disease on the disposition of norethin¬ drone after norethindrone acetate administration has not

Acetate

for

Depot

Suspension

Plus

Norethindrone Acetate

Two clinical studies with treatment duration of 12 months were conducted to evaluate the effect of coadministration of leuprolide acetate for depot suspension and norethindrone acetate on the loss of bone mineral density iBMD) associ¬ ated with leuprolide acetate for depot suspension and on the efficacy of leuprolide acetate for depot suspension in reliev¬ ing symptoms of endometriosis. (All patients in these stud¬ ies received calcium supplementation with 1000 mg elemen¬ tal calcium). A total of 242 women were treated with monthly administration of leuprolide acetate 3.75 mg (13 injections) and with 5 mg norethindrone acetate taken daily. The population age range was 17-43 years old. The majority of patients were Caucasian (87V). One coadministration study was a controlled, randomized and double-blind study included 51 women treated monthly with leuprolide acetate for depot suspension alone and 55 women treated monthly with leuprolide acetate for depot suspension plus norethindrone acetate daily. Women in this trial were followed for up to 24 months after completing one

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Look for PDR drug information and services in your EHR year of treatment. The other study was an open-label single arm clinical study in 136 women of one year of treatment with leuprolide acetate for depot suspension and norethindrone acetate, with follow-up for up to 12 months after completing treatment. The second study was an open label, single arm study in which 136 women were treated monthly with leuprolide acetate for depot suspension plus norethindrone acetate daily, with follow-up for up to 12 months after completing treatment. The assessment of efficacy was based on the investigator’s or the patient’s monthly assessment of five signs or symp¬ toms of endometriosis (dysmenorrhea, pelvic pain, deep dyspareunia. pelvic tenderness and pelvic induration). Table 6 below provides detailed efficacy data regarding re¬ lief of symptoms of endometriosis based on the two studies of coadministration of leuprolide acetate and norethindrone acetate. ISee table 6 at top of previous page! Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was main¬ tained throughout treatment in 84% and 73% of patients re¬ ceiving leuprolide acetate and norethindrone acetate, in the controlled study and open label study, respectively. The me¬ dian time for menses resumption after treatment with leuprolide acetate and norethindrone acetate was 8 weeks. Changes in Bone Density The effect of leuprolide acetate for depot suspension and norethindrone acetate on bone mineral density was evalu¬ ated by dual energy x-ray absorptiometry (DXA) scan in the two clinical trials. For the open-label study, success in mit¬ igating BMD loss was defined as the lower bound of the 95% confidence interval around the change from baseline at one year of treatment not to exceed -2.2%. The bone mineral density data of the lumbar spine from these two studies are presented in Table 7. [See table 7 at top of previous page) The change in BMD following discontinuation of treatment is shown in Table 8. [See table 8 above) These clinical studies demonstrated that coadministration of leuprolide acetate and norethindrone acetate 5 mg daily is effective in significantly reducing the loss of bone mineral density that occurs with leuprolide acetate for depot sus¬ pension treatment, and in relieving symptoms of endometri¬ osis. 15

REFERENCES

Leuprolide Acetate for Depot Suspension 1. NIOSH Alert: Preventing occupational exposures to anti¬ neoplastic and other hazardous drugs in healthcare set¬ tings. 2004. U.S. Department of Health and Human Ser¬ vices, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004165. 2. OS HA Technical Manual, TED 1-0.15A. Section VI: Chap¬ ter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. httpj7www.osha.gov/dts/osta/otm/ otin. vi/otm .vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J HealthSyst Pharm. 2006; 63; 1172-1193. 4. Polovicb, M„ White, J.M.. & Kelleher. L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommen¬ dations for practice (2nd. Ed.) Pittsburgh. PA: Oncology Nursing Society. 16

HOW SUPPLIED/STORAGE AND HANDLING

LUPANETA PACK for 3-month copackaged kit (NDC 0074-1053-05) is available in cartons containing: leuprolide acetate for depot suspension 11.25 mg for 3-month administration Kit (NDC 0074-3663-04) norethindrone acetate 5 mg tablets; 90 count bottle i NDC 0074-1049-04) 1. Leuprolide acetate for depot suspension 11.25 mg for 3-month administration kit contains: • one prefilled dual-chamber syringe • one plunger • two alcohol swabs Each syringe contains sterile Ivophilized microspheres of leuprolide acetate incorporated in a biodegradable poly¬ mer of polylactic acid. When mixed with 1.5 mL of the dil¬ uent, leuprolide acetate for depot suspension 11.25 mg for 3-month administration is administered as a single intra¬ muscular injection. 2. Norethindrone acetate 5 mg 90 count bottle White* to off-white oval, fiat faced beveled edged, uncoated tablets deboesed with ‘G with breakline' on one side and 304 on other side. Store at 26”C (77*F); excursions permitted to 15 to 30*C 159 to 86’Fl ISee USP Controlled Room Temperature)

LUPANETA PACK 11.25 MG • ABBVIE/503 Table 8. Mean Percent Change from Baseline in BMD of Lumbar Spine in Post-Treatment Follow-up Period Controlled Study Post Treatment Measurement

Open Label Study

LA-Only

LA/N

LA/N

N

Mean % Change

95% Cl (%)

N

Mean % Change

95% Cl (%)

N

Month 8

19

-3.3

(-4.9, -1.8)

23

-0.9

(-2.1, 0.4)

89

-0.6

(-1.2, 0.0)

Month 12

16

-2.2

(-3.3, -1.1)

12

-0.7

(-2.1, 0.6)

65

0.1

(-0.6, 0.7)

Mean % Change

95% Cl (%)* *

1 Patients with post treatment measurements 2 95% Cl (2-sided) of percent change in BMD values from baseline

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling {Patient Information)

Counsel patients about the Warnings and Precautions for LUPANETA PACK, including: • Do not use this drug if they have experienced an allergic reaction to GnRH agonists or progestins • Do not use this drug if they are pregnant or planning a pregnancy, suspect they may be pregnant, or are breast¬ feeding • Risk of loss of bone mineral density and limitation of treatment to two six-month courses of treatment • Risk to an exposed fetus and need to use nonhormonal contraception • Discontinue norethindrone if they develop sudden loss of vision, double vision or sudden migraine • The possibility of development or worsening of depression during treatment with leuprolide acetate for depot sus¬ pension • Need for close monitoring if they have cardiovascular risk factors, or conditions like epilepsy, migraine or renal dys¬ function • Notify their healthcare provider if they develop new or worsened symptoms after beginning treatment Leuprolide Acetate for Depot Suspension 11.25 mg: Manufactured for AbbVie Inc. North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645 Norethindrone acetate Manufactured for AbbVie Inc. North Chicago, IL 60064 Manufactured by Glenmark Generics Ltd. Colvale-Bardez, Goa 403 513, India LUPANETA PACK Packaged by: AbbVie Inc. North Chicago, IL 60064 Revised 10/2013 PATIENT INFORMATION LUPANETA PACK® (loo-pan-e-ts piekl (leuprolide acetate for depot suspension and norethindrone acetate tablets)

Read this Patient Information before you start taking LUPANETA PACK and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condi¬ tion or your treatment. What is LUPANETA PACK?

LUPANETA PACK contains 2 different prescription medi¬ cines: • leuprolide acetate for depot suspension is a medicine in¬ jected into your muscle and used to treat pain due to en¬ dometriosis. • norethindrone acetate tablets is a medicine taken by mouth and used to help lower the side effect of bone thin¬ ning that is caused by leuprolide acetate for depot suspen¬ sion. LUPANETA PACK should not be used longer than 6 months at a time after you first start treatment for your endometri¬ osis symptoms. LUPANETA PACK should not be used for more than a total of 12 months during your treatment It is not known if LUPANETA PACK is safe and effective in children under 18 years of age. Who should not take LUPANETA PACK? Do not take LUPANETA PACK if you:

• have had an allergic reaction to medicines like leuprolide acetate for depot suspension or norethindrone acetate tab¬ lets. See the end of this leaflet for a complete list of ingre¬ dients in LUPANETA PACK • have uterine bleeding for which a cause has not been found • are pregnant or may be pregnant. LUPANETA PACK may harm your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if LUPANETA PACK passes into your breast milk. • had or have breast cancer or other cancers that are sensi¬ tive to hormones • have problems with blood clots, a stroke or a heart attack • have liver problems What should I tell my doctor before taking LUPANETA PACK? Before you take LUPANETA PACK, tell your doctor if you:

• drink alcohol • have a family history of bone loss (osteoporosis) • have high cholesterol • have migraine headaches • have epilepsy

• smoke • have depression • have had blood clots, a stroke or a heart attack • have diabetes • have kidney problems

Tell your doctor about all the medicines you take, including

prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take anticonvulsant (sei¬ zure) or corticosteroid medicines. Ask your doctor for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show vour doctor and pharmacist when you get a new medicine. How should I take LUPANETA PACK?

• Leuprolide acetate for depot suspension for 3-month ad¬ ministration is injected into your muscle 1 time every 3 months by a healthcare professional in your doctor's office. • Take norethindrone acetate tablets exactly as your doctor tells you to take them. Take 1 norethindrone acetate tablet by mouth every day for 3 months after you receive your ir\jection. • Talk to your doctor about the birth control method that is right for you before you start taking LUPANETA PACK. You will need to use a form of birth control that does not contain hormones, such as: o a diaphragm with spermicide °condoms with spermicide ° a copper IUD • If you become pregnant while taking LUPANETA PACK, stop taking the norethindrone acetate tablets and call vour doctor right away. How well does LUPANETA PACK work?

LUPANETA PACK is used to treat pain due to endometrio¬ sis. The pain from endometriosis can happen when you have your period, during other times of the month, or during in¬ tercourse (sex). Most women feel some relief from their en¬ dometriosis pain after taking both drugs in LUPANETA PACK. The tablets in LUPANETA PACK help lower the side effect of bone thinning that is caused by leuprolide acetate for de¬ pot suspension. Women taking both drugs in LUPANETA PACK lost an average of 1% of their bone density after about 1 year of treatment. Women regained jiome of their bone density about 1 year after they stopped treatment with LUPANETA PACK What are the possible side effects of LUPANETA PACK? LUPANETA PACK may cause serious side effects, including: • bone thinning (decreased bone mineral density) • harm to your unborn baby

• vision problems. Call your doctor right away if you have sudden loss of vision, double vision, bulging eyes, or mi¬ graine headaches. • depression or worsening depression • allergic reactions. Get medical help right away if you have any of these symptoms of a serious allergic reaction

• swelling of your face, lips, mouth, or tongue* • trouble breathing » wheezing

Information on the AbbVie, Inc pages of

is

July

from 31.

the

2015.

products listed on these

prescribing For

more

information information,

rxabbvie.com or call 1-800-633-9110.

Free mobile?DR app for fast drug references on Apple or Android devices

in

use

please

as

visit

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

504/ABBVIE • LUPANETA PACK 11.25 MG OH

severe itching skin rash, redness, or swelling dizziness or fainting fast heartbeat or pounding in your chest (tachycardia) • sweating

OH

OH

OH

OH

OH

O /"'N O H

OH

it

n

C-

C-N-CH-C-N-L C - N-Ch^CHa • ,.2CH3COOH

i

ii

O

CH2 CHj

• worsening endometriosis symptoms when you start tak¬

CH2

ing LUPANETA PACK • swelling (fluid retention)

N-H

The most common side effects of LUPANETA PACK include: • hot flashes and sweats • headaches or migraine headaches • • depression and mood swings • nausea and vomiting • problems sleeping • nervousness or feeling anxious • pain • acne • weakness • vaginal infection or inflammation • weight gain • constipation or diarrhea Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of LUPANETA PACK. For more information, ask your doctor or pharma¬ cist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store norethindrone acetate tablets in the LUPANETA PACK?

• Store norethindrone acetate tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep LUPANETA PACK and all medicines out of the reach of children. General information about the safe and effective use of LUPANETA PACK.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LUPANETA PACK for a condition for which it was not pre¬ scribed. Do not give LUPANETA PACK to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most im¬ portant information about LUPANETA PACK. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about LUPANETA PACK that is written for health professionals. For more information, go to www.lupanetapack.com or call 1-800-633-9110. What are the ingredients in LUPANETA PACK? leuprolide acetate for depot suspension:

Active Ingredients: leuprolide acetate for depot suspen¬ sion Inactive Ingredients: polylactic acid, D-mannitol, carboxymethylcellulose sodium, polysorbate 80, water for injection, USP, and glacial acetic acid, USP norethindrone acetate tablets:

Active Ingredients: norethindrone acetate USP Inactive Ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellu¬ lose and talc. This Patient Information has been approved by the U.S. Food and Drug Administration. Leuprolide Acetate for Depot Suspension:

Manufactured for AbbVie Inc. North Chicago, IL 60064 By Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645

C =NH NH2

FIGURE 1-PERCENT OF PATIENTS WITH SIGN/SYMPTOMS AT BASELINE, FINAL TREATMENT VISIT, AND AFTER 6 AND 12 MONTHS OF FOLLOW-UP B = BASELINE p»~] F = FINAL TREATMENT VISIT 6 = 6 MO. FOLLOW-UP (36%)* □ 12 = 12 MO. FOLLOW-UP (26%)*

* % refers to % of original patients who elected to participate in the follow-up study. Only 75% of the original patients enrolled in the follow-up study.

100 90 80 70 60 50 40 30 20 10 % B

F

6

12

PELVIC PAIN

B

F

6

12

DYSPAREUNIA

B

F

Manufactured for AbbVie Inc. North Chicago, IL 60064 By Glenmark Generics Ltd Colvale-Bardez, Goa 403 513, India 03-A587 October. 2013 Shown in Product Identification Guide, page 303

I{

natural hormone. The chemical name is 5-oxo-L-prolvl-Lhistidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-N-ethyl-L-prolinamide acetate (salt) with the fol¬ lowing structural formula: [See chemical structure above) LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection. The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copol¬ ymer (33.1 mg), and D-mannitol (6.6 mgi. The second cham¬ ber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP. and glacial acetic acid. USP to control pH. During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.

Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their mainte¬ nance become quiescent. This effect is reversible on discon¬ tinuation of drug therapy. Leuprolide acetate is not active when given orally. Intra¬ muscular injection of the depot formulation provides plasma concentrations of leuprolide over a period of one month. Pharmacokinetics

(leuprolide acetate for depot suspension) Rx only

This is combined labeling. Examples of different fonts and colors appear below. • General information • Information on endometriosis • Information on utenne fibroids

DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of nat¬ urally occurring gonadotropin-releasing hormone iGnKH or LH-RHi The analog possesses greater potency than the

6

12

PELVIC TENDERNESS

CLINICAL PHARMACOLOGY

Norethindrone acetate:

LUPRON DEPOT® 3.75 mg [lew-pr6n]

I

Absorption A single dose of LUPRON DEPOT 3.75 mg was adminis¬ tered by intramuscular itviection to healthy female volun¬ teers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concen¬ tration ranging from 4.6 to 10.2 ng/mL at four hours post¬ dosing. However, intact leupnilide and an inactive metabo¬ lite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and re¬ mained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.

B

F

6

12

INDURATION

B

F

6

12

DYSMENORRHEA

Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma pro¬ teins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide ad¬ ministered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of uC-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite iM-I) plasma concentrations mea¬ sured in 5 prostate cancer patients reached maximum con¬ centration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-l concentrations were approxi¬ mately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine. Special Populations The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined. Drug Interactions

No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, be¬ cause leuprolide acetate is a peptide that is primarily de¬ graded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES Endometriosis In controlled dinicol studies, LUPRON DEPOT 3.75 mg monthly for six months wos shown to be comparable to donazol 800 mg/day in relieving the clinical sign/symploms of endometriosis (pelvic pain, dysmenorrhea, dyspareuma. pelvic tenderness, and indura¬ tion) ond in reducing the sue ol endometrial implonts as evi-

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Look for PDR drug information and services in your EHR denced by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time, and in addition laparoscopic staging of endometriosis does not necessarily corre¬ late wilb the severity of symptoms. LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first and second treatment months respectively Most of the remaining patients reported episodes of only light Weeding or spotting. In the first, second and third post¬ treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those who become pregnant Figure 1 illustrates the percent of patients with symptoms at base¬ line, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during two controlled clinical studies. This included all patients ot end or treatment and those who elected to participate in the follow-up period This might provide a slight bios in the results at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months. ISee figure 1 at top of previous page!

LUPRON DEPOT 3.75 MG • ABBVIE/505 Figure 2 Treatment Period Mean Pain Scores for LD/N* Patients 4 = Severe Baseline Treatment Average

3= Moderate

Hormonal replacement therapy Two clinical studies with a treatment duration of 12 months indi¬ cate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral density associated with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis (All patients in these studies receivedcalcium supplementation with 1000 mg elemental calcium). One controlled, randomized and double-blind study included 51 women treated with LUPRON DEPOT alone and 55 women treated with LUPRON plus norelhindrone acetate 5 mg daily The second study was an open label study in which 136 women were treated with LUPRON plus norelhindrone acetate 5 mg daily. This study confirmed the reduction in loss of bone mineral density that was observed in the controlled study. Suppression of menses was maintained throughout treat¬ ment in 84% and 73% of patients receiving LD/N in the controlled study and open label study, respectively. The median time for men¬ ses resumption after treatment with LD/N was 8 weeks Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study. [See figure 2 above) Uterine Leiomyomata (Fibroids) In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months was shown to de¬ crease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal bloating, pelvic pain, and pres¬ sure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters. In three clinical trials, enrollment was not based on hemato¬ logic status. Mean uterine volume decreased by 41% and my¬ oma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. These patients also experienced a de¬ crease in symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit occurred by three months of therapy, but additional gain was observed with an additional three months of LUPRON DEPOT 3.75 mg Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively. Post-treatment follow-up was carried out for a small percent¬ age of LUPRON DEPOT 3.75 mg patients among the 77% who demonstrated a 2 25% decrease in uterine volume while on therapy. Menses usually returned within two months of ces¬ sation of therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to pretreatment uterine volume In another controlled clinical study, enrollment was based on hematocrit s 30% and/or hemoglobin S 10.2 g/dL Administra¬ tion of LUPRON DEF’OT 3 75 mg, concomitantly with iron, pro¬ duced an increase of 2 6% hematocrit and 2 2 g/dL hemoglo¬ bin in 77% of patients at three months of therapy. The mean change in hematocrit was 10.1% and the mean change in he¬ moglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of 2 36% arid hemoglobin of 2 12 g/dL, thus allow¬ ing for autologous blood donation prior to surgery. At three months. 75% of patients met this criterion. At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia As with the previous stud¬ ies. episodes of spotting and menstrual-like bleeding were noted in some patients In this same study, a decrease of 2 25% was seen in uterine and myoma volumes in 60% and 54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure. Then1 in no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT 3.75 mg.

Dysmenorrhea

Pelvic Pain

Deep Dyspareunla

LUPRON DEPOT 3.75 mg is indicated (or management of endo¬ metriosis. including pain relief and reduction of endometriotic le¬ sions LUPRON DEPOT monthly with norethindrone acetate 5 mg

Pelvic Induration

* LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily

daily is also indicated for initial management of endometriosis and for management of recurrence of symptoms. (Refer also to norethindrone acetate prescribing information for WARNINGS, PRE¬ CAUTIONS, CONTRAINDICATIONS and ADVERSE REACTIONS associated with norethindrone acetate). Duration of initial treat¬ ment or retrealment should be limited to 6 months. Uterine Leiomyomata (Fibroids) LUPRON DEPOT 3-75 mg concomitantly with iron therapy is indicated for the preoperative hematologic improvement of pa¬ tients with anemia caused by uterine leiomyomata. The clini¬ cian may wish to consider a one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone. (See Table 1.) LUPRON may be added if the response to iron alone is considered inadequate. Recommended dura¬ tion of therapy with LUPRON DEPOT 3.75 mg is up to three months. Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older. Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN 2 12 GM/DL Treatment Group LUPRON DEPOT 3.75 mg with Iron Iron Alone

Week 4

Week 8

Week 12

41*

71f

79*

17

40

56

• P-Value < 0.01 ' P-Value < 0.001

CONTRAINDICATIONS

When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their physician if they be¬ lieve they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus. During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing. The following applies to co-treatment with LUPRON and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis. diplopia, or migraine. If exam¬ ination reveals papilledema or retinal vascular lesions, medication should be withdrawn. Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindrone acetate. Assessment and management of risk factors for cardiovas¬ cular disease is recommended prior to initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women with risk factors, in¬ cluding lipid abnormalities or cigarette smoking.

1. Hypersensitivity to GnRH. GnRH agonist analogs or any of the excipients in LUPRON DEPOT. PRECAUTIONS 2. Undiagnosed abnormal vaginal bleeding. Information for Patients 3. LUPRON DEPOT is contraindicated in women who are Patients should be aware of the following information: or may become pregnant while receiving the drug. 1. Since menstruation usually stops with effective doses of LUPRON DEPOT may cause fetal harm when adminis¬ LUPRON DEPOT, the patient should notify her physi¬ tered to a pregnant woman. Major fetal abnormalities cian if regular menstruation persists. PatienLs missing were observed in rabbits but not in rats after administra¬ successive doses of LUPRON DEPOT may experience tion of LUPRON DEPOT throughout gestation There breakthrough bleeding. was increased fetal mortality and decreased fetal weights 2. Patients should not use LUPRON DEPOT if they are in rats and rabbits (See Pregnancy section.1 The effects pregnant, breast feeding, have undiagnosed abnormal on fetal mortality are expected consequences of the al¬ vaginal bleeding, or are allergic to any of the ingredients terations in hormonal levels brought about by the drug. If in LUPRON DEPOT this drug is used during pregnancy, or if the patient be¬ j 3. Safe use of the drug in pregnancy has not been estab¬ comes pregnant while taking this drug, the patient lished clinically. Therefore, a non-hormonal method of should be apprised of the potential hazard to the fetus. contraception should be used during treatment. Patients 4. Use in women who are breast-feeding. (See Nursing should be advised that if they miss successive doses of Mothers section ) LUPRON DEPOT, breakthrough bleeding or ovulation 5. Norethindrone acetate is contraindicated in women with may occur with the potential for conception If a patient the following conditions: becomes pregnant during treatment, she should discon¬ "Thrombophlebitis, thromboembolic disorders, cerebral tinue treatment and consult her physician. apoplexy, or a past history of these conditions ’ 4. Adverse events occurring in clinical studies with * Markedly impaired liver function or liver disease LUPRON DEPOT that are associated with hypoestro• Known or suspected carcinoma of the breast WARNINGS

INDICATIONS ANI) USAGE Endometriosis

Pelvic Tenderness

Safe use of WuproUde acetate or norethindrone acetate in pregnancy has not been established clinically. Before start¬ ing treatment with LUPRON DEPOT, pregnancy must be excluded.

Information on the AbbVie, Inc product* listed on these pages is from the prescribing information in use at of July 31, 2015. For more information, please visit rxabbvie.com or cell 1-800 633-9110

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506/ABBVIE • LUPRON DEPOT 3.75 MG Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN > 5% OF PATIENTS

Uterine Fibroids (4 Studies)

Endometriosis (2 Studies)

Body as a Whole Asthenia General pain Headache* Cardiovascular System Hot flashes/sweats* Gastrointestinal System Nausea/vomiting GI disturbances* Metabolic and Nutritional Disorders Edema Weight gain/loss Endocrine System Acne Hirsutism Musculoskeletal System Joint disorder* Myalgia* Nervous System Decreased libido* Depression/emotional lability* Dizziness Nervousness* Neuromuscular disorders* Paresthesias Skin and Appendages Skin reactions Urogenital System Breast changes/tendemess/pain* Vaginitis*

LUPRON DEPOT 3.75 mg N=166 N (%)

N

(%)

(0) (3) (6)

14 14 43

(8.4) (8.4) (25.9)

8 10 29

(4.9) (6.1) (17.8)

9

(29)

121

(72.9)

29

(17.8)

(13) (6)

1 1

(3) (3)

8 5

(4.8) (3.0)

6 2

(3.7) (1.2)

17 36

(13) (26)

1 0

(3) (0)

9 5

(5.4) (3.0)

2 2

(1-2) (1.2)

(10) (1)

27 9

(20) (7)

0 1

(0) (3)

0 1

(0) (0.6)

0 0

(0) (0)

14 1

(8) (1)

11 7

(8) (5)

0 0

(0) (0)

13 1

(7.8) (0.6)

5 0

(3.1) (0)

19 36 19 8 11 12

(11) (22) (11) (5) (7) (7)

6 27 4 11 17 11

(4) (20) (3) (8) (13) (8)

0 1 0 0 0 0

(0) (3) (0) (0) (0) (0)

3 18 3 8 3 2

(1.8) (10.8) (1.8) (4.8) (1.8) (1.2)

0 7 6 1 0 1

(0) (4.3) (3.7) (0.6) (0) (0.6)

Danozol N= 1 36

Placebo N=31

LUPRON DEPOT 3.75 mg N=166 N (%)

N

(%)

N

(%)

5 31 53

(3) (19) (32)

9 22 30

(7) (16) (22)

0 1 2

139

(84)

77

(57)

21 11

(13) (7)

17 8

12 22

(7) (13)

17 2

Placebo N=163

Pregnancy

17

(10)

20

(15)

1

(3)

5

(3.0)

2

(1-2)

10 46

(6) (28)

12 23

(9) (17)

0 0

(0) (0)

3 19

(18) (11.4)

7 3

(4.3) (1.8)

In these same studies, symptoms reported in

Total Cholesterol (>240 mg/dL) HDL Cholesterol (160 mg/dL) LDL/HDL Ratio (>4.0) Triglycerides (>200 mg/dL)

* Includes all patients regardless of baseline value. During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of depres¬ sion or other psychiatric illness. Patients should be coun¬ seled on the possibility of development or worsening of de¬ pression during treatment with LUPRON. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and pho¬ tosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder, gastrointestinal distress, and shortness of breath) have been reported individually and collectively. Other events reported are: Hepato-biliary disorder: Rarely reported serious liver in¬ jury Injury, poisoning and procedural complications: Spinal fracture Investigations: Decreased WBC Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms Nervous System Disorder: Convulsion, peripheral neurop¬ athy, paralysis Vascular Disorder: Hypotension Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient is¬ chemic attack. Although a temporal relationship was re¬ ported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH ana¬ logs and these events. Pituitary apoplexy During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administra¬ tion of gonadotropin-releasing hormone agonists. In a ma¬ jority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, al¬ tered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection pack¬ age inserts for other events reported in different patient populations.

before retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not recommended for retreatment. If norethindrone acetate is contraindicated for the individual pa¬ tient, then retreatment is not recommended. An assessment of cardiovascular risk and management of risk fac¬ tors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.

Uterine Leiomyomata (Fibroids) Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms associated with uterine leiomyomata will recur following discontinuation of ther¬ apy. If additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initia¬ tion of therapy to ensure that values are within normal limits. The recommended dose of LUPRON DEPOT is 3.75 mg, in¬ corporated in a depot formulation. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS), read and follow the following instructions: Reconstitution and Administration Instructions • The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. • Since LUPRON DEPOT does not contain a preservative,^ the suspension should be injected immediately or dis¬ carded if not used within two hours. • As with other drugs administered by injection, the injec¬ tion site should be varied periodically. 1. The LUPRON DEPOT powder should be visually in¬ spected and the syringe should NOT BE USED if clump¬ ing or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.

5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to ex¬ pel the air from the syringe. Now the syringe is ready for injection. 7. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, an¬ terior thigh, or deltoid; injection sites should be alter¬ nated.

NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally pen¬ etrated. If present, blood can be seen through the trans¬ parent LuproLoc® safety device. If blood is present re¬ move the needle immediately. Do not inject the medication.

8. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. AFTER INJECTION

9. Withdraw the needle. Once the syringe has been with¬ drawn, activate immediately the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt.

OVERDOSAGE In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local ir¬ ritation at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon. In early clini¬ cal trials using daily subcutaneous leuprolide acetate in pa¬ tients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.

3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.

ADDITIONAL INFORMATION

DOSAGE AND ADMINISTRATION

• Dispose of the syringe according to local regulations/pro¬ cedures.

LUPRON DEPOT Must Be Administered Under The Super¬ vision Of A Physician. Endometriosis

HOW SUPPLIED

The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with norethindrone acetate is six months The choice of LUPRON DEPOT alone or LUPRON DEPOT plus norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be made by the hearth care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone. If the symptoms of endometriosis recur after a course of therapy, retrealmenl with a six-month course of LUPRON DEPOT adminis¬ tered monthly and norethindrone acetate 5 mg daily may be con¬ sidered Retreatment beyond this one six-month course cannot be recommended It is recommended that bone density be assessed

4. Keep the syringe UPRIGHT Mix the microspheres (pow¬ der) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or cak¬ ing/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension.

Each LUPRON DEPOT 3.75 mg kit ; excursions permitted to 15-30*C l59-86*F) (See USP Controlled Room Temporaturel

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LUPRON DEPOT 11.25 MG • ABBVIE/509

REFERENCES 1. NIOSH Alert: Preventing occupational exposures to anti¬ neoplastic and other hazardous drugs in healthcare set¬ tings. 2004. U.S. Department of Health and Human Ser¬ vices, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chap¬ ter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/ otm.vi/otm. vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J HealthSyst Pharm. 2006; 63; 1172-1193. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommen¬ dations for practice (2nd. Ed.) Pittsburgh, PA: Oncology Nursing Society. Manufactured for AbbVie Inc. North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645 ™ - Trademark ® - Registered Trademark (No. 3641) Ref: 03-A891-Revised October, 2013 © 2013 AbbVie Inc. Shown in Product Identification Guide, page 303 LUPRON DEPOT® -3 MONTH 11.25 MG [lew-prdn]

OH

OH

OH

OH

OH

OH

OH

II I

II I

II I

II I

II I

II I

II I

n

O H

II

I

C-N-CH-C-N-CH-C-N-CH-C-N-CH-C-N-CH-C-N-CH-C-N-CH-C -N-L -C—N—CHzCHj • kjCHjCOOH

I CHi CH-

I CHj N—H C = NH

I NH2

FIGURE 1 - PERCENT OF PATIENTS WITH SIGN/SYMPTOMS OF ENDOMETRIOSIS AT BASELINE, FINAL TREATMENT VISIT, AND AFTER 6 AND 12 MONTHS OF FOLLOW-UP

B = BASELINE ^ F = FINAL TREATMENT VISIT ] 6 = 6 MO. FOLLOW-UP |

[ 12 = 12 MO. FOLLOW-UP

I*

I

(leuprolide acetate for depot suspension) 3-MONTH FORMULATION Rx only

This is combined labeling. Examples of different fonts and colors appear below. • General information • Information on endometriosis

• Information on uterine fibroids DESCRIPTION Leuprolide acetate is a synthetic nonapeptide analog of nat¬ urally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-Lhistidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-N-ethyl-L-prolinamide acetate (salt) with the fol¬ lowing structural formula: [See chemical structure above) LUPRON DEPOT-3 Month 11.25 mg is available in a pre¬ filled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY THREE MONTHS. The front chamber of LUPRON DEPOT-3 Month 11.25 mg prefilled dual-chamber syringe contains leuprolide acetate (11.25 mg), polylactic acid (99.3 mg) and D-mannitol (19.45 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for injection, USP, and gla¬ cial acetic acid, USP to control pH. During the manufacture of LUPRON DEPOT-3 Month 11.25 mg, acetic acid is lost, leaving the peptide. CLINICAL PHARMACOLOGY Leuprolide acetate is a long-acting GnRH analog. A single injection of LUPRON DEPOT-3 Month 11.25 mg will result in an initial stimulation followed by a prolonged suppres¬ sion of pituitary gonadotropins. Repeated dosing at quar¬ terly (LUPRON DEPOT-3 Month 11.25 mg) intervals re¬ sults in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Pharmacokinetics

Absorption Following a single injection of the three month formulation of LUPRON DEPOT-3 Month 11.25 mg in female subjects, a mean plasma leuprolide concentration of 36.3 ng/mL was observed at 4 hours. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels dur¬ ing the third week after dosing and mean levels then de¬ clined gradually to near the lower limit of detection by 12 weeks. The mean every 12 weeks or intramuscular 3.75 mg LUPRON DEPOT (n=15) every 4 weeks was administered for 24 weeks. There was no statistically significant difference in changes of serum estradiol concentration from baseline be¬ tween the 2 treatment groups. M-I plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-l metabolite in the urine. Special Populations The pharmacokinetics of the drug in hcpatically and renally impaired patients have not been determined. Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, be¬ cause leuprolide acetate is a peptide that is primarily de¬ graded by peptidase and not by cytochrome P-450 enzymes

BF6 12 (152) (152) (40) (28) INDURATION

BF6 12 (155) (155) (45) (30) DYSMENORRHEA

as noted in specific studies, and the drug is only about 46'. bound to plasma proteins, drug interactions would not be expected to occur. CLINICAL STUDIES In a pharmacokinetic/pharmacodynamic study of healthy female subjects (N=20). the onset of estradiol suppression was observed for individual subjects between day 4 and week 4 after dosing. By the third week following the injec¬ tion, the mean estradiol concentration (8 pg/mL> was in the menopausal range. Throughout the remainder of the dosing period, mean serum estradiol levels ranged from the meno¬ pausal to the early follicular range. Serum estradiol was suppressed to 6% hematocrit and > 2 g/dL hemoglo¬ bin in 77% of patients at three months of therapy. The mean change in hematocrit was 10.1% and the mean change in he-, moglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of £ 36% and hemoglobin of > 12 g/dL, thus allow¬ ing for autologous blood donation prior to surgery. At two and three months respectively, 71% and 75% of patients met this criterion (Table 1). These data suggest however, that some pa¬ tients may benefit from iron alone or 1 to 2 months of LUPRON DEPOT 3.75 mg. Table 1 PERCENT OF PATIENTS ACHIEVING HEMATOCRIT a 36% AND HEMOGLOBIN ;> 12 GM/DL

WARNINGS Treatment Group

Week 4

Week 8

Week 12

40*

71'

.75* .

17

39

49

LUPRON DEPOT 3.75 mg with Iron (N=104) Iron Alone (N=98)

and 98% of the patients otter the first and second treatment months respectively. Most of the remaining patients reported episodes of only light bleeding or spotting. In tne first, second and third post¬

• P-Value < 0.01 f P-Value < 0.001

treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those who became pregnant. Figure 1 illustrates the percent of patients with symptoms at base¬ line, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during the two controlled clinical studies. A total of 166 patients received LUPRON DEPOT 3.75 mg. Seventy-five percent (N=l 25) of these elected to participate in the follow-up period. Of these patients, 36% and 24% are included in the 6 month and 12 month follow-up analysis, respectively All the patients who had a pain evaluation at baseline and at a minimum of one treatment visit, are included in the Baseline (B) and final treatment visit (F) analysis.

(See figure 1 at top of previous page)) Hormonal add-back therapy Two clinical studies with a treatment duration of 12 months indi¬ cate that concurrent hormonal therapy (norethindrone acetate 5 mg doily) is effective in significantly reducing the loss of bone mineral density associated with LUPRON, without compromising the efficocy of LUPRON in relieving symptoms of endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental calcium) One controlled, randomized and double-blind study included 51 women treated with LUPRON DEPOT 3.75 mg alone and 55 women treated with LUPRON DEPOT 3.75 mg plus norethindrone ocetote 5 mg (LD/N) daily. The second study was an open lobel study in which 136 women were treated wim monthly LUPRON DEPOT 3.75 mg plus norelhindrone acetate 5 mg daily. This study confirmed the reduction in loss of bone mineral density that was observed in the controlled study Suppression of menses was maintained throughout treat¬ ment in 84% and 73% of patients receiving LD/N, in the controlled study and open label study, respectively The median time for men¬ ses resumption after treatment with LD/N was 8 weeks

1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT. 2. Undiagnosed abnormal vaginal bleeding. 3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while receiving the drug. LUPRON DEPOT may cause fetal harm when adminis¬ tered to a pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after administra¬ tion of LUPRON DEPOT throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits. (See Pregnancy section.) The effects on fetal mortality are expected consequences of the al¬ terations in hormonal levels brought about by the drug. If this drug is used during pregnancy or if the patient be¬ comes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 4. Use in women who are breast-feeding. (See Nursing Mothers section.) 5. Norethindrone acetate is contraindicated in women with the following conditions: • Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these conditions “ Markedly impaired liver function or liver disease » Known or suspected carcinoma of the breast

Excessive vaginal bleeding (menorrhagia or menometrorrhagia) decreased in 80% of patients at three months. Episodes of spotting and menstrual-like bleeding were noted in 16% of pa¬ tients at final visit. In this same study, a decrease of 2. 25% was seen in uterine and myoma volumes in 60% and 54% of patients respectively. The mean fibroid diameter was 6.3 cm at pretreatrnent and de¬ creased to 5.6 cm at the end of treatment. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure. In three other controlled clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. The mean fibroid diameter was 5.6 cm at pretreatment and decreased to 4.7 cm at the end of treatment. These patients also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenor¬ rhea during the first, second, and third treatment months re¬ spectively. In addition, posttreatment follow-up was carried out in one clin¬ ical trial for a small percentage of LUPRON DEPOT 3.75 mg patients (N=46) among the 77% who demonstrated a 2 25% decrease in uteripe volume while on therapy. Menses usually returned within two months ot cessation of therapy. Mean time to return to pretreatment uterine Size was 8.3 months. Re¬ growth did not appear to be related to pretreatment uterine vol¬ ume. There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT. INDICATIONS AND USAGE Endometriosis

Figure 2 Illustrates the mean pain scores for the LD/N group from the controlled study

LUPRON DEPOT-3 Month 11.25 mg Is indicated (or management

I Sue figure 2 abovel

ol endometriosis, including pain relief and reduction of endome¬

1: As the effects of LlTPRON DEPOT-3 Month 11.25 mg are present throughout the course of therapy, the drug should only be used in patients who require hormonal suppres¬ sion for at least three months. 2. Experience with LUPRON DEPOT-3 Month 11.25 mg in females has been limited to six months: therefore, expo¬ sure should be limited to six months of therapy. 3. Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically. Before starting treatment with LUPRON DEPOT pregnancy must bo excluded. 4. When used at the recommended dose and dosing interval. LUPRON DEPOT usually inhibits ovulation and stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients should use non-hormonal methods of contraception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treat¬ ment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus. (See CONTRAINDICATIONS section.) 5. During the early phase of therapy, sex steroids temporar¬ ily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy. 6. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing. 7. The following applies to co-treatment with LUPRON and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If exam¬ ination reveals papilledema or retinal vascular lesions, medication should be withdrawn. Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindrone acetate. Assessment and management of risk factors for cardiovas¬ cular disease is recommended prior to initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women with risk factors, in¬ cluding lipid abnormalities or cigarette smoking.

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LUPRON DEPOT 11.25 MG • ABBVIE/511

Look for PDR drug information and services in your EHR PRECAUTIONS

Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN 2 5% OF PATIENTS

Information for Patients

Convulsions

There have been postmarketing reports of convulsions in patients on leuprolide acetate therapy. These included pa¬ tients with and without concurrent medications and comorbid conditions. Laboratory Tests

See ADVERSE REACTIONS section Drug Interactions

See CLINICAL PHARMACOLOGY,

Pharmacokinetics

Drug/Laboratory Test Interactions

Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system Nor¬ mal function is usually restored within throe months after treatment is discontinued Therefore, diagnostic tests of pi¬ tuitary gonadotropic and gonadal functions conducted dur¬ ing treatment and for up to three months after discontinu¬ ation of LUPRON DEPOT may be misleading. Carcinogenesis. Mutagenesis. Impairment of Fertility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hy¬ perplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses 18 years) with leuprolide acetate and similar analogs have shown re¬ versibility of fertility suppression when the drug is discon¬ tinued after continuous administration for periods of up to 24 weeks. Although no clinical studies have been completed in children to assess the full reversibility of fertility sup¬ pression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. Pregnancy

Teratogenic Effects Pregnancy Category X (See CONTRAINDICATIONS sec¬ tion). When administered on day 6 of pregnancy at test dos¬ ages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dost*) to rabbits, LUPRON DEPOT produced a doserelated increase in major fetal abnormalities. Similar stud¬ ies in rats failed to demonstrate an increase in fetal malfor¬ mations. There was increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats. Nursing Mothers

It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of LUPRON DEPOT on lacta¬ tion and/or the breast-fed child have not boen determined. LUPRON DEPOT should not be used by nursing mothers. Pediatric Use

Safety and effectiveness of LUPRON DEPOT-3 Month 11.25 mg have not been established in pediatric patients. Experience with LUPRON DEPOT for treatment of endo¬ metriosis has been limited to women 18 years of age and older See LUPRON DEPOT PED* (leuprolide acetate for depot suspension) labeling for the safety and effectiveness in children with central precocious puberty.

Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in thiB population. ADVERSE REACTIONS Clinical Trials The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Ad¬ verse events reported in £ 5'i of patients in either of these populations and thought to be potentially relaU*d to drug are noted in the following table. [See table 2 abovel In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with utenne fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia, lactation, pyelonephritis, and unnary disorders Generally, a higher incidence ol hypoestrogenic effects was observed at the higher dose. In a pharmacokinetic trial involving 20 healtfjy female sub¬ jects receiving LUPRON DEPOT-3 Month 11.25 mg, a few adverse events were reported with this formulation that were not reported previously. These included face edema, agitation, laryngitis, and ear pain. In o Phoje IV study involving endometriosis potients receiving LUPRON DEPOT 3.75 mg (M-20) or LUPRON DEPOT-3 Month 11 25 mg |N«21), similar adverse events were reported by the Iwo groups of patients In general the safety profiles of the two formulations were comparable in this study Table 3 lists the potentially drug-related odverse events observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the odd-bock clinical studies, in which pa tients were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate co-treatment

[See

table

3

at

top of next page)

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110.

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512/ABBVIE • LUPRON DEPOT 11.25 MG Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN i 5% OF PATIENTS Controlled Study

Adverse Events Any Adverse Even) Body as a Whole Asthenia Headache/Migraine Injection Site Reaction Pain Cardiovascular System Hot flashes/Sweats Digestive System Altered Bowel Function Changes in Appetite Gl Disturbance Nausea/Vomiting Metabolic and Nutritional Disorders Edema Weight Changes Nervous System Anxiety Depression/Emotional Lability Dizziness/Vertigo Insomnia/Sleep Disorder Libido Changes Memory Disorder Nervousness Neuromuscular Disorder Skin and Appendages Alopecia Androgen-Like Effects Skin/Mucous Membrane Reaction Urogenital System Breast Changes/Pain/Tenderness Menstrual Disorders Voginitis

Open Label Study LD/N’ N=136

LD - Only* N =51 N l%l

LD/N’ N=55 N

1%)

N

(%)

50

(98)

53

(96)

126

(93)

9 33 1 12

(18) (65) (2) (24)

10 28 5 16

(18) (51) (9) (29)

15 63 4 29

(11) (46) (3) (21)

50

(98)

48

(87)

78

(57)

7 2 2 13

(M) (4) (4) (25)

8 0 4 16

(15) (0) (7) (29)

14 8 6 17

(10) (6) (4) (13)

0 6

(0) (12)

5 7

(9) (13)

9 6

(7) (4)

3 16 8 16 5 3 4 1

(6) (31) (16) (31) (10) (6) (8) (2)

0 15 6 7 2 1 2 5

(0) (27) (11) (13) (4) (2) (4) (9)

11 46 10 20 10 6 15 4

(8) (34) (7) (15) (7) (4) (11) (3)

0 2 2

(0) (4) (4)

5 3 5

(9) (5) (9)

4 24 15

(3) (18) (11)

3 1 10

(6) (2) (20)

7 0 8

(13) (0) (15)

11 7 11

(8) (5) (8)

' LD-Only = LUPRON DEPOT 3.75 mg * LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg

Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR SPINE LUPRON DEPOT 3.75 mg

LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily —

r

'

"

Controlled Study

Week 24* Week 52'

Controlled Study

—

Open Label Study

N

Change (Mean, 95% CD*

N

Change (Mean, 95% CD*

N

Change (Mean, 95% CD*

41 29

-3.2% (-3.8, -2.6) -6.3% (-7.1, -5.4)

42 32

-0.3% (-0.8, 0.3) -1.0% (-1.9, -0.1)

115 84

-0.2% (-0.6, 0.2) -1.1% (-1.6, -0.5)

* Includes on-treatment measurements that fell within 2-252 days after the first day of treatment. Includes on-treatment measurements >252 days after the first day of treatment. * 95% Cl: 95% Confidence Interval

Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT WEEK 24 LUPRON DEPOT 3.75 mg

LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily

Controlled Study In=39>

Tbtal Cholesterol HDL Cholesterol LDL Cholesterol LDL/HDL Ratio Triglycerides

Controlled Study (n=41)

Open Label Study |n=117)

Baseline Value*

Wk 24 % Change

Baseline Value*

Wk 24 % Change

Baseline Value*

Wk 24 % Change

170.5 52.4 96.6 2.0T 107.8

9.2% 7.4% 10.9% 5.0% 17.5%

179.3 51.8 101.5 2.1* 130.2

0.2% -18.8% 14.1% 43.4% 9.5%

181.2 51.0 109.1 2.3* 105.4

2.8% -14.6% 13.1% 39.4% 13.8%

* mg/dl. ' ratio In the controlled clinical trial, 50 of 51 (98%) patients in the LD group (LUPRON DEPOT 3 75 mg) and 48 of 55 (87%) patients in the LD/N group (LUPRON DEPOT 3,75 mg plus norethindrone ocetole 5 mg doily) reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported having experienced hot Rashes. The mean number of days on which hoi flashes were reported during

I this month of treatment was 19 and 7 in the LD ond LD/N treat¬ ment groups, respectively. The mean maximum number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD ond LD/N treatment groups, respectively. Changes in Bone Density In controlled clinical studies, patients with endometriosis i six months of therapy) or uterine fibroids i three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In

endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with the pre¬ treatment value. Clinical studies demonstrate that concur¬ rent hormonal therapy (norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly re¬ ducing the loss of bone mineral density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis. LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a control group in one study. The bone mineral density data of the lumbar spine from these two studies are presented in Table 4. (See table 4 above] In the Phase TV, six-month pharmacokinetic/pharmacody¬ namic study in endometriosis patients who were treated with LUPRON DEPOT 3.75 mg or LUPRON DEPOT-3 Month 11.25 mg, vertebral bone density measured by DEXA decreased compared with baseline by an average of 3.0% and 2.8% at six months for the two groups, respectively. When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, vertebral trabecu¬ lar bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% com¬ pared with baseline. Six months after discontinuation of therapy, a trend toward recovery was observed. Use of LUPRON DEPOT for longer than three months (uterine fi¬ broids) or six months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended. Changes in Laboratory Values During Treatment Liver Enzymes Three percent of uterine fibroid patients treated with LUPRON DEPOT 3.75 mg, manifested posttreatment transaminase values that were at least twice the baseline value and above the upper limit of the normal range None of the laboratory increases were associated with clinical symptoms. In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal I SGPT or GGT. Five of the 6 increases were observed beyond 6 months of treatment. None were associated with an elevated bilirubin concentra¬ tion. Lipids Triglycerides were increased above the upper limit of nor¬ mal in 12% of the endometriosis patients who received LUPRON DEPOT 3.75 mg and in 32% of the subjects re¬ ceiving LUPRON DEPOT-3 Month 11.25 mg. Of those endometriosis and uterine fibroid patients whose pretreatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to + 17 mg/dL in endometriosis patients and +11 mg/dL to +29 mg/dL in uterine fibroid patients. In the endometriosis treated patients, increases from the pretreatment values were statistically significant (p. There was essentially no increase in the LDL/HDL ratio in patients from either population receiving LUPRON DEPOT 3.75 mg In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily were evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one study. Percent changes from base¬ line for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies are summarized in the tables below. ISee table 5 above] Changes from baseline tended to-be greater at Week 52. Af¬ ter treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values. [See table 6 at top of next pagel Low HDL-cholesterol (160 mg/dL) are recognized risk factors for car¬ diovascular disease. The long-term significance of the ob¬ served treatment-related changes in serum lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be considered prior to ini¬ tiation of concurrent treatment with LUPRON and noreth¬ indrone acetate. Chemistry Slight to moderate mean increases were noted lor glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases were clinically significant. In the hor¬ monal add-back studies LL’PRON DEPOT in combination with norethindrone acetate was associated with elevations of GGT and SGPT in 6% to 7% of patients. Postmarketing The following adverse reactions have been identified during postapproval use of LITRON DEPOT. Because these reac¬ tions are reported voluntarily from a population of uncer¬ tain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug expo¬ sure.

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LUPRON DEPOT 11.25 MG • ABBV1E/513

Look for PDR drug information and services in your EHR During postmarketing surveillance with other dosage forms and in the same and/or different populations, the following adverse events were reported. Like other drugs in this class, mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and at¬ tempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients should be counseled on the possibility of development or worsening of depression during treatment with LUPRON. Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and pho¬ tosensitivity reactions have also been reported. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (eg: joint and mus¬ cle pain, headaches, sleep disorders, gastrointestinal dis¬ tress. and shortness of breath I have been reported individ¬ ually and collectively. Other events reported are: Hepato-biliary disorder. Rarely reported serious liver in¬ jury Injury, poisoning and procedural complications: Spinal fracture Investigations: Decreased WBC Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms Nervous System Disorder: Convulsion, peripheral neurop¬ athy, paralysis Vascular Disorder: Hypotension Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient is¬ chemic attack. Although a temporal relationship was re¬ ported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH ana¬ logs and these events. Pituitary apoplexy During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administra¬ tion of gonadotropin-releasing hormone agonists. In a ma¬ jority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, al¬ tered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection pack¬ age inserts for other events reported in the same and differ¬ ent patient populations.

Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL RANGE LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily

LUPRON DEPOT 3.75 mg

Controlled Study (n=39l

Total Cholesterol (>240 mg/dL) HDL Cholesterol (160 mg/dL) LDL/HDL Ratio (>4.0) Triglycerides (>200 mg/dL)

WkO 15% 15% 0% 0% 13%

Controlled Study ln=41)

Wk 24* 23% 10% 8%’ 3% 13%

WkO 15% 15% 5% 2% 12%

Wk 24* 20% 44% 7% 15% 10%

Open Label Study (n=117) WkO 6% 15% 9% 7% 5%

Wk 24* 7% 41% 11% 21% 9%

* Includes all patients regardless of baseline value.

same dose of the monthly formulation and should not be given. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS), read and follow the following instructions: Reconstitution and Administration Instructions • The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. • Since LUPRON DEPOT does not contain a preservative, the suspension should be injected immediately or dis¬ carded if not used within two hours. • As with other drugs administered by injection, the injec¬ tion site should be varied periodically. 1. The LUPRON DEPOT powder should be visually in¬ spected and the syringe should NOT BE USED if clump¬ ing or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.

the needle at a 90 degree angle into the gluteal area, an¬ terior thigh, or deltoid; injection sites should be alter¬ nated.

luer lock connection if a blood vessel is accidentally pen¬ etrated. If present, blood can be seen through the trans¬ parent LuproLoc* safety device. If blood is present re¬ move the needle immediately. Do not inject the medication.

OVERDOSAGE In clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects dif¬ fering from those observed with the 1 mg/day dose. DOSAGE AND ADMINISTRATION LUPRON DEPOT Must Be Administered Under the Supervi¬ sion of a Physician.

3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.

Endometriosis The recommended duration of treatment with LUPRON DEPOT-3 Month 1 I 25 mg alone or in combination with norethindrone ocetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus norethindrone ocetate therapy for initial management of the symptoms and signs of endometriosis should

8. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately. AFTER INJECTION 9. Withdraw the needle. Once the syringe hds been with drawn, activate immediately the LuproLoc* safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt.

be mode by the health care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone If the symptoms of endometriosis recur after a course of therapy, retreotment with a six-month course of LUPRON DEPOT-3 Month 11 25 mg administered every three months and norethindrone acetate 5 mg daily may be considered Retreatment beyond this one six month course cannot be recommended It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not recommended for retreotment If norethindrone acetate is contra¬ indicated for the individual patient, then retreotment is not recom¬ mended An assessment of cardiovascular risk ond management of risk fac¬ tors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and norethindrone ocetate

Uterine Leiomyomata (Fibroids) The recommended dose of LUPRON DEPOT-3 Month 11 25 mg is one injection. The symptoms associated with uter¬ ine leiomyomata will recur following discontinuation of therapy. If additional treatment with LUPRON DEPOT-3 Month 11.25 mg is contemplated, bone density should be assessed poor to initiation ot therapy to ensure that values are within nor¬ mal limits. Due to different release characteristics, a fractional dose of the 3-month depot formulation is not equivalent to the

Free

4. Keep the syringe UPRIGHT. Mix the microspheres (pow¬ der) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or cak¬ ing/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension. [See figure at top of next column] 5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to ex¬ pel the air from the syringe. Now the syringe is ready for injection. 7. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting

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514/ABBVIE • LUPRON DEPOT 11.25 MG ADDITIONAL INFORMATION • Dispose of the syringe according to local regulations/procedures. HOW SUPPLIED Each LUPRON DEPOT - 3 Month 11.25 mg kit (NDC 00743663-03) contain^: • one prefilled dual-chamber syringe • one plunger • two alcohol swabs • a complete prescribing information enclosure Each syringe contains sterile lyophilized microspheres which are leuprolide acetate incorporated in a biodegrad¬ able polymer of polylactic acid. When-mixed with 1.5 mL of the diluent, LUPRON DEPOT-3 Month 11.25 mg is admin¬ istered as a single IM injection EVERY THREE MONTHS. Store at 25°C (77°?); excursions permitted to 15-30°C (5986°F) [See USP Controlled Room Temperature] REFERENCES 1. NIOSH Alert: Preventing occupational exposures to anti¬ neoplastic and other hazardous drugs in healthcare set¬ tings. 2004. U.S. Department of Health and Human Ser¬ vices, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chap¬ ter 2. Controlling OccupatiQnal Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/ otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J HealthSyst Pharm. 2006; 63; 1172-1193. 4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommen¬ dations for practice (2nd. Ed.) Pittsburgh, PA: Oncology Nursing Society. Manufactured for AbbVie Inc. North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645 ™ - Trademark ® - Registered Trademark (No. 3663) Ref: 03-A892 - Revised October, 2013 © 2013, AbbVie Inc. * Shown in Product Identification Guide, page 303

LUPRON DEPOT® [lu-prdn] (leuprolide acetate for depot suspension) 7.5 mg for 1-Month Administration 22.5 mg for 3-Month Administration 30 mg for 4-Month Administration 45 mg for 6-Month Administration HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LUPRON DEPOT safely and effectively. See full pre¬ scribing information for LUPRON DEPOT. LUPRON DEPOT (leuprolide acetate for depot suspension) Initial U.S. Approval: 1989 -RECENT MAJOR CHANGESWarnings and Precautions, Convulsions. (5.5) 7/2013 Warnings and Precautions, Effect on QT/QTc 6/2014 Interval. (5.41 -INDICATIONS AND USAGELUPRON DEPOT is a gonadotropin releasing hormone (GnRH) agonist indicated for: • palliative treatment of advanced prostatic cancer. (1) -DOSAGE AND ADMINISTRATIONLUPRON DEPOT must be administered under the supervi¬ sion of a physician. Due to different release characteristics, the dosage strengths are not additive find must be selected based upon the desired dosing schedule. (2) • LUPRON DEPOT 7.5 mg for 1-month administration, given as a single intramuscular injection every 4' weeks. (2.1) • LUPRON DEPOT 22.5 mg for 3-month administration, given as a single intramuscular injection every 12 weeks. (2.2)

• LUPRON DEPOT 30 mg for 4-month administration, given as a single intramuscular injection every 16 weeks. (2.3)

• LUPRON DEPOT 45 mg for 6-month administration, given as a single intramuscular injection every 24 weeks. (2.4) -DOSAGE FORMS AND STRENGTHS7.5 mg, 22.5 mg, 30 mg, and 45 mg injections in a kit with prefilled dual chamber syringe. (3) -CONTRAINDICATIONS• Hypersensitivity to GnRH, GnRH agonist or any of the ex¬ cipients in LUPRON DEPOT. (4) • Pregnancy. (4, 8.1) -WARNINGS AND PRECAUTIONS• Increased serum testosterone (- 50% above baseline) dur¬ ing first week of treatment; monitor serum testosterone and PSA. (5.1, 5.6) • Isolated cases of transient worsening.of symptoms, or ad¬ ditional signs and symptoms of prostate cancer during the first few weeks of treatment. (5.1) 0 A small number of patients may experience a temporary increase in bone pain which can be managed symptom¬ atically. (5.1) ° Isolated cases of ureteral obstruction and spinal cord compression have been reported with GnRH agonists, which may contribute to paralysis with or without fatal complications. (5.1) " : . • Hyperglycemia and Diabetes: Hyperglycemia and an in¬ creased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. (5.2) • Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been re¬ ported in association with use of GnRH analogs in men. Monitor for cardiovascular disease and manage according to current clinical practice. (5.3) • Effect on QT/QTc Interval: Androgen deprivation ther¬ apy may prolong the QT interval. Consider risks and ben¬ efits. (5.4) ! , • Convulsions have been observed in patients with or with¬ out a history of predisposing factors. Manage convulsions according to the current clinical practice. (5.5) -ADVERSE REACTIONS• LUPRON DEPOT 7.5 mg for 1-month administra¬ tion: The most common adverse reactions (>10%) were general pain, hot flashes/sweats, GI disorders, edema, res¬ piratory disorder, urinary disorder. (6.1) • LUPRON DEPOT 22,5 mg for 3-month administra¬ tion: The most common adverse reactions (>10%) were general pain, injection site reaction, hot flashes/sweats, GI disorders, joint disorders, testicular atrophy, urinary dis¬ orders. (6.2) • LUPRON DEPOT 30 mg for 4-month administra¬ tion: The most common adverse reactions (>10%) were asthenia, flu syndrome, general pain, headache, injection site reaction, hot flashes/sweats, GI disorders, edema, skin reaction, urinary disorders, (6.3) • LUPRON DEPOT 45 mg for 6-month administra¬ tion: The most common adverse reactions (>10%) were hot flush, injection site pain, upper respiratory infection, and fatigue. (6.4) In postmarketing experience, mood swings, depression, rare reports of suicidal ideation and attempt, rare reports of pi¬ tuitary apoplexy, and rare reports of serious drug-induced liver injury have been reported. (6.5) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

-USE IN SPECIFIC POPULATIONS• Pediatric: These LUPRON DEPOT formulations are not indicated for use' in children. See the LUPRON DEPOT PED® package insert for the use of leuprolide acetate in children with central precocious puberty. • Geriatric: This label reflects clinical trials for LUPRON DEPOT in prostate cancer in which the majority of the subjects studied were at least 65 years of age. See 17 for PATIENT COUNSELING INFORMATION. Revised: 06/2014

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration 2.2 LUPRON DEPOT 22.5 mg for 3-Month Administration 2.3 LUPROlST DEPOT 30 mg for 4-Month Administration

Table 1. LUPRON DEPOT Recommended Dosing Dosage

7.5 mg for 1-Month Administration

22.5 mg for 3-Month Administration

30 mg for 4-Month Administration

45 mg for 6-Month Administration

Recommended dose

1 injection every 4 weeks

1 injection every 12 • weeks

1 injection every 16 weeks

1 injection every 24 weeks

2.4

LUPRON DEPOT 45 mg for 6-Month Administration 2.5 Reconstitution and Administration for Injection of LUPRON DEPOT 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tumor Flare 5.2 Hyperglycemia and Diabetes 5.3 Cardiovascular Diseases 5.4 Effect on QT/QTc Interval 5.5 Convulsions 5.6 Laboratory Tests 6 ADVERSE REACTIONS 1-Month for 6.1 LUPRON DEPOT 7.5 mg Administration 22.5 mg for 3-Month 6.2 LUPRON DEPOT Administration for 4-Month LUPRON DEPOT 30 mg 6.3 Administration LUPRON DEPOT for 6-Month 6.4 45 mg Administration 6.5 Postmarketing 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Males of Reproductive Potential 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility 14 CLINICAL STUDIES DEPOT 14.1 LUPRON 7.5 mg for 1-Month Administration 14.2 LUPRON DEPOT 22.5 mg for 3-Month Administration' 14.3 LUPRON DEPOT 30 mg for 4-Month Administration 14.4 LUPRON DEPOT 45 mg for 6-Month Administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

LUPRON DEPOT 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, and 45 mg for 6-month administration (leuprolide acetate) are indicated in the palliative treatment of advanced prostatic cancer. LUPRON DEPOT is a gonadotropin releasing hormone (GnRH) agonist. 2

DOSAGE AND ADMINISTRATION

LUPRON DEPOT must be administered under the supervi¬ sion of a physician. [See table 1 below) 2.1 LUPRON DEPOT 7.5 mg for 1-Month Administration The recommended dose of LUPRON DEPOT 7.5 mg for 1-month administration is one injection every 4 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different re¬ lease characteristics. Incorporated in a depot formulation, the lyophilized micro¬ spheres must be reconstituted and should be administered every 4 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS), read and follow the instructions in Section 2.5. 2.2 LUPRON DEPOT 22.5 mg for 3-Month Admin¬ istration The recommended dose of LUPRON DEPOT 22.5 mg for 3-month administration is one injection every 12 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different re¬ lease characteristics. Incorporated in a depot formulation, the lyophilized micro¬ spheres must be reconstituted and should be administered every 12 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS), read and follow the instructions in Section 2.5.

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LUPRON DEPOT 7.5,22.5,30,45 MG • ABBVIE/515

2.3 LUPRON DEPOT 30 mg for 4-Month Administration The recommended dose of LUPRON DEPOT 30 mg for 4-month administration is one injection every 16 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different re¬ lease characteristics. Incorporated in a depot formulation, the lyophilized micro¬ spheres must be reconstituted and should be administered every 16 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS), read and follow the instructions in Section 2.5. 2.4 LUPRON DEPOT 45 mg for 6-Month Administration The recommended dose of LUPRON DEPOT 45 mg for 6-month administration is one injection every 24 weeks. Do not use concurrently a fractional dose, or a combination of doses of this or any depot formulation due to different re¬ lease characteristics. Incorporated in a depot formulation, the lyophilized micro¬ spheres must be reconstituted and should be administered every 24 weeks as a single intramuscular injection. For optimal performance of the prefilled dual chamber sy¬ ringe (PDSt, read and follow the instructions in Section 2.5. 2.5 Reconstitution and Administration for Injection of LUPRON DEPOT • Reconstitute and administer the lyophilized microspheres as a single intramuscular injection. • Inject the suspension immediately or discard if not used within two hours, because LUPRON DEPOT does not con¬ tain a preservative. 1. Visually inspect the LUPRON DEPOT powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear and colorless. 2. Tb prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).

cipients in LUPRON DEPOT. Reports of anaphylactic re¬ actions to GnRH agonists have been reported in the med¬ ical literature. • Pregnancy LUPRON DEPOT may cause fetal harm when adminis¬ tered to a pregnant woman. Expected hormonal changes that occur with LUPRON DEPOT treatment increase the risk for pregnancy loss and fetal harm when administered to a pregnant woman. LUPRON DEPOT is contraindi¬ cated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be ap¬ prised of the potential hazard to the fetus [see Use in Spe¬ cific Populations (8.1)].

Middle Slodoers

Finger Grip

Barrel

From Stopper

5. Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to ex¬ pel the air from the syringe. Now the syringe is ready for injection. 7. After cleaning the injection site with an alcohol swab, ad¬ minister the intramuscular injection by inserting the nee¬ dle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated (see Figure 5).

o

Needle and Cap

Diluent Leuprolide Acetate Microsphere Powder

NOTE; If a blood vessel is accidentally penetrated, aspi¬ rated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc® safety device. If blood is present, remove the needle immediately. Do not inject the medication.

Figure 1

If a blood vessel is injured, btood will be visible in this section of the syringe

Figure 6

3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds! the plunger until the first middle stopper is at the blue line in the middle of ■, the barrel (see Figure 3).

8. Inject the entire contents of the syringe intramuscularly. 9. Withdraw the needle. Once the syringe has been with¬ drawn, immediately activate the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).

5 WARNINGS AND PRECAUTIONS 5.1 Tumor Flare Initially, LUPRON DEPOT, like other GnRH agonists, causes increases in serum levels of testosterone to approxi¬ mately HOVr above baseline during the first weeks of treat¬ ment. Isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. Transient worsening of symptoms may develop. A small number of pa¬ tients may experience a temporary increase in bone pain, which can be managed symptomatically. Patients with metastatic vertebral lesions and/or with uri¬ nary tract obstruction should be closely observed during the first few weeks of therapy. 5.2 Hyperglycemia and Diabetes Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hy¬ perglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabe¬ tes. Monitor blood glucose and/or glycosylated hemoglobin (HbAlc) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyper¬ glycemia or diabetes. 5.3 Cardiovascular Diseases Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when deter¬ mining a treatment for patients with prostate cancer. Pa¬ tients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardio¬ vascular disease and be managed according to current clin¬ ical practice. 5.4 Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT/QTc in¬ terval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in pa¬ tients taking drugs known to prolong the QT interval. Elec¬ trolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. 5.5 Convulsions Postmarketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included pa¬ tients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been as¬ sociated with convulsions such as bupropion and SSRls. Convulsions have also been reported in patients in the ab¬ sence of any of the conditions mentioned above. Patients re¬ ceiving a GnRH agonist who experience convulsion should be managed according to current clinical practice. 5.6 Laboratory Tests Monitor serum levels of testosterone following injection of LUPRON DEPOT 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, or 45 mg for 6-month administration In the majority of patients, testosterone levels increased above baseline, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks. Isee Clinical Studies (14) and Adverse Reactions (6)]. 6

Figure 7 10. Dispose of the syringe according to local regulations/ procedures. 3

4. Keep the syringe UPRIGHT. Mix the microspheres i pow¬ der I thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or cak¬ ing/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).

DOSAGE FORMS AND STRENGTHS

LUPRON DEPOT 7.5 mg for 1-month administration, 22.5 mg for 3-month administration, 30 mg for 4-month administration, and 45 mg for 6-month administration are each supplied as a kit with prefilled dual chamber syringe. 4

CONTRAINDICATIONS

LUPRON DEPOT is contraindicated in: • Hypersensitivity LUPRON DEPOT is contraindicated in individuals with known hypersensitivity to GnRH agonists or any of the ex¬

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 LUPRON DEPOT 7.5 mg for 1-Month Administration In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment.

Information on the AbbVie. Inc products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110.

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516/ABBVIE • LUPRON DEPOT 7.5,22.5,30,45 MG Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematu¬ ria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms /see Warnings and Precautions (5.1)]. In a clinical trial of LUPRON DEPOT 7.5 mg for 1-month administration, the following adverse reactions were re¬ ported in 5% or more of the patients during the initial 24-week treatment period.

Table 2. Adverse Reactions Reported in 2 5% of Patients LUPRON DEPOT 7.5 mg for 1-Month Administration (N=56> N

(%)

General pain

13

(23.2)

Infection

3

(5.4)

32

(57.1)

8

(14.3)

8

(14.3)

3

(5.4)

6

(10.7)

Urinary disorder

7

(12.5)

Impotence*

3

(5.4)

Testicular atrophy*

3

(5.4)

Body As A Whole

Cardiovascular System Hot flashes/sweats* Digestive System GI disorders Metabolic and Nutritional Disorders Edema Nervous System Libido decreased* Respiratory System Respiratory disorder Urogenital System

* Due to the expected physiologic effect of decreased testosterone levels. In this same study, the following adverse reactions were re¬ ported in less than 5% of the patients on LUPRON DEPOT 7.5 mg for 1-montb administration. Body As A Whole - Asthenia, Cellulitis, Fever, Headache, In¬ jection site reaction, Neoplasm Cardiovascular System - Angina, Congestive heart failure Digestive System - Anorexia, Dysphagia, Eructation, Pepticulcer Hemic and Lymphatic System - Ecchymosis Musculoskeletal System - Myalgia Nervous System - Agitation, Insomnia/sleep disorders, Neu¬ romuscular disorders Respiratory System - Emphysema, Hemoptysis, Lung edema. Sputum increased Skin and Appendages - Hair disorder, Skin reaction Urogenital System - Balanitis. Breast enlargement, Urinary tract infection Laboratory Abnormalities Abnormalities of certain parameters were observed, but their relationship to drug treatment are difficult to assess in this population. The following were recorded in 25% of pa¬ tients at final visit: Decreased albumin, decreased hemoglo¬ bin/hematocrit, decreased prostatic acid phosphatase, de¬ creased total protein, decreased urine specific gravity, hyperglycemia, hyperuricemia, increased BUN, increased creatinine, increased liver function tests (AST, LDH), in¬ creased phosphorus, increased platelets, increased prostatic acid phosphatase, increased total cholesterol, increased urine specific gravity, leukopenia. 6.2 LUPRON DEPOT 22.5 mg for 3-Month Admin¬ istration In two clinical trials of LUPRON DEPOT 22.5 mg for 3-month administration, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician in 5% or more of the patients receiving the drug. Often, causality is difficult to assess in patients with metastatic prostate cancer. Re¬ actions considered not drug-related are excluded.

Body As A Whole - Abscess, Accidental injury. Allergic reac¬ tion, Cyst, Fever, Generalized edema, Hernia, Neck pain. Table 3. Adverse Reactions Reported in 2 5% of Patients Neoplasm Cardiovascular System - Atrial fibrillation, Deep thrombo¬ LUPRON DEPOT 22.5 mg for 3-Month Administration phlebitis, Hypertension Digestive System - Anorexia, Eructation, Gastrointestinal N=94 (%) Body System/Reaction hemorrhage, Gingivitis, Gum hemorrhage, Hepatomegaly, Increased appetite, Intestinal obstruction, Periodontal ab¬ Body As A Whole scess Hemic and Lymphatic System - Lymphadenopathy (7.4) 7 Asthenia Metabolic and Nutritional Disorders - Healing abnormal, Hypoxia, Weight loss 25 (26.6) General Pain Musculoskeletal System - Leg cramps, Pathological frac¬ ture, Ptosis (6.4) 6 Headache Nervous System - Abnormal thinking. Amnesia, Confusion, Convulsion, Dementia, Depression, Insomnia/sleep disor¬ (13.8) 13 Injection Site Reaction ders, Libido decreased", Neuropathy, Paralysis Respiratory System - Asthma, Bronchitis, Hiccup, Lung dis¬ Cardiovascular System order, Sinusitis, Voice alteration Skin and Appendages - Herpes zoster, Melanosis (58.5) 55 Hot flashes/Sweats Urogenital System - Bladder carcinoma, Epididymitis, Im¬ potence , Prostate disorder, Testicular atrophy", Urinary in¬ Digestive System continence, Urinary tract infection. * Physiologic effect of decreased testosterone. 15 (16.0) GI Disorders Laboratory Abnormalities Abnormalities of certain parameters were observed, but Musculoskeletal System their relationship to drug treatment is difficult to assess in 11 (11.7) this population. The following were recorded in > 5% of pa¬ Joint Disorders tients: Decreased bicarbonate, Decreased hemoglobin/heCentral/Peripheral Nervous System matocrit/RBC, Hyperlipidemia (total cholesterol, LDLcholesterol, triglycerides), Decreased HDL-cholesterol, (6.4) 6 Dizziness/Vertigo Eosinophilia, Increased glucose, Increased liver function tests (ALT, AST, GGTP, LDH), Increased phosphorus. Addi¬ (8.5) 8 Insomnia/Sleep Disorders tional laboratory abnormalities were reported: Increased BUN and PT, Leukopenia, Thrombocytopenia, Uricaciduria. (9.6) 9 Neuromuscular Disorders 6.4 LUPRON DEPOT 45 mg for 6-Month Administration One open label, multicenter study was conducted with Respiratory System LUPRON DEPOT 45 mg for 6-month administration in 151 prostate cancer patients. Patients were treated for (6.4) 6 Respiratory Disorders 48 weeks, with 139/151 receiving two injections 24 weeks apart. Skin and Appendages In the above described clinical trial, the following adverse events were reported in > 5% of the patients during the 8 (8.5) Skin Reaction treatment period. The Table 5 includes all adverse events reported in >5% of patients as well as the incidences of Urogenital System these adverse events that were considered, by the treating physician, to have a definite or possible relationship to (20.2) 19 Testicular Atrophy LUPRON. [See table 5 at top of page 518] 14 (14.9) Urinary Disorders The following adverse events led to discontinuation; fatigue, hot flush, second primary neoplasm, asthenia, coronary ar¬ In these same studies, the following adverse reactions were tery disease, constipation, hyperkalemia, and sleep disor¬ reported in less than 5% of the patients on LUPRON der. Serious adverse events in > 2% of patients, regardless DEPOT 22.5 mg for 3-month administration. of causality, included chronic obstructive pulmonary dis¬ Body As A Whole - Enlarged abdomen, Fever ease, coronary artery disease/angina, cerebrovascular acci¬ Cardiovascular System - Arrhythmia, Bradycardia, Heart dent/transient ischemic attack, pneumonia, and second pri¬ failure, Hypertension, Hypotension, Varicose vein mary neoplasms. Digestive System - Anorexia, Duodenal ulcer, Increased ap¬ Laboratory Abnormalities petite, Thirst/dry mouth At baseline, 13.9% of patients had a CTCAE v4.0 grade 1 or Hemic and Lymphatic System - Anemia, Lymphedema 2 decreased hemoglobin. During the study, 42.4% of subjects had grade 1 decreased hemoglobin (10 - 400 mg/dL) during the study. Special Senses - Abnormal vision. Amblyopia, Dry eyes, Tin¬ 6.5 Postmarketing nitus The following adverse reactions have been identified during Urogenital System - Gynecomastia, Impotence', Penis dis¬ post-approval use of LUPRON DEPOT. Because these reac¬ orders, Testis disorders. tions are reported voluntarily from a population of uncer¬ ’ Physiologic effect of decreased testosterone. tain size, it is not always possible to reliably estimate their Laboratory Abnormalities frequency or establish a causal relationship to drug expo¬ Abnormalities of certain parameters were observed, but are sure. difficult to assess in this population. The following were re¬ During postmarketing surveillance, which includes other corded in >5% of patients: Increased BUN, Hyperglycemia, dosage forms and other patient populations, the following Hyperlipidemia (total cholesterol, LDL-cholesterol, triglyc¬ adverse reactions were reported. erides), Hyperphosphatemia, Abnormal liver function tests, Like other drugs in this class, mood swings, including de¬ Increased PT, Increased PTT. Additional laboratory abnor¬ pression, have been reported. There have been very rare re¬ malities reported were: Decreased platelets, Decreased po¬ ports of suicidal ideation and attempt. Many, but not all, of tassium and Increased WBC. these patients had a history of depression or other psychi¬ 6.3 LUPRON DEPOT 30 mg for 4-Month Administration atric illness. Patients should be counseled on the possibility The 4-month formulation of LUPRON DEPOT 30 mg was of development or worsening of depression during treat¬ utilized in clinical trials that studied th,e drug in 49 nonment with LUPRON. orchiectomized prostate cancer patients for 32 weeks or Symptoms consistent with an anaphylactoid or asthmatic longer and in 24 orchiectomized prostate cancer patients for process have been rarely (incidence rate of about 0.002%) 20 weeks reported. Rash, urticaria, and photosensitivity reactions In the above described clinical trials, the following adverse have also been reported. reactions were reported in > 5% of the patients during the Changes in Bone Density - Decreased bone density has been treatment period. reported in the medical literature in men who have had or¬ [See table 4 at top of next page) , chiectomy or who have been treated with a GnRH agonist In these same studies, the following adverse reactions were analog. In a clinical trial, 25 men with prostate cancer, 12 of whom had been treated previously with leuprolide acetate reported in less than 5% of the patients on LUPRON I for at least six months, underwent bone density studies as a DEPOT 30 mg for 4-month administration.

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LUPRON DEPOT 7.5,22.5,30,45 MG • ABBVIE/517

Look for PDR drug information and services in your EHR result of pain. The leuprolide-treated group had lower bone density scores than the nontreated control group. It can be anticipated that long periods of medical castration in men will have effects on bone density. Pituitary apoplexy - During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome second¬ ary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has pre¬ sented as sudden headache, vomiting, visual changes, oph¬ thalmoplegia. altered mental status, and sometimes cardio¬ vascular collapse. Immediate medical attention has been required. Localized reactions including induration and abscess have been reported at the site of injection. Symptoms consistent with fibromyalgia (e.g., joint and mus¬ cle pain, headaches, sleep disorders, gastrointestinal dis¬ tress, and shortness of breath) have been reported individ¬ ually and collectively. Cardiovascular Svstem - Hypotension, Myocardial infarction, Pulmonary embolism Respiratory, thoracic and mediastinal disorder - Interstitial lung disease Hepato-biliary disorder - Serious drug-induced liver injury Hemic and Lymphatic System - Decreased WBC Central/Peripheral Nervous Svstem - Convulsion, Periphoral neuropathy. Spinal fracture/paralysis Endocrine System - Diabetes Musculoskeletal System - Tenosvnovitis-like symptoms Urogenital System - Prostate pain See other LUPRON DEPOT and LUPRON Injection pack¬ age inserts for other reactions reported in women and pedi¬ atric populations. 7

DRUG INTERACTIONS

No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. 7.1 Drug/Laboratory Test Interactions Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal system. Nor¬ mal function is usually restored within three months after treatment is discontinued. Due to the suppression of the pituitary-gonadal system by LUPRON DEPOT, diagnostic tests of pituitary gonadotropic and gonadal functions con¬ ducted during treatment and up to three months after dis¬ continuation of LUPRON DEPOT may be affected. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X /see Contraindications 5% of Patients LUPRON DEPOT 30 mg for 4-Month Administration Body System/Events

Nonorchiectomized

Orcfiiectomized

Study 013

Study 012

N=49

Asthenia

6

(12.2)

1

(4.2)

Flu Syndrome

6

(12.2)

0

(0.0)

General Pain

16

(32.7)

1

(4.2)

Headache

5

(10.2)

1

(4.2)

Injection Site Reaction

4

(8.2)

9

(37.5)

23

(46.9)

2

(8.3)

5

(10.2)

3

(12.5)

Dehydration

4

(8.2)

0

(0.0)

Edema

4

(8.2)

5

(20.8)

Joint Disorder

8

(16.3)

1

(4.2)

Myalgia

4

(8.2)

0

(0.0)

Dizziness/Vertigo

3

(6.1)

2

(8.3)

Neuromuscular Disorders

3

(6.1)

1

(4.2)

Paresthesia

4

(8.2)

1

(4.2)

4

(8.2)

1

(4.2)

6

(12.2)

0

(0.0)

5

(10.2)

4

(16.7)

Body As A Whole

Cardiovascular System Hot fl ashes/Sweata Digestive System GI Disorders Metabolic and Nutritional Disorders

Musculoskeletal System

Nervous System

Respiratory System Respiratory Disorder Skin and Appendages Skin Reaction Urogenital System Urinary Disorders

8.5 Geriatric Use In the clinical trials for LUPRON DEPOT in prostate cancer 80% of the subjects studied were at least 65 years of age. Therefore, the labeling reflects the efficacy and safety of LUPRON DEPOT in this population. 8.6 Males of Reproductive Potential Infertility LUPRON DEPOT may reduce fertility based on animal studies and its mechanism of action. There are no data in humans relating to male fertility following treatment with leuprolide acetate. In animal studies, administration of leuprolide acetate to rats as a monthly depot formulation caused atrophy of the reproductive organs and suppression of reproductive function. These changes were reversible upon cessation of treatment [see Nonclinical Toxicology (13. t)J. 10

OVERDOSAGE

There is no experience of overdosage in clinical trials. In rats, a single subcutaneous dose of 100 mg/kg (approxi¬ mately 4,000 times the estimated daily human dose based on body surface areal, resulted in dyspnea, decreased activ¬ ity, and excessive scratching. In early clinical trials with daily subcutaneous leuprolide acetate, doses as high as 20 mg/day for up to two years caused no adverse effects dif¬ fering from those observed with the 1 mg/day dose. 11

DESCRIPTION

Leuprolide acetate is a synthetic nonapeptide analog of nat¬ urally occurring gonadotropin-releasing hormone (GnRH). The analog possesses greater potency than the natural hor¬ mone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-

tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-Nethyl-L-prolinamide acetate (salt) with the following structural formula: (See chemical structure at top of next page! LUPRON DEPOT 7.5 mg for 1-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, becomes a suspension intended as a monthly intra¬ muscular injection The front chamber of LUPRON DEPOT 7.5 mg for 1-month administration prefilled dual-chamber syringe contains leuprolide acetate (7.5 mg', purified gelatin (1.3 mg). DL-lactic and glycolic acids copolymer (66.2 mgl, and D-mannitol (13.2 mgi. The second chamber of diluent con¬ tains carboxymethylcellulose sodium (5 mg). D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 22.5 mg for 3-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 12 WEEKS The front chamber of LUPRON DEPOT 22.5 mg for 3-month administration prefilled dual-chamber syringe con¬ tains leuprolide acetate (22.5 mgl, poly lactic acid 1198.6 mgi and D-mannitol (38.9 mg). The second chamber of diluent

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110.

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518/ABBVIE • LUPRON DEPOT 7.5,22.5,30,45 MG Table 5. Adverse Events in > 5% of Patients LUPRON DEPOT 45 mg for 6-Month Administration

Treatment Related

Treatment Emergent N = 151

(%)

N = 151

(%)

Hot Flush/Flushing

89

58.9

88

58.3

Injection Site Pain/Discomfort

29

19.2

16

10.6

Upper Respiratory Tract Infection/Influenza-like Illness1

32

21.2

0

Fatigue/Lethargy

20

13.2

18

11.9

Constipation

15

9.9

5

3.3

Arthralgia

14

9.3

2

1.3

Insomnia/Sleep Disorder

13

8.6

5

3.3

Headache/Sinus Headache

12

7.9

3

2.0

Musculoskeletal Pain/ Myalgia

.12

7.9

3

2.0

Second Primary Neoplasm2

11

7.3

0

0

Cough

10

6.6

2

1.3

Hematuria/Hemorrhagic Cystitis

10

6.6

0

0

Hypertension/BP Increased

10

6.6

3

2.0

Rash

9

6.0

3

2.0

Dysuria

9

6.0

1

0.7

Urinary Tract Infection/Cystitis

9

6.0

0

0

Anemia/Hemoglobin Decreased

10

6.6

2

1.3

Back Pain

8

5.3

0

0

COPD

8

5.3

0

0

Dizziness

8

5.3

3

2.0

Dyspnea/Dyspnea on Exertion

8

5.3

2

1.3

Nocturia

8

5.3

2

1.3

Peripheral/Pitting Edema

8

5.3

2.

1.3

Coronary Artery Disease/Angina

8

5.3

1

0.7

Adverse Event

•

'

0

'includes influenza, nasal congestion, nasopharyngitis, rhinorrhea, upper respiratory tract infection, and viral upper respiratory tract infection "Includes basal cell carcinoma, bladder transitional cell carcinoma, lung neoplasm, malignant melanoma, non-Hodgkin’s lymphoma, and squamous cell carcinoma

OH

I-IS

OH

?

ii

i

OH

OH

n

ii

i

i

O OH

"

n

OH

’

"

OH

1

O

"i

ii

I

O

H

,

2 3 > ,.2CH3COOH

CH -C-N-CH - C - N-CH - C - N-CH - C C-N-CH - C-N-CH -C-N-CH-C-N-Lq _ N - CH CH

2

ch

CHo

I^^N-H

2

2

CH

ow

CH3t CH

ch t CH3-CH CH

3

CH,

ch

2 ch2 I ch2 CH

I N -H

03

i

C=NH

i

2

nh

contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for in¬ jection, USP, and glacial acetic acid, USP to control pH. LUPRON DEPOT 30 mg for 4-month administration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an intramuscular injection to be given ONCE EVERY 16 WEEKS The front chamber of LUPRON DEPOT 30 mg for 4-month administration prefilled dual-chamber syringe contains leuprolide acetate (30 mg), polylactic acid (264.8 rag) and D-mannitol 2 patients) adverse reactions were: injection site pain, weight increased, headache, mood altered, and injection site swelling. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or

CPP is defined as early onset of secondary sexual character¬ istics (generally earlier than 8 years of age in girls and 9 years of age in boys) associated with pubertal pituitary go¬ nadotropin activation. It may show a significantly advanced bone age that can result in diminished adult height. Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentra¬ tions of luteinizing hormone (LH) (basal or stimulated with a GnRH analog), sex steroids, and assessment of bone age versus chronological age. Baseline evaluations should in¬ clude height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumor), pelvic/ testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumor), and adrenal ster¬ oid measurements to exclude congenital adrenal hyperpla¬ sia. 2 DOSAGE AND ADMINISTRATION 2.1 Dose and Principles of Dosing 7.5 mg, 11.25 mg, or 15 mg for 1-month administration LUPRON DEPOT-PED must be administered under the su¬ pervision of a physician. LUPRON DEPOT-PED is administered as a single intra¬ muscular injection once a month. The starting dose will be dictated by the child’s weight, as indicated in the table be¬ low.

Table 1. Dosing Recommendations Based on Body Weight for LUPRON DEPOT-PED 1-month Formulations

www.fda.gov/medwatch

Body Weight

Recommended Dose

S 25 kg

7.5 mg

> 25-37.5 kg

11.25 mg

> 37.5 kg

15 mg

-USE IN SPECIFIC POPULATIONS• The use of LUPRON DEPOT-PED in children under 2.. years is not recommended. (8.4) See 17 for PATIENT COUNSELING INFORMATION Revised: 06/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dose and Principles of Dosing 7.5 mg, 11.25 mg, or 15 mg for 1-month administra¬ tion 2.2 Dose and Principles of Dosing 11.25 mg or 3ft mg for 3-month administration 2.3 Reconstitution and Administration Instruc¬ tions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Initial Rise of Gonadotropins and Sex Steroid Levels 5.2 Convulsions 5.3 Monitoring and Laboratory Tests 6 ADVERSE REACTIONS 6.1 LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration - Clinical Trials Experience 6.2 LLTPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration - Clinical Trials Ex¬ perience 6.3 Postmarketing 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric U$(e 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PILARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis. Mutagenesis. Impairment of Fertility 14 CONICAL STUDIES 14.1 LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration 14.2 LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

LITRON DEPOT-PED is indicated in the treatment of chil¬ dren with central precocious puberty (CPP).

The dose of LLTPRON DEPOT-PED must be individualized for each child. If adequate hormonal and clinical suppres¬ sion is not achieved with the starting dose, it should be in¬ creased to the next available higher dose (e.g. 11.25 mg or 15 mg at the next monthly injection). Similarly, the dose may be adjusted with changes in body weight. The injection site should be varied periodically The goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical pa¬ rameters should be monitored after 1-2 months of initiating therapy and with each dose change to ensure adequate pi¬ tuitary gonadotropin suppression. Once a dose that results in adequate hormonal suppression is found, it can often be maintained for the duration of therapy in most children. It is recommended, however, that adequate hormonal suppres¬ sion be verified in such patients as weight can increase sig¬ nificantly while on therapy. Each LUPRON DEPOT-PED strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose. LUPRON DEPOT-PED should be discontinued at the ap¬ propriate age of onset of puberty at the discretion of the physician. For optimal performance of the prefilled dual chamber sy¬ ringe (PDS). read and follow the instructions in Section 2.3. 2.2 Dose and Principles of Dosing 11.25 mg or 30 mg for 3-month administration LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration must be administered under the supervision of a physician. LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration should be administered once every three months (12 weeks) as a single intramuscular injection. Re¬ gardless of the dose chosen, the goal of therapy is to sup¬ press pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteris¬ tics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other avail¬ able GnRH agonists indicated for the treatment of CPP should be considered. Each LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration strength and formulation has different re¬ lease characteristics. Do not use partial syringes or a com¬ bination of syringes to achieve a particular dose. LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration treatment should be discontinued at the ap¬ propriate age of onset of puberty at the discretion of the physician. For optimal performance of the prefilled dual chamber sy¬ ringe l PDS). read and follow the instructions in Section 2.3.

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LUPRON DEPOT-PED • ABBVIE/521

Reconstitution and Administration Instructions

5.2

• The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. • Since LUPRON DEPOT-PED does not contain a preserva¬ tive, the suspension should be injected immediately or dis¬ carded if not used within two hours. • As with other drugs administered by injection, the injec¬ tion site should be varied periodically. 1. The LUPRON DEPOT-PED powder should be visually in¬ spected and the syringe should NOT BE USED if clump¬ ing or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear. 2. TY> prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.

NOTE: Aspirated blood would be visible just below the hier look connection if a blood vessel is accidentally pen¬ etrated. If present, blood can be seen through the trans¬ parent I.uproLoc' safety device. If blood is present re¬ move the needle immediately. Do not inject the medication.

8. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT-PED should be mixed and. used immediately. AFTER INJECTION

3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.

Convulsions

Post marketing reports of convulsions have been observed in patients on leuprolide acetate therapy. These included pa¬ tients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associ¬ ated with convulsions such as bupropion and SSRIs. Con¬ vulsions have also been reported in patients in the absence of any of the conditions mentioned above. 5.3 Monitoring and Laboratory Tests Response to LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration should bo monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels beginning 1-2 months following initia¬ tion of therapy, with changing doses, or potentially during therapy in order to confirm maintenance of efficacy. Mea¬ surement of bone age for advancement should be done every 6-12 months. Response to LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels at months 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. Ad¬ ditionally, height (for calculation of growth rate) and bone age should be assessed every 6-12 months. Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Go¬ nadotropins and/or sex steroids may increase or rise above prepubertal levels if the dose is inadequate. Noncompliance with drug regimen or inadequate dosing may result in in¬ adequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels /sec Clinical Studies (14) and Adverse Reactions (6)1. 6

9. Withdraw the needle. Once the syringe has been with¬ drawn, activate immediately the LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device is fully extended over the needle and a CLICK is heard or felt.

ADVERSE REACTIONS

The most common adverse reactions with GnRII agonists including LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration and LUPRON DEPOTPED 11.25 mg or 30 mg for 3-month administration are in¬ jection site reactions/pain including abscess, general pain, headache, emotional lability and hot flushes/sweating. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimula¬ tory effect of the drug (hormonal flare effect). Therefore, an increase in clinical signs and symptoms of puberty may be observed /see Warnings and Precautions (5.1)1. 6.1

LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for

1-month administration - Clinical Trials Experience

4. Keep the syringe UPRIGHT. Mix the microspheres (pow¬ der) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your fin¬ ger to disperse. DO NOT USE if any of the powder has not gone into suspension.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the follow¬ ing adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions which are not considered drug-related are excluded. ADDITIONAL INFORMATION

Table 2. Percentage of Patients with Treatment-Emergent

• Dispose of the syringe according to local regulations/procedures. 3

Adverse Reactions Occurring in S2% of Pediatric Patients Receiving LUPRON DEPOT-PED 1-month

DOSAGE FORMS AND STRENGTHS Number of Patients

LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration and LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is provided in a prefilled dual chamber syringe for intramuscular injec¬ tion. 4

5. Hold the syringe l BRIGHT. With the opposite hand pull the needle cap upward without twisting. 6. Keep the syringe UPRIGHT. Advance the plunger to ex¬ pel the air from the syringe. Now the syringe is ready for injection. 7. After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, an¬ terior thigh, or shoulder, injection sites should hi’ alter¬ nated.

IN = 421)

1%)

N 0

Body as a Whole

CONTRAINDICATIONS

• Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOT-PED. Reports of anaphy¬ lactic reactions to GnRH agonists have been reported in the medical literature. • All formulations of LUPRON DEPOT may cause fetal harm if administered to a pregnant woman. When LUPRON DEPOT was administered subcutaneously to rabbits it pnxluced a dose related increase in major fetal abnormalities, and fetal mortality. The possibility exists that spontaneous alx>rtion may occur if the drug is admin¬ istered during pregnancy. LUPRON DEPOT-PED is con¬ traindicated in women who are or may become pregnant If this drug is inadvertently used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Initial Rise o< Gonadotropins and Sex Steroid Levels During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug Therefore, an increase in clinical signs and symptoms of puberty may be observed /sec Clini¬ cal Pharmacology (12.31!.

Injection Site Reactions Including Abscess*

37

(9)

General Rain

12

(3)

1 leadache

11

(3)

9

(2)

Cardiovascular System Vasodilation

Integumentary System (Skin and Appendages)

j i |

Acne/Seborrhea

13

(3)

Rash Including Erythema Mulliforme

12

(3)

Information on the AbbVie, Inc products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110.

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522/ABBVIE • LUPRON DEPOT-PED

ch2

Safe use of leuprolide acetate in pregnancy has not been es¬ tablished in clinical studies. Before starting and during treatment with leuprolide acetate, it is advisable to estab¬ lish whether the patient is pregnant. Leuprolide acetate is not a contraceptive. If contraception is required, a nonhormonal method of contraception should be used. When LUPRON DEPOT was administered subcutaneously to groups of rabbits as one time dosing on day 6 of preg¬ nancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/1900 to 1/19 of the human pediatric dose) it produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and de¬ creased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose in rats. No fe¬ tal malformations but increase in fetal resorptions and mor¬ tality were observed in rat and rabbit when the daily injec¬ tion formulation of leuprolide acetate was dosed subcutaneously once daily at lower doses (0.1-1 mcg/kg/day in rabbit; 10 mcg/kg/day in rat) during the period of organ¬ ogenesis. The effects on fetal mortality are logical conse¬ quences of the alterations in hormonal levels brought about by this drug. Therefore, the possibility exists that spontane¬ ous abortion may occur if the drug is administered during pregnancy.

ch2

8.3

Table 3. Percentage of Patients with Treatment-Emergent Adverse Reactions Occurring in 2 2 Pediatric Patients Receiving LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration. Overall

30 mg every 3 Months N=42

11.25 mg every 3 Months N=42

N = 84

N

%

N

%

N

%

8

(19)

9

(21)

17

(20)

Weight increased

3

(7)

3

(7)

6

(7)

Headache

1

(2)

3

(7)

4

(5)

Mood altered

2

(5)

2

(5)

4

(5)

Injection site swelling

1

(2)

1

(2)

2

(2)

•

Injection site pain

O H

OH

O H

O

11 1

II 1

II

II

1

-C-N-CH-■C-N-CH-C--N-CH-C-

I CH2

CH2

ch2 O I

OH

1

H 'N-H

ch2

ch2 -oI

I

ch3-ch .

CH3

ch3

-CH2CH3 • ,_2CH3COOH

ch2 N—H C—NH nh2

8.4

6.3 Postmarketing

Emotional Lability

19

(5)

Urogenital System Vaginitis/Vaginal Bleeding/ Vaginal Discharge

13

(3)

* Most events were mild or moderate in severity. Less Common Adverse Reactions The following treatment-emergent adverse reactions were reported in less than 2% of the patients and are listed below by body system. Body as a Whole - aggravation of preexisting tumor and de¬ creased vision, allergic reaction, body odor, fever, flu syn¬ drome, hypertrophy, infection; Cardiovascular System bradycardia, hypertension, peripheral vascular disorder, syncope; Digestive System - constipation, dyspepsia, dys¬ phagia, gingivitis, increased appetite, nausea/vomiting; En¬ docrine System - accelerated sexual maturity, feminization, goiter; Hemic and Lymphatic System - purpura; Metabolic and Nutritional Disorders - growth retarded, peripheral edema, weight gain; Musculoskeletal System - arthralgia, joint disorder, myalgia, myopathy; Nervous System - de¬ pression, hyperkinesia, nervousness, somnolence; Respira¬ tory System - asthma, epistaxis, pharyngitis, rhinitis, sinusitis; Integumentary System (Skin and Appendages) alopecia, hair disorder, hirsutism, leukoderma, nail disor¬ der, skin hypertrophy; Urogenital System - cervix disorder/ neoplasm, dysmenorrhea, gynecomastia/breast disorders, menstrual disorder, urinary incontinence. Laboratory. The following laboratory events were re¬ ported as adverse reactions; antinuclear antibody present and increased sedimentation rate. 6.2 LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration - Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ISee table 3 above) Less Common Adverse Reactions The following treatment-emergent adverse reactions were reported in one patient and are listed below by system or¬ gan class: Gastrointestinal Disorders - abdominal pain, nausea; Gen¬ eral Disorders and Administration Site Conditions - asthe¬ nia, gait disturbance, injection site abscess sterile, injection site hematoma, injection site induration, injection site warmth, irritability; Metabolic and Nutritional Disorders decreased appetite, obesity; Musculoskeletal and Connective Tissue Disorders - musculoskeletal pain, pain in extremity; Nervous System Disorders - crying, dizziness; Psychiatric Disorders - tearfulness; Respiratory. Thoracic and Medias¬ tinal Disorders - cough; Skin and Subcutaneous Tissue Dis¬ orders - hyperhidrosis; Vascular Disorders - pallor.

The following adverse events have been observed with this or other formulations of leuprolide acetate injection. As leuprolide has multiple indications, and therefore patient populations, some of these adverse events may not be appli¬ cable to every patient. Allergic reactions (anaphylactic, rash, urticaria, and photo¬ sensitivity reactions) have also been reported. Gastrointestinal Disorders: nausea, abdominal pain, vom¬ iting; General Disorders and Administration Site Conditions: chest pain, injection site reactions including induration and abscess have been reported; Investigations: decreased WBC, weight increased; Metabolism and Nutrition Disorders: diabetes mellitus; Musculoskeletal and Connective Tissue Disorders: teno¬ synovitis-like symptoms; Nervous System Disorders: neuropathy peripheral, con¬ vulsion, spinal fracture/paralysis; Skin and Subcutaneous Tissue Disorders: hot flush, flush¬ ing, hyperhidrosis; Reproductive System and Breast Disorders: prostate pain; Vascular Disorders: hypertension, hypotension. Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome second¬ ary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has pre¬ sented as sudden headache, vomiting, visual changes, oph¬ thalmoplegia, altered mental status, and sometimes cardio¬ vascular collapse. Immediate medical attention has been required. See other LUPRON DEPOT and LUPRON Injection pack¬ age inserts for other events reported in different patient populations. 7

DRUG INTERACTIONS

No pharmacokinetic-based drug-drug interaction studies have been conducted; however, drug interactions are not ex¬ pected to occur [see Clinical Pharmacology (12.3)]. 7.1

Drug/Laboratory Test Interactions

Administration of LUPRON DEPOT-PED in therapeutic doses results in suppression of the pituitary-gonadal sys¬ tem. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to six months after discontinuation of LUPRON DEPOTPED may be affected. Normal pituitary-gonadal function is usually restored within six months after treatment with LUPRON DEPOT-PED is discontinued. 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category X LUPRON DEPOT-PED is contraindicated in women who are or may become pregnant while receiving the drug /see Contraindications (4)].

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of LUPRON DEPOT-PED in children under 2 years is not recommended. 8.5

Nervous System

Nursing Mothers

It is not known whether leuprolide acetate is excreted in hu¬ man milk. LUPRON DEPOT-PED should not be used by nursing mothers.

Geriatric Use

LUPRON DEPOT 1-month 7.5 mg and 4-month 30 mg are indicated for the palliative treatment of advanced prostate cancer. For LUPRON DEPOT-PED 11.25 mg or 15 mg for 1-month administration and LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration, no clinical information is available for persons aged 65 and over. 10

OVERDOSAGE

In early clinical trials using leuprolide acetate in adult pa¬ tients, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose. In rats, subcutaneous administration of leuprolide acetate as a single dose 225 times the recommended human pediat¬ ric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injec¬ tion site. There is no evidence at present that there is a clin¬ ical counterpart of this phenomenon. In cases of overdosage, standard of care monitoring and management principles should be followed. 11

DESCRIPTION

Leuprolide acetate is a synthetic nonapeptide analog of nat¬ urally occurring gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-Lhistidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-N-ethyl-L-prolinamide acetate (salt) with the fol¬ lowing structural formula: (See chemical structure above] LUPRON DEPOT-PED 7.5 mg, 1-month administration

11.25 mg,

or

15 mg for

LUPRON DEPOT-PED is available in a prefilled dual¬ chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension in¬ tended as a single intramuscular injection. The front chamber of LUPRON DEPOT-PED 7.5 mg. 11.25 mg, and 15 mg prefilled dual-chamber syringe con¬ tains leuprolide acetate (7.5/11.25/15 mg), purified gelatin (1.3/1.95/2.6 mg). DL-lactic and glycolic acids copolymer (66.2/99.3/132.4 mg), and D-mannitol (13.2/19.8/26.4 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP. and glacial acetic acid, USP to control pH. LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as an in¬ tramuscular injection to be given ONCE EVERY THREE MONTHS

The front chamber of LUPRON DEPOT-PED 11.25 mg for 3-month administration prefilled dual-chamber syringe con¬ tains leuprolide acetate (11.25 mg), polylactic acid (99.3 mgi and D-mannitol (19.45 mg). The second chamber of diluent contains carboxymethylcellulose sodium (7.5 mg), D-mannitol (75.0 mg), polysorbate 80 (1.5 mg), water for in¬ jection, USP, and glacial acetic acid, USP to control pH The front chamber of LUPRON DEPOT-PED 30 mg for 3-month administration prefilled dual-chamber syringe con¬ tains leuprolide acetate (30 mg), polylactic acid (264.8 mg) and D-mannitol (51.9 mg'. The second chamber of diluent 1 contains carboxymethylcellulose sodium (7.5 mg), ; D-mannitol (75.0 mg), polysorbate 80 (1.5 mgi, water for in¬ jection, LTSP, and glacial acetic acid. USP to control pH.

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Look for PDR drug information and services in your EHR 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Leuprolide acetate, a GnRH agonist, acts as a potent inhib¬ itor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide acetate results in suppression or “downregulation’ of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are re¬ versible on discontinuation of drug therapy. Leuprolide acetate is not active when given orally. 12.3 Pharmacokinetics Absorption LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration Following a single LUPRON DEPOT-PED 7.5 mg for 1-month administration to adult patients, mean peak leuprolide plasma concentration was almost 20 ng/mL at 4 hours and then declined to 0.36 ng/mL at 4 weeks. However, intact leuprolide and an inactive major metabolite could not be distinguished by the assay which was employed in the study. Nondetectable leuprolide plasma concentrations have been observed during chronic LUPRON DEPOT-PED 7.5 mg administration, but testosterone levels appear to be maintained at castrate levels. In a study of 55 children with central precocious puberty, doses of 7.5 mg, 11.25 mg and 15.0 mg of LUPRON DEPOTPED were given every 4 weeks and in a subset of 22 chil¬ dren, trough leuprolide plasma levels were determined ac¬ cording to weight categories as summarized below:

Patient Weight Range (kg)

Group Weight Average (kg)

Dose (mg)

Trough Plasma Leuprolide Level Mean ±SD (ng/mL)*

20.2 - 27.0

22.7

7.5

0.77±0.033

28.4 - 36.8

32.5

11.25

1.25±1.06

39.3 - 57.5

44.2

15.0

1.59±0.65

* Group average values determined at Week 4 immediately prior to leuprolide injection. Drug levels at 12 and 24 weeks were similar to respective 4 week levels. LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration Following a single LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration to children with CPP, leuprolide concentrations increased with increasing dose with mean peak leuprolide plasma concentration of 19.1 and 52.5 ng/mL at 1 hour for the 11.25 and 30 mg dose lev¬ els, respectively. The concentrations then declined to 0.08 and 0.25 ng/mL at 2 weeks after dosing for the 11.25 and 30 mg dose levels. Mean leuprolide plasma concentration remained constant from month 1 to month 3 for both 11.25 and 30 mg doses. The mean leuprolide concentrations 3 months after the first and second injections were similar in¬ dicating no accumulation of leuprolide from repeated ad¬ ministration. Distribution The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma pro¬ teins ranged from 43% to 49%. Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide ad¬ ministered intravenously revealed that the mean systemicclearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration of uC-labeled leuprolide was shown to be metabolized to smaller inactive peptides; a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations mea¬ sures! in 5 prostate cancer patients reaches! maximum con¬ centration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approxi¬ mately 20% of mean leuprolide concentrations. Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose* was recovered as parent and M-I metabolite in the urine. Specific Populations The pharmacokinetics of LUPRON DEPOT-PED has not been determined in patients with hepatic or renal impair¬ ment.

LUPRON DEPOT-PED • ABBVIE/523 Drug-Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT-PED. How¬ ever, because leuprolide acetate is a peptide that is primar¬ ily degraded by peptidase and not by cytochrome P-450 en¬ zymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions are not expected to occur. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hy¬ perplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell ad¬ enomas in females and of testicular interstitial cell ad¬ enomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities. Following subcutaneous administration of LUPRON DEPOT to male and female rats before mating there was atrophy of the reproductive organs and suppression of re¬ productive performance. Following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover his¬ tologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive perfor¬ mance of the FI generation has been evaluated using LUPRON DEPOT formulation to groups of rats as one-time subcutaneous dose of 0.024 mg/kg (1/19 of the pediatric dose) on Day 15 of gestation or dosing on parturition day at doses up to 8 mg/kg (18 fold of the pediatric dose). There was no effect on growth, morphological development and re¬ productive performance of FI generation. 14 CLINICAL STUDIES 14.1 LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration In children with central precocious puberty (CPP), thera¬ peutic doses of LUPRON DEPOT-PED reduce stimulated and basal gonadotropins to prepubertal levels. Testosterone and estradiol are also reduced to prepubertal levels in males and females respectively. Reduction of gonadotropins and sex steroids allow a return to age-appropriate physical and psychological growth and development. The following ef¬ fects have been noted with the chronic administration of leuprolide: cessation of menses (in girls), normalization and stabilization of linear growth and bone age advancement, stabilization of clinical signs and symptoms of puberty. 55 CPP subjects (49 females and 6 males, naive to previous GnRHa treatment), were treated with LUPRON DEPOTPED 1-month formulations until age appropriate for entry into puberty (see treatment period data below) and a subset of 40 subjects were then followed post-treatment (see follow-up period data below). Treatment Period Data: During the treatment period, LUPRON DEPOT-PED sup¬ pressed gonadotropins and sex steroids to prepubertal lev¬ els. Suppression of peak stimulated LH concentrations to < 1.75 mlU/mL was achieved in 96% of subjects by month 1. Five subjects required increased doses of study drug to achieve or retain LH suppression. The number and percent¬ age of subjects with suppression of peak stimulated LH < 1.75 mlU/mL and mean ± SD peak stimulated LH over time is shown in Table 4. The mean ± SD age at the start of treatment was 7 ± 2 years and the duration of treatmenf was 4 ± 2 years. Six months after the treatment period was finished, the mean peak stimulated LH was 20.6 ± SD 13.7 mlU/mL (n=30>.

Table 4. The number and percentage of patients with peak stimulated LH < 1.75 mlU/mL and Mean (SD) peak LH at each clinic visit n with peak stimulated LH < 1.75 mlU/mL/N with a LH measurement for that week Study

n/N

%

Mean (SD) peak LH

Baseline

0/55

0%

35.0(21.32)

Week 4

53/55

96.4%

0.8 (0.57)'

Week 12

48/54

88.971

1.1 (1.77)

Week 24

48/53

90.6%

0.8 (0.79)

Week 36

51/54

94.4%

0.6 (0.43)

Week 48

51/54

94.4%

0.6 (0.47)

Week 72

52/52

100%

0.5 (0.30)

Week 96

46/46

100%

0.4 (0.33)

Week 120

40/40

100%

0.4 (0.27)

Week 144

36/36

100%

0.4 (0.24)

Week 168

27/28

96.4%

1.2 (4.58)

Week 216

18/19

94.7%

0.5 (0.90)

Week 240

16/17

94.1%

0.4 (0.62)

Week 264

14/15

95.3%

0.4 (0.41)

Week 288

11/11

100%.

0.3 (0.22)

Week 312

9/9

100%

0.4 (0.20)

Week 336

6/6

100%

0.3 (0.10)

Week 360

6/6

100%

0.3 (0.13)

Week 384

5/5

100%

0.2 (0.10)

Week 408

3/3

100%

0.2 (0.09)

Week 432

2/2

100%

0.3 (0.04)

Week 456

2/2

100%

0.2 (0.04)

Week 480

1/1

100%

0.2 (NA)

Week 504

1/1

100%

0.2 (NA)

Suppression (defined as regression or no change) of the clin¬ ical/physical signs of puberty was achieved in most patients. In females, suppression of breast development ranged from 66.7 to 90.6% of subjects during the first 5 years of treat¬ ment. The mean stimulated estradiol was 15.1 pg/mL at baseline, decreased to the lower level of detection (5.0 pg/mL) by Week 4 and was maintained there during the first 5 years of treatment. In males, suppression of genitalia development ranged from 60% to 100% of subjects during the first 5 years of treatment. The mean stimulated testos¬ terone was 347.7 ng/dL at baseline and was maintained at levels no greater than 25.3 ng/dL during the first 5 years of treatment. A “flare effect” of transient bleeding or spotting during the first 4 weeks of treatment was observed in 19.4% (7/36) fe¬ males who had not reached menarche at baseline. After the first 4 weeks and for the remainder of the treatment period, no subject reported menstrual-like bleeding, and only rare spotting was noted. In many subjects, growth rate decreased on treatment, as did bone age: chronological age ratio. Through year 5, the mean growth rate ranged between 3.4 and 5.6 cm/yr. The mean ratio of bone age to chronological age decreased from 1.5 at baseline to 1.1 by end of treatment. The mean height standard deviation score changed from 1.6 at baseline to 0.7 at the end of the treatment phase. Follow-up Period Data: 35 females and 5 males participated in a post-treatment follow-up period to assess reproductive function (in females) and final height. At 6 months post-treatment, most subjects reverted to pubertal levels of LH (87.9%) and clinical signs of resumption of pubertal progression were evident with in¬ crease in breast development in girls (66.7%) and increase in genitalia development in boys (80%). Of the 40 patients evaluated in the follow-up. 33 were ob¬ served until they reached final or near-final adult height. These patients had a mean increase in final adult height compared to baseline predicted adult height. The mean final adult height standard deviation score was -0.2. After stopping treatment, regular menses were reported for all female subjects who reached 12 years of age during follow-up: mean time to menses was approximately 1.5 years; mean age of onset of menstruation after stopping treatment was 12.9 years. Data to assess reproductive func-

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110

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524/ABBVIE • LUPRON DEPOT-PED Table 5. Suppression of Peak-Stimulated LH from Month 2 Through Month 6 LUPRON DEPOT-PED 30 mg every 3 Months

LUPRON DEPOT-PED 11.25 mg every 3 Months

Parameter Percent with Suppression 2-sided 95% Cl

Naive N = 21

Prev Trta N = 21

Total N = 42

Naive N = 21

Prev TrC N = 21

Total N = 42

.76.2

81.0

78.6

90.5

100

95.2

63.2, 89.7

69.6, 98.8

83.9, 100

83.8, 99.4

52.8, 91.8

58.1, 94.6

and 30 mg groups, respectively, at month 6. Clinical sup¬ pression of puberty in males was observed in 1 of 2 (50.0% > and 2 of 5 (40.0% ) patients in the 11.25 mg and 30 mg groups, respectively, at month 6. In subjects with complete data for bone age, 29 of 33 (87.9 %,) in the 11.25 mg group and 30 of 40 in the 30 mg group (75.0% l had a decrease in the ratio of bone age to chronological age at month 6 com¬ pared to screening. 16

LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration is packaged as follows:

a. Previously treated with GnRHa for at least 6 months prior to enrollment in pivotal Study L-CP07-167.

Figure 1. Mean Peak Stimulated LH for LUPRON DEPOT-PED 11.25 mg for 3-month administration

HOW SUPPLIED/STORAGE AND HANDLING

1-month Kit with prefilled dual-chamber syringe

7.5 mg

NDC 0074-2108-03

1-month Kit with prefilled dual-chamber syringe

11.25 mg

NDC 0074-2282-03

1-month Kit with prefilled dual-chamber syringe

15 mg

NDC 0074-2440-03

LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration is packaged as follows:

Figure 2. Mean Peak Stimulated LH for LUPRON DEPOT-PED 30 mg for 3-month administration

3-month Kit with prefilled dual-chamber syringe

11.25 mg

NDC 0074-3779-03

3-month Kit with prefilled dual-chamber syringe

30 mg

NDC 0074-9694-03

LUPRON DEPOT-PED prefilled syringe for 1-month ad¬ ministration contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid/glycolic acid copolymer. LUPRON DEPOT-PED prefilled syringe for 3-month ad¬ ministration contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid polymer. When mixed with 1 milliliter of accompanying diluent, LUPRON DEPOT-PED for 1-month administration is ad¬ ministered as a single intramuscular injection. When mixed with 1.5 milliliter of accompanying diluent. LUPRON DEPOT-PED for 3-month administration is administered as a single intramuscular injection. Each kit contains: • one prefilled dual-chamber syringe containing Wi inch needle with LuproLoc® safety device • one plunger • two alcohol swabs • population, dose and frequency confirmation insert • a complete prescribing information enclosure Store at 25°C (77°F); excursions permitted to 15-3D*C (59-86°F) [See USP Controlled Room Temperature] 17

Study Week

tion was collected in a post-study survey of 20 girls who reached adulthood (ages 18-26): menstrual cycles were re¬ ported to be normal in 80% of women; 12 pregnancies were reported for a total of 7 of the 20 subjects, including multi¬ ple pregnancies for 4 subjects. 14 2 LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration In a randomized, open-label clinical study of LUPRON DEPOT-PED 3-Month formulations, 84 subjects (76 female, 8 male) between 1 and 11 years of age received the LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month ad¬ ministration formulation. Each dose group had an equal number of treatment-naive patients who had pubertal LH levels and patients previously treated with GnRHa thera¬ pies who had prepubertal LH levels at the time of study en¬ try. The percentage of subjects with suppression of peak-

stimulated LH to < 4.0 mlU/mL, as determined by assessments at months 2, 3 and 6 is 78.6% in the 11.25 mg dose and 95.2% in the 30 mg dose as shown in Table 5. [See table 5 above] The mean peak stimulated LH levels for all visits are showm by dose and subgroup (naive vs. previously treated subjects) in Figures 1 and 2. [See figure 1 above] ISee figure 2 above] For the LUPRON DEPOT-PED 11.25 mg dose for 3-month administration, 93% (39/42) of subjects and for LUPRON DEPOT-PED 30 mg dose for 3-month administration 100% (42/42) of subjects had sex steroid (estradiol or testosterone) suppressed to prepubertal levels at all visits. Clinical sup¬ pression of puberty in female patients was observed in 29 of i 32 i90.6%) and 28 of 34 (82.4%) of patients in the 11.25 mg

PATIENT COUNSELING INFORMATION

Information for Parents Prior to starting therapy with LUPRON DEPOT-PED. pa¬ tients should be informed that: • All formulations are contraindicated in women who are or may become pregnant. If this drug is used during preg¬ nancy. or if the pat ient becomes pregnant while taking the drug, the patient should be informed of the potential risk to the fetus. • Continuous therapy is important and that adherence to the recommended drug administration schedule (monthly for LUPRON DEPOT-PED for 1-month administration and every three months for LUPRON DEPOT-PED for 3-month administration) must be accepted if therapy is to be successful If the injection schedule is not followed, pu¬ bertal development may begin again. • During the first weeks of treatment, signs of puberty, eg., vaginal bleeding, may occur. This is a common initial ef¬ fect of the drug. If these symptoms continue beyond the second month of treatment, the physician should be noti¬ fied. • The most common side effects related to treatment with LUPRON DEPOT-PED for 1-month or 3-month adminis¬ tration in clinical studies are: pain, acne/seborrhea, injec¬ tion site reactions including pain, swelling and abscess, rash including erythema multiforme, vaginitis/bleeding/ discharge, increased weight, headache, and altered mood. • After injection, some pain and irritation is expected; how¬ ever if more severe symptoms occur, the physician should be contacted. Any unusual signs or symptoms should be reported to the physician. • The parents should notify the physician if new or wors¬ ened symptoms develop after beginning treatment. Manufactured for AbbVie Inc. North Chicago, IL 60064 by Takeda Pharmaceutical Company Limited Osaka, Japan 540-8645

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Look for PDR drug information and services in your EHR ™ - Trademark ® - Registered Trademark Ref: 03-A822-R23-Revised: June, 2013 ©2013 AbbVie Inc. Shown in Product Identification Guide, page 303

MAVIK®

]£

[MAH-vie] (trandolapril tablets)

WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue MAVIK as soon as possible. • Drugs that act directly on the renin-angiotensin sys¬ tem can cause injury and death to the developing fetus (See WARNINGS: Fetal Toxicity).

DESCRIPTION Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. Trandolapril is chemically described as (2S, 3aR, 7aS)1- [(S)-N-[(S)-l-Carboxy-3-phenyIpropyIjalanyl] hexahydro2- indolinecarboxylic acid, 1-ethyl ester. Its empirical formula is and its structural formula is H

COOR

R » C2 H5. Trandolapril « H , Trandofaprilat (diacid)

M.W. = 430.54 Melting Point = 125°C Trandolapril is a white or almost white powder that is sol¬ uble (> 100 mg/mL) in chloroform, dichloromethane, and methanol. MAVIK tablets contain 1 mg, 2 mg, or 4 mg of trandolapril for oral administration. Each tablet also con¬ tains corn starch, croscarmellose sodium, hypromellose, iron oxide, lactose monohydrate, povidone, sodium stearyl fumarate. CLINICAL PHARMACOLOGY Mechanism of Action Trandolapril is deesterified to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. ACE is a peptidyl dipepti¬ dase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion. The effect of trandolapril in hy¬ pertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing angio¬ tensin II formation, decreasing vasoconstriction, decreasing aldosterone secretion, and increasing plasma renin. De¬ creased aldosterone secretion leads to diuresis, natriuresis, and a small increase of serum potassium. In controlled clin¬ ical trials, treatment with MAVIK alone resulted in mean increases in potassium of 0.1 mEq/L (see PRECAU¬ TIONS) ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of trandolapril remains to be elucidated. While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, trandolapril exerts antihypertensive actions even in patients with low-renin hypertension. MAVIK was an effec¬ tive antihypertensive in all races studied. Both black pa¬ tients (usually a predominantly low-renin group) and non¬ black patients responded to 2 to 4 mg of MAVIK. Pharmacokinetics and Metabolism 1’harmacokinetics Trandolapril’s ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat. Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion. Absolute bioavailability after oral adminis¬ tration of trandolapril is about 10% as trandolapril and 7091 as trandolaprilat. After oral trandolapril under fasting con¬ ditions, peak trandolapril levels occur at about one hour and peak trandolaprilat levels occur between 4 and 10 hours. The elimination half-life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing bind¬

MAVIK • ABBVIE/525 ing to plasma and tissue ACE. During multiple dosing of trandolapril, there is no significant accumulation of tran¬ dolaprilat. Food slows absorption of trandolapril. but does not affect AUC or Cln„, of trandolaprilat or CmM of trandolapril. Metabolism and Excretion After oral administration of trandolapril, about 33% of par¬ ent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces. The extent of the absorbed dose which is biliary excreted has not been deter¬ mined. Plasma concentrations (CraM and AUC of trandolapril and Cm„, of trandolaprilat) are dose propor¬ tional over the 1-4 mg range, but the AUC of trandolaprilat is somewhat less than dose proportional. In addition to trandolaprilat, at least 7 other metabolites have been found, principally glucuronides or deesterification products. Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration. The volume of distribution of trandolapril is about 18 liters. Total plasma clearances of trandolapril and trandolaprilat after approximately 2 mg IV doses are about 52 liters/hour and 7 liters/hour respectively. Renal clearance of trandola¬ prilat varies from 1-4 liters/hour, depending on dose. Special Populations Pediatric Trandolapril pharmacokinetics have not been evaluated in patients < 18 years of age. Geriatric and Gender Trandolapril pharmacokinetics have been investigated in the elderly (> 65 years) and in both genders. The plasma concentration of trandolapril is increased in elderly hyper¬ tensive patients, but the plasma concentration of trandola¬ prilat and inhibition of ACE activity are similar in elderly and young hypertensive patients. The pharmacokinetics of trandolapril and trandolaprilat and inhibition of ACE activ¬ ity are similar in male and female elderly hypertensive pa¬ tients. Race Pharmacokinetic differences have not been evaluated in dif¬ ferent races. Renal Insufficiency Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in pa¬ tients with creatinine clearance below 30 ml/min and in pa¬ tients on hemodialysis. Dosage adjustment is recommended in renally impaired patients (see DOSAGE AND ADMIN¬ ISTRATION). Hepatic Insufficiency Following oral administration in patients with mild to mod¬ erate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be con¬ sidered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION) Drug Interactions Trandolapril did not affect the plasma concentration (pre¬ dose and 2 hours post-dose) of oral digoxin (0.25 mg). Coad¬ ministration of trandolapril and cimetidine led to an in¬ crease of about 44% in Cm„x for trandolapril, but no difference in the pharmacokinetics of trandolaprilat or in ACE inhibition. Coadministration of trandolapril and furosemide led to an increase of about 25% in the renal clear¬ ance of trandolaprilat, but no effect was seen on the phar¬ macokinetics of furosemide or trandolaprilat or on ACE inhibition. Pharmacodynamics and Clinical Effects A single 2-mg dose of MAVIK produces 70 to 85% inhibition of plasma ACE activity at 4 hours with about 10% decline at 24 hours and about half the effect manifest at 8 days. Maxi¬ mum ACE inhibition is achieved with a plasma trandolaprilat concentration of 2 ng/mL. ACE inhibition is a function of trandolaprilat concentration, not trandolapril concentra¬ tion. The effect of trandolapril on exogenous angiotensin I was not measured. Hypertension Four placebo-controlled dose response studies were con¬ ducted using once-daily oral dosing of MAVIK in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once-daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supme diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect di¬ minished somewhat at the end of the dosing interval, but trough/peak ratios are well above 50% for all effective doses. There was a slightly greater effect on the diastolic pressure, but no difference on systolic pressure with b.i.d. dosing. During chronic therapy, the maximum reduction in blixid I

pressure with any dose is achieved within one week. Follow¬ ing 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 2 to 4 mg lowered supine or standing systolic/ diastolic blood pressure 24 hours after posing by an average 7-10/4-5 mmHg below placebo responses in non-black pa¬ tients. Once-daily doses of 2 to 4 mg lowered blood pressure 4-6/3-4 mmHg in black patients. Trough to peak ratios for effective doses ranged from 0.5 to 0.9. There were no differ¬ ences in response between men and women, but responses were somewhat greater in patients under 60 than in pa¬ tients oyer 60 years old. Abrupt withdrawal of MAVIK has not been associated with a rapid increase in blood pressure. Administration of MAVIK to patients with mild to moderate hypertension results in a reduction of supine, sitting and standing blood pressure to about the same extent without compensatory tachycardia. Symptomatic hypotension is infrequent, although it can oc¬ cur in patients who are salt- and/or volume-depleted (see WARNINGS). Use of MAVIK in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone, and the additional effect of trandolapril is similar to the effect of monotherapy. Heart Failure Post Myocardial Infarction or Left Ventricular Dysfunction Post Myocardial Infarction The Trandolapril Cardiac Evaluation (TRACE) Trial was a Danish, 27-center, double-blind, placebo controlled, parallelgroup study of the effect of trandolapril on all-cause mortal¬ ity in stable patients with echocardiographic evidence of left ventricular dysfunction 3 to 7 days after a myocardial in¬ farction. Subjects with residual ischemia or overt heart fail¬ ure were included. Patients tolerant of a test dose of 1 mg trandolapril were randomized to placebo (n=873) or trandolapril (n=876) and followed for 24 months. Among pa¬ tients randomized to trandolapril, who began treatment on 1 mg, 62% were successfully titrated to a target dose of 4 mg once daily over a period of weeks. The use of trandolapril was associated with a 16% reduction in the risk of all-cause mortality (p=0.042), largely cardiovascular mortality. Trandolapril was also associated with a 20% reduction in the risk of progression of heart failure (p=0.047), defined by a time-to-first-event analysis of death attributed to heart failure, hospitalization for heart failure, or requirement for open-label ACE inhibitor for the treatment of heart failure. There was no significant effect of treatment on other end¬ points: subsequent hospitalization, incidence of recurrent myocardial infarction, exercise tolerance, ventricular func¬ tion, ventricular dimensions, or NYHA class. The population in TRACE was entirely Caucasian and had less usage than would be typical in a U.S. population of other post-infarction interventions: 42% thrombolysis, 16% beta-adrenergic blockade, and 6.7% PTCA or CABG during the entire period of follow-up. Blood pressure control, espe¬ cially in the placebo group, was poor: 47 to 53% of patients randomized to placebo and 32 to 40% of patients random¬ ized to trandolapril had blood pressures > 140/95 at 90-day follow-up visits. INDICATIONS AND USAGE Hypertension MAVIK is indicated for the treatment of hypertension It may be used alone or in combination with other antihyper¬ tensive medication such as hydrochlorothiazide. Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction MAVIK is indicated in stable patients who have evidence of left-ventricular systolic dysfunction (identified by wall mo¬ tion abnormalities) or who are symptomatic from congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of trandolapril to Caucasian patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risk of heart failure-related hospitalization (see CLINICAL PHARMACOLOGY - Heart Failure or Left-Ventricular Dys¬ function Post Myocardial Infarction for details of the sur¬ vival trial). CONTRAINDICATIONS MAVIK is contraindicated in patients who are hypersensi¬ tive to this product, in patients with hereditary/idiopathic angioedema and in patients with a history of angioedema related to previous treatment with an ACE inhibitor. Do not co-administer aliskiren with MAVIK in patients with diabetes (see PRECAUTIONS, Drug Interactions:

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin converting enzyme inhibi¬ tors affect the metabolism of eicosanoids and polypeptides,

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110

Free mobile PDR app for fast drug references on Apple or Android devices

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526/ABBVIE • MAVIK including endogenous bradykinin, patients receiving ACE inhibitors, including MAVIK, may be subject to a variety of adverse reactions, some of them serious. Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same pa¬ tients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered. Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients di¬ alyzed with high-flux membranes and treated concomi¬ tantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipo¬ protein apheresis with dextran sulfate absorption. Head and Neck Angioedema In controlled trials ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients. Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including MAVIK. Symptoms suggestive of angio¬ edema or facial edema occurred in 0.13% of MAVIK-treated patients. Two of the four cases were life-threatening and re¬ solved without treatment or with medication (corticoster¬ oids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with MAVIK should be discon¬ tinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symp¬ toms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency ther¬ apy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mLl should be promptly admin¬ istered (see PRECAUTIONS - Information for Patients and ADVERSE REACTIONS). Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdom¬ inal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-l esterase levels were normal. The angioedema was diag¬ nosed by procedures including abdominal CT scan or ultra¬ sound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be in¬ cluded in the differential diagnosis of patients on ACE in¬ hibitors presenting with abdominal pain. Hypotension MAVIK can cause symptomatic hypotension. Like other ACE inhibitors, MAVIK has only rarely been associated with symptomatic hypotension in uncomplicated hyperten¬ sive patients. Symptomatic hypotension is most likely to oc¬ cur in patients who have been salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt re¬ striction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with MAVIK (see PRECAUTIONS - Drug Interactions and ADVERSE REACTIONS). In controlled and uncontrolled studies, hypotension was reported as an adverse event in 0.6% of patients and led to discontinuations in 0.1% of pa¬ tients. In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be as¬ sociated with oliguria or azotemia, and rarely, with acute renal failure and death. In such patients, MAVIK therapy should be started at the recommended dose under close medical supervision. These patients should be followed closely during the first 2 weeks of treatment and, thereafter, whenever the dosage of MAVIK or diuretic is increased (see DOSAGE AND ADMINISTRATION). Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal sa¬ line may be administered intravenously. A transient hypo¬ tensive response is not a contraindication to further doses; however, lower doses of MAVIK or reduced concomitant di¬ uretic therapy should be considered. Neutropenia/Agranulocytosis Another ACE inhibitor, captopril. has been shown to cause agranulocytosis and bone marrow depression rarely in pa¬ tients with uncomplicated hypertension, but more fre¬ quently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleruderma. Available data from clinical trials of trandolapril are insufficient to show that trandolapnl does not cause agranulocytosis at similar rates. As w ith other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.

Hepatic Failure ACE inhibitors rarely have been associated with a syn¬ drome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not under¬ stood. Patients receiving ACE inhibitors who develop jaun¬ dice should discontinue the ACE inhibitor and receive ap¬ propriate medical follow-up. Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system dur¬ ing the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal mor¬ bidity and death. Resulting oligohydramnios can bq associ¬ ated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When preg¬ nancy is detected, discontinue MAVIK as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin system from other antihypertensive agents. Ap¬ propriate management of maternal hypertension during pregnancy, is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin sys¬ tem for a particular patient, apprise the mother of the po¬ tential risk to the fetus. Perform serial ultrasound exami¬ nations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue MAVIK, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irrever-* sible injury. Closely observe infants with histories of in utero exposure to MAVIK for hypotension, oliguria, and hyperkalemia (See PRECAUTIONS, Pediatric Use). Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/ kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/ mz/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on bodyweight and body-surface-area, respectively assuming a 50 kg woman. PRECAUTIONS General Impaired Renal Function As a consequence of inhibiting the renin-angiotensinaldosterone system, changes in renal function may be antic¬ ipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activ¬ ity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including MAVIK® (trandolapril), may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, es¬ pecially when ACE inhibitors have been given concomi¬ tantly with a diuretic. This is more likely to occur in pa¬ tients with preexisting renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhib¬ itor may be required. Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). Hyperkalemia and Potassium-sparing Diuretics In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4'% of hyperten¬ sive patients receiving MAVIK. In most cases, elevated serum potassium levels were isolated values, which re¬ solved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with MAVIK (see PRECAU¬ TIONS - Drug Interactions). Cough Presumably due to the inhibition of the degradation of en¬ dogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving af¬ ter discontinuation of therapy. ACE inhibitor-induced cough

should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, MAVIK will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Information for Patients Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including MAVIK. Patients should be so advised and told to report im¬ mediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS and ADVERSE REACTIONS) Symptomatic Hypotension Patients should be cautioned that light-headedness can oc¬ cur, especially during the first days of MAVIK therapy, and should be reported to a physician. If actual syncope occurs, patients should be told to stop taking the drug until they have consulted with their physician (see WARNINGS). All patients should be cautioned that inadequate fluid in¬ take, excessive perspiration, diarrhea, or vomiting, result¬ ing in reduced fluid volume, may precipitate an excessive fall in blood pressure with the same consequences of light¬ headedness and possible syncope. Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor that has a long duration of action. Hyperkalemia Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician (see PRECAUTIONS). Neutropenia Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. Pregnancy Female patients of childbearing age should be told about the consequences of exposure to MAVIK during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to pa¬ tients being treated with MAVIK is warranted. This infor¬ mation is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor block¬ ers, ACE inhibitors, or aliskiren is associated with in¬ creased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal func¬ tion and electrolytes in patients on MAVIK and other agents that affect the RAS. Do not co-administer aliskiren with MAVIK in patients with diabetes. Avoid use of aliskiren with MAVIK in patients with renal impairment (GFR . No information is available comparing NORVIR tablets to NORVIR capsules under fasting conditions. Effect of Food on Oral Absorption When the oral solution was given under non-fasting condi¬ tions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting condi¬ tions. Dilution of the oral solution, within one hour of ad¬ ministration, with 240 mL of chocolate milk, Advera® or En¬ sure® did not significantly affect the extent and rate of ritonavir absorption. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mg»h per mL. A food effect is observed for NORVIR tablets. Food de¬ creased the bioavailability of the ritonavir tablets when a single 100 mg dose of NORVIR was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% car¬ bohydrates), a 23% decrease in mean AUC(0.^, [90% confi¬ dence intervals: i30%--ll5%], and a 23% decrease in mean Cm [90% confidence intervals: l34%-ill%]) was observed relative to fasting conditions. Under moderate fat condi¬ tions, a 21% decrease in mean AUC((>J. [90% confidence in¬ tervals: i28%-ll3%], and a 22% decrease in mean Cm„x [90% confidence intervals: l33%>-i9%l) was observed rela¬ tive to fasting conditions. However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals. Metabolism Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attrib¬ uted to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabo¬ lite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3AI is the ma¬ jor isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2. Elimination In a study of five subjects receiving a 600 mg dose of l4C-ritonavir oral solution, 11.3 ± 2.8% of the dose was ex¬ creted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related* increase in clearance. Table 6. Ritonavir Pharmacokinetic Characteristics Parameter

N

Values (Mean * SD)

Vj/F:

91

0.41 ± 0.25 L/kg 3 - 5 h

tl/3

Antiarrhythmics: disopyramide, lidocaine, mexiletine

T antiarrhythmics

Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.

(Table continued on next page)

CL/FSS

10

8.8 ± 3.2 L/h

CL/F:

91

4.6 ± 1.6 L/h

CLH

62

4 ND without first talking with your doctor. R-Warfarin 4- 33% (-38, ND How should I take NORVIR? -27%>)4 • Take NORVIR exactly as prescribed by your doctor. • You should stay under a doctor’s care when taking 200 q8h, 4 d 300 q6h, 4 d 4 25% (15, 34%) 4 27% (4, 45%) ND Zidovudine 9 NORVIR. Do not change your dose of NORVIR or stop your treatment without talking with your doctor first. 1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after a 15%-fat breakfast • If your child is taking NORVIR, your child’s doctor will (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after a 15%-fat breakfast decide the right dose based on your child’s height and (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cmjn was also increased 4-fold. Effects were assessed relative to an weight. Tell your doctor if your child’s weight changes. indinavir 800 mg q8h regimen under fasting conditions. Your child should take NORVIR with food. If your child 2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose. does not tolerate NORVIR Oral Solution, ask your child’s 3 Sulfamethoxazole and trimethoprim taken as single combination tablet. doctor for advice. 4 90% Cl presented for R- and S-warfarin AUC and Cmax ratios. • Swallow NORVIR tablets whole. Do not chew, break, or 5 This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma crush tablets before swallowing. If you cannot swallow NORVIR tablets whole, tell your doctor. You may need a cortisol AUC. different medicine. 6 For the reference arm: N=14 for Cmillt and AUCllWnf> and for the test arm: N=13 for Cm and N=4 for AUC,nrafl. • Take NORVIR with meals. 7 90% Cl presented for rivaroxaban • NORVIR Oral Solution is peppermint or caramel flavored. 8 90% Cl presented for simeprevir (change in exposure presented as percentage increase) You can take it alone, or may improve the taste by mixing T Indicates increase. it with 8 ounces of chocolate milk, Ensure®, or Advera . i Indicates decrease. NORVIR Oral Solution should be taken within 1 hour if Indicates no change. mixed with these fluids. Ask your doctor, nurse or phar¬ * Parallel group design; entries are subjects receiving combination and control regimens, respectively. macist about other ways to improve the taste of NORVIR Oral Solution. • Do not run out of NORVIR. Get your NORVIR prescription refilled from you doctor or pharmacy before you run out. • If you miss a dose of NORVIR, take it as soon as possible How should I store NORVIR? • dizziness and then take your next scheduled dose at its regular • Store NORVIR Oral Solution at room temperature be¬ • lightheadedness time. If it is almost time for your next dose, wait and take tween 68bF to 77°F (20°C to 250C).‘ • feel faint or pass out the next dose at the regular time. Do not double the next • Store NORVIR tablets below 30°C (86°F). Exposure to • abnormal heart beat dose. temperatures up to 50°C (122°Fl for seven days permitted. • Increase in cholesterol and triglyceride levels. Treatment • If you take too much NORVIR, call your local poison con¬ • Do not refrigerate NORVIR Oral Solution.' with NORVIR may increase your blood levels of choles¬ trol center or go to the nearest hospital emergency room • Shake NORVIR Oral Solution well before each use. terol and triglycerides. Your doctor should do blood tests right away. • Keep NORVIR Oral Solution away from heat. before you start your treatment with NORVIR and regu¬ What are the possible side effects of NORVIR? • Store NORVIR tablets and NORVIR oral solution in the larly to check for an increase in your cholesterol and tri¬ NORVIR can cause serious side effects including: original container given to you by the pharmacist. glycerides levels. • Exposure of NORVIR tablets to high humidity outside the • See “What is the most important information I should • Diabetes and high blood sugar (hyperglycemia). Some original container for longer than 2 weeks is not recom¬ know about NORVIR?” people who take protease inhibitors including NORVIR mended. • Liver disease. Some people taking NORVIR in combina¬ can get high blood sugar, develop diabetes, or your diabe¬ • Use NORVIR tablets and NORVIR Oral Solution by the tion with other anti-HIV medicines have developed liver tes can get worse. Tell your doctor if you notice an increase expiration date on the bottle. problems which may be life-threatening. Your doctor Keep NORVIR and all medicines out of the reach of chil¬ in thirst or urinate often while taking NORVIR. should do regular blood tests during your combination dren. • Changes in your immune system (Immune reconstitution treatment with NORVIR. If you have chronic hepatitis B General information about NORVIR syndrome) can happen when you start taking HIV medi¬ or C infection, your doctor should check your blood tests Medicines are sometimes prescribed for purposes other than cines. Your immune system may get stronger and begin to more often because you have an increased chance of devel¬ those listed in a Patient Information Leaflet. Do not use this fight infections that have been hidden in your body for a oping liver problems. Tell your doctor if you have any of medicine for a condition for which it was not prescribed. Do long time. Call your doctor right away if you start having the below signs and symptoms of liver problems: not share this medicine with other people. new symptoms after starting your HIV medicine. • loss of appetite This leaflet summarizes the most important information • Change in body fat. These changes can happen in people • pain or tenderness on your right side below your ribs about NORVIR. If you would like more information, talk to who take antiretroviral therapy. The changes may include • yellowing of your skin or whites of your eyes your doctor. You can ask your doctor or pharmacist for in¬ an increase amount of fat in the upper back and neck • itchy skin formation about NORVIR that is written for healthcare pro¬ (“buffalo hump”), breast, and around the back and stom¬ • Swelling of your pancreas (Pancreatitis). NORVIR can fessionals. ach area. Loss of fat from the legs, arms, and face may also cause serious pancreas problems, which may lead to For more information, call 1-800-633-9110. happen. The exact cause and long-term health effects of death. Tell your doctor right away if you have signs or What are the ingredients in NORVIR? these conditions are not known. symptoms of pancreatitis such as; Active ingredient: ritonavir • Increased bleeding for hemophiliacs. Borne people with • nausea Inactive ingredients: hemophilia have increased bleeding with protease inhibi¬ • vomiting NORVIR Tablet: copovidone, anhydrous dibasic calcium tors including NORVIR. • stomach (abdomen) pain phosphate, sorbitan monolaurate. colloidal silicon dioxide, The most common side effects of NORVIR include: •.Allergic Reactions. Sometimes these allergic reactions can and sodium stearyl fumarate. The film coating contains: hy• diarrhea become severe and require treatment in a hospital. You promellose, titanium dioxide, polyethylene glycol 400, hy• nausea should call your doctor right away if you develop a rash. droxypropyl cellulose, talc, polyethylene glycol 3350, colloi¬ • vomiting Stop taking NORVIR and get medical help right away if dal silicon dioxide, and polysorbate 80. • upper and lower stomach (abdomen) pain you have any of the following symptoms of a severe aller¬ NORVIR Oral Solution: ethanol, water, polyoxyl 35 castor • tingling feeling or numbness in hands or feet or around gic reaction: oil, propylene glycol, anhydrous citric acid to adjust pH, sac¬ the lips • trouble breathing charin sodium, peppermint oil, creamy caramel flavoring, • rash • wheezing and FD&C Yellow No. 6. • feeling weak or tired • dizziness or fainting This Patient Information has been approved by the U.S. NORVIR liquid contains a large amount of alcohol. If a tod¬ • throat tightness or hoarseness Food and Drug Administration. dler or young child accidentally drinks more than the rec¬ • fast heartbeat or pounding in your chest (tachycardia) NORVIR tablets and oral solution are manufactured by: ommended dose of NORVIR, it could make him/her sick • sweating AbbVie Inc. from too much alcohol. Contact your local poison control • swelling of your face, lips or tongue North Chicago, IL 60064 USA center or emergency room immediately if this happens. • muscle or joint pain Tfell your doctor if you have any side effect that bothers you • blisters or skin lesions or that does not go away. • mouth sores or ulcers Information on the AbbVie, Inc. products listed on these These are not all of the possible side effects of NORVI R. For • Changes in the electrical activity of your heart called PR pages is from the prescribing information in use as prolongation. PR prolongation can cause irregular heart¬ ! more information, ask your doctor or pharmacist. of July 31, 2015. For more information, please visit beats. Thll your doctor right away if you have symptoms [ Call your doctor lor medical advice about side effects. You rxabbvie.com or call 1-800-633-9110. I may report side effects to FDA at 1-800-FDA-1088. such as:

Free mobile PDR app for fast drug references on Apple or Android devices

574/ABBV1E • NORVIR TABLETS/ORAL SOLUTION

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

Revised: March 2015 The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. © 2015 AbbVie Inc. All rights reserved. 03-B123 Shown in Product Identification Guide, page 304

PROMETRIUM®

IJ

Ipro-me-tre-um] (progesterone, USP) Capsules 100 mg Capsules 200 mg

TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women Conjugated Estrogens

Conjugated Estrogens plus PROMETRIUM Capsules

^max (ng/mL)

^max (hr)

AUC(0.24hl (ng x h/mL)

^max (ng/mL)

T"max (hr)

AUC|0.Mhl (ng x h/mL)

Estradiol

0.037 ± 0.048

12.7 ± 9.1

0.676 ± 0.737

0.030 ± 0.032

17.32 ± 1.21

0.561 ± 0.572

Estrone Total8

3.68 ± 1.55

10.6 ± 6.8

61.3 ± 26.36

4.93 ± 2.07

7.5 ± 3.8

85.9 ± 41.2

Equilin Total”

2.27 ±0.95

6.0 ± 4.0

28.8 ± 13.0

3.22 ± 1.13

5.3 ± 2.6

38.1 ± 20.2

Drug

a Total estrogens is the sum of conjugated and unconjugated estrogen. WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY

TABLE 3. Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment

Cardiovascular Disorders and Probable Dementia Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or demen¬ tia I See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Probable dementia.) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] com¬ bined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. (See CLINICAL STUD¬ IES and WARNINGS, Cardiovascular disorders.) The WHI Memory Study (WHIMS) estrogen plus pro¬ gestin ancillary study of the WHI reported an in¬ creased risk of developing probable dementia in post¬ menopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmeno¬ pausal women. (See CLINICAL STUDIES and WARNINGS, Probable dementia and PRECAU¬ TIONS, Geriatric Use.) Breast Cancer The WHI estrogen plus progestin substudy also dem¬ onstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS, Malig¬ nant neoplasms, Breast Cancer.) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of es¬ trogens and progestins. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the indi¬ vidual woman.

DESCRIPTION PROMETRIUM® (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and a molecular formula of C21H30O2. Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically in¬ soluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting be¬ tween 126° and 131°C. The structural formula is:

Endometrial Diagnosis

Treatment Group Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg (cyclical) Number of patients

% of patients

Number of patients

n=117 HYPERPLASIA a

% of patients

Placebo

Number of patients

n=115

7

6

Adenocarcinoma

0

0

Atypical hyperplasia

1

Complex hyperplasia Simple hyperplasia

% of patients

n=116

74

64

3

3

0

0

1

1

1

14

12

0

0

0

0

27

.23

1

1

6

5

33

29

1

1

'

a Most advanced result to least advanced result: Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia CLINICAL PHARMACOLOGY PROMETRIUM Capsules are an oral dosage form of mi¬ cronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization. Pharmacokinetics A. Absorption After oral administration of progesterone as a micronized soft-gelatin capsule formulation, maximum serum concen¬ trations were attained within 3 hours. The absolute bio¬ availability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized softgelatin capsule formulation. TABLE 1. Pharmacokinetic Parameters of PROMETRIUM Capsules PROMETRIUM Capsules Daily Dose Parameter

Cmax (ng/mL) T,„ax (hr) AUC|q.i„, (ng x hr/mL)

100 mg

200 mg

300 mg

17.3 ± 21.9a

38.1 ± 37.8

60.6 ± 72.5

1.5 ± 0.8

2.3 ± 1.4

1.7 ± 0.6

43.3 ± 30.8

101.2 ± 66.0

175.7 ± 170.3

“ Mean ± S.D.

Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. PROMETRIUM Capsules are avail¬ able in multiple strengths to afford dosage flexibility for op¬ timum management. PROMETRIUM Capsules contain 100 mg or 200 mg micronized progesterone. The inactive ingredients for PROMETRIUM Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, FD&C Red No. 40, and D&C Yellow No. 10. The inactive ingredients for PROMETRIUM Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6.

Conjugated Estrogens 0.625 mg (alone)

Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of PROMETRIUM® (progesterone, USP) Capsules 100 mg over the dose range 100 mg per day to 300 mg per day in postmenopausal women. Although doses greater than 300 mg per day were not studied in females, serum concen¬ trations from a study in male volunteers appeared linear and dose proportional between 100 mg per day and 400 mg per day. The pharmacokinetic parameters in male volun¬ teers were generally consistent with those seen in post¬ menopausal women. B. Distribution Progesterone iB approximately 96 percent to 99 percent bound to serum proteins, primarily to serum albumin (50 to 54 percent) and transcortin (43 to 48 percent).

C. Metabolism Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are ex¬ creted in the bile may be deconjugated and may be further metabolized in the intestine via reduction, dehvdroxylation, and epimerization. D. Excretion The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kid¬ neys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be ex¬ creted in the feces. E. Special Populations The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients. Hepatic Insufficiency: The effect of hepatic impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied. Renal Insufficiency: The effect of renal impairment on the pharmacokinetics of PROMETRIUM Capsules has not been studied. F. Food-Drug Interaction Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg. G. Drug Interactions The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole lIC50 0.30. Results of the studies at 28 days of age are shown in Table 1. TABLE 1 Study 1

Number infants studied Incidence of RDS %) Death due to RDS (%) Death or BPD due to RDS *> Death due to any cause 160 mg/day) Glucocorticoids - (e.g., Dexamethasone >4 mg/day) Propylthiouracil (PTU)

(

Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).

Miscellaneous

Overdosage The signs and symptoms of overdosage are those of hyper¬ thyroidism (see PRECAUTIONS and ADVERSE REAC¬ TIONS). In addition, confusion and disorientation may oc¬ cur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Treatment of Overdosage Levothyroxine sodium should be reduced in dose or tempo¬ rarily discontinued if signs or symptoms of overdosage oc¬ cur. Acute Massive Overdosage This may be a life-threatening emergency, therefore, symp¬ tomatic and supportive therapy should be instituted imme¬ diately. If not contraindicated (e.g., by seizures, coma, or loss of the gag reflex), the stomach should be emptied by emesis or gastric lavage to decrease gastrointestinal absorp¬ tion. Activated charcoal or cholestyramine may also be used to decrease absorption. Central and peripheral increased sympathetic activity may be treated by administering 11-receptor antagonists, e.g., propranolol, provided there are no medical contraindications to their use. Provide respira¬ tory support as needed; control congestive heart failure and arrhythmia; control fever, hypoglycemia, and fluid loss as necessary. Large doses of antithyroid drugs (e.g., methimazole or propylthiouracil) followed in one to two hours by large doses of iodine may be given to inhibit synthesis and release of thyroid hormones. Glucocorticoids may be given to inhibit the conversion of T4 to T3. Plasmapheresis, char¬ coal hemoperfusion and exchange transfusion have been re¬ served for cases in which continued clinical deterioration oc¬ curs despite conventional therapy. Because T4 is highly protein bound, very little drug will be removed by dialysis.

Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives

Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.

Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)

Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Tbxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.

Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin

Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.

Cardiac Glycosides

Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.

Cytokines - Interferon-a - Interleukin-2

Therapy with interferon-u has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-(j and -y have not been reported to cause thyroid dysfunction.

DOSAGE AND ADMINISTRATION General Principles The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of sup¬ pressive therapy is to inhibit growth and/or function of ab¬ normal thyroid tissue. The dose of SYNTHROID that is ad¬ equate to achieve these goals depends on a variety of factors Growth Hormones including the patient's age, body weight, cardiovascular sta¬ - Somatrem tus, concomitant medical conditions, including pregnancy, - Somatropin concomitant medications, and the specific nature of the con¬ dition being treated (see WARNINGS and PRECAU¬ TIONS). Hence, the following recommendations serve only as dosing guidelines. Dosing must bo individualized and ad¬ justments made bast'd on periodic assessment of the pa¬ tient’s clinical response and laboratory parameters (see PRECAUTIONS - Laboratory Tests). SYNTHROID is administered as a single daily dose, prefer- . Caution should be exercised when administering ably one-half to one-hour before breakfast. SYNTHROID | SYNTHROID to patients with underlying cardiovascular should be taken at least 4 hours apart from drugs that are j disease, to the elderly, and to those with concomitant adre¬ nal insufficiency (see PRECAUTIONS! known to interfere with its absorption (see PRECAU¬ Specific Patient Populations TIONS - Drug Interactions!. Hypothyroidism in Adults and in Children in Whom Growth Due to the long half-life of levothyroxine, the peak thera¬ and Puberty are Complete peutic effect at a given dose of levothyroxine sodium may (see WARNINGS and PRECAUTIONS - Laboratory Tests not be attained for 4-6 weeks.

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. {Table continued on next page)

Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthy¬ roidism or who have been hypothyroid for only a short time (such as a few-months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium

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TARKA • ABBVIE/585

Table 2 (cont.l Drug-Thyroidal Axis Interactions

> 12 years but growth and puberty incomplete Growth and puberty complete

Effect

Drug or Drug Class Miscellaneous (cont.) Ketamine

Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.

Methylxanthine Bronchodilators - (e.g., Theophylline)

Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.

Radiographic Agents

Thyroid hormones may reduce the uptake of l23I, l3lI, and y9mrj^.

Sympathomimetics

Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.

Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics

These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Strength (meg)

Color

NDC# for bottles of 90

NDC # for bottles of 100

NDC # for bottles of 1000

25 50 75 88 100 112 125 137 150 175 200 300

orange white violet olive yellow rose brown turquoise blue lilac pink green

0074-4341-90 0074-4552-90 0074-5182-90 0074-6594-90 0074-6624-90 0074-9296-90 0074-7068-90 0074-3727-90 0074-7069-90 0074-7070-90 0074-7148-90 0074-7149-90

0074-4341-13 0074-4552-13 0074-5182-13 0074-6594-13 0074-6624-13 0074-9296-13 0074-7068-13 0074-3727-13 0074-7069-13 0074-7070-13 0074-7148-13 0074-7149-13

0074-4341-19 0074-4552-19 0074-5182-19 0074-6594-19 0074-6624-19 0074-9296-19 0074-7068-19 0074-3727-19 0074-7069-19 0074-7070-19 0074-7148-19 0074-7149-19

doses greater than 200 mcg/day are seldom required. An in¬ adequate response to daily doses > 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions. For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients w’ith cardiac dis¬ ease is 12.5-25 mcg/day. with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is gener¬ ally adjusted in 12.5-25 meg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized. In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized. In patients with secondary (pituitary) or tertiary (hypothal¬ amic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free- T4 level is restored to the upper half of the normal range. Pediatric Dosage - Congenital or Acquired Hypothyroidism (see PRECAUTIONS - Laboratory Tests) General Principles In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diag¬ nosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and develop¬ ment. Undertreatment and overtreatment should be avoided (see PRECAUTIONS - Pediatric Use SYNTHROID may be ad¬ ministered to infants and children who cannot swallow in¬ tact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or by dropper. DO NOT STORE THE SUSPENSION Foods that decrease absorption of levothyroxine. such as

NDC # for unit dose cartons of 100

_ 0074-4552-11 0074-5182-11 -

1

0074-6624-11 -

0074-7068-11 0074-7069-11

Table 3. Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism Daily Dose Per Kg Body Weight*

0-3 months

10-15 meg/kg/day

3-6 months

8-10 meg/kg/day

6-12 months

1.7 meg/kg/day

* The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTIONS Laboratory Tests and Pediatric Use Pregnancy Pregnancy may increase levothyroxine requirements (see PREGNANCY) Subclinical Hypothyroidism If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 meg/kg/day) than that used for full replace¬ ment may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory param¬ eters. TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of SYNTHROID used for TSH suppression should be individualized based on the specific disease and the patient being treated. In the treatment of well-differentiated (papillary and follic¬ ular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is sup¬ pressed to 100 mg/mL) in chlo¬ roform, dichloromethane, and methanol. TARKA tablets are formulated for oral administration, con¬ taining verapamil hydrochloride as a controlled release for¬ mulation und trandolapril as an immediate release formu¬ lation. The tablet strengths are trandolapril 2 mg/ verapamil hydrochloride ER 180 mg, trandolapril 1 mg/ verapamil hydrochloride ER 240 mg, trandolapril 2 mg/ verapamil hydrochloride ER 240 mg, and trandolapril 4 mg/ verapamil hydrochloride ER 240 mg. The tablets also contain the following ingredients: corn starch, dioctyl so¬ dium sulfosuccinate, ethanol, hydroxypropy! cellulose, hypromellose, lactose monohydrate, magnesium stearate, mi¬ crocrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumnrate, synthetic iron oxides, talc, and titanium dioxide. CLINICAL PHARMACOLOGY Verapamil hydrochloride and trandolapril have been used individually and in combination for the treatment of hyper¬ tension. For the four dosing strengths, the antihypertensive effect of the combination is approximately additive to the individual components. Verapamil Component Verapamil is a calcium channel blocker that exerts its phar¬ macologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in cunduclile and contractile myocardial cells. Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia. During isometric or dynamic exercise, verapamil does not alter sys¬ tolic cardiac function in patients with normal ventricular function. Verapamil does not alter total serum calcium lev¬ els. Trandolapril Component Trandolapril is do-osterifiod to its diacid metabolite, trandolaprilat Both inhibit angiotensin-convorting enzyme (ACE! in human subjects nnri in animals. Trandulaprilnt is about 8 times more potent than trandolapril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angioten¬ sin 1 to the vasoconstrictor, angiotensin 11. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin 11, which leads to decreased vasopressor activity and to de¬ creased aldosterone secretion. The latter decrease may re¬ sult in a small increase of serum potassium. In controlled clinical trials, treatment with TARKA resulted in mean in¬ creases in potassium of 0,1 iuKq/L (see PRECAUTIONS: Removul of angiotensin II negative feedback on renin secre¬ tion leads to increased plasma renin activity (PRA). ACE is identical to kininase 11, an enzyme that degrades brndykimn Whether increased levels of bradvkinin, a po¬ tent vasodepressor peptide, play a role in the therapeutic effect of TARKA remains to be elucidated While the mechanism through which trandolapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, trandolapril has an

antihypertensive effect even in patients with low renin hy¬ pertension. Trandolapril is an effective antihypertensive in all races studied. Both black patients (usually a predomi¬ nantly low renin group) and non-black patients respond to 2 to 4 mg of trandolapril. Pharmacokinetics and Metabolism TARKA Following a single oral dose of TARKA in healthy subjects, peak plasma concentrations are reached within 0.5-2 hours for trandolapril and within 4-15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5-15 hours. Cleavage of the ester group converts trandolapril to its ac¬ tive diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2-12 hours. The pharmacoki¬ netics of trandolapril and trandolaprilat are not altered when trandolapril is administered in combination with verapamil, compared to monotherapy. The AUC and Cm„, for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg trandolapril. The in¬ crease in C„ul, is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Ad¬ ministration of TARKA 4/240 (4 mg trandolapril and 240 mg verapamil hydrochloride ER) with a high-fat meal does not alter the bioavailability of trandolapril whereas verapamil peak concentrations and area under the curve (AUC) decrease 37% and 28%, respectively. Food thus de¬ creases verapamil bioavailability and the time to peak plasma concentration for both verapamil and norverapamil are delayed by approximately 7 hours. Both optical isomers of verapamil are similarly affected. The elimination half life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing bind¬ ing to plasma and tissue ACE. The terminal half-life of verapamil is 6-11 hours. Steadystate plasma concentrations of the two components are achieved after about a week of once-daily dosing of TARKA. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral TARKA dose. The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (£65 years) than in younger subjects. The bioavailability of verapamil and nor¬ verapamil are increased by 87% and 77%, respectively, and that of trandolapril by approximately 35% in the elderly. AUCs are approximately 80% and 35% higher, respectively. Verapamil Component With the immediate release formulation, more than 90%/ of the orally administered dose is absorbed with peak plasma concentrations of verapamil observed 1 to 2 hours after dos¬ ing. A delayed rate but similar extent of absorption is ob¬ served for the sustained release formulation when com¬ pared to the immediate release formulation. Because of the rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20% to 35%. A nonlinear correlation exists be¬ tween verapamil dose and plasma concentrations. In early dose titration with verapamil, a relationship exists between plasma concentrations of verapamil and prolonga¬ tion of the PR interval. However, during chronic adminis¬ tration, this relationship may disappear. No relationship has been established between the plasma concentration of verapamil and reduction in blood pressure. In healthy subjects, orally administered verapamil under¬ goes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Approximately 70% of an ad¬ ministered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Urinary excretion of unchanged drug is about 3% to 4% of the dose. Verapamil is approximately 90% bound to plasma proteins. In putionts with hepatic insufficiency, verapamil clearance is decreased about 30% and the elimination half-life is pro¬ longed up to 14 to 16 hours (see PRECAUTIONS). In pa¬ tients with liver dysfunction, a dosage adjustment may be required. In the elderly (£65 years), verapamil clearance is reduced resulting in increases in elimination half-life. Trandolapril Component Following oral administration of trandolapril. the absolute bioavailability of trandolapril is approximately 10% as trandolapril and 70% as trandolaprilat, Plasma concentra¬ tions of trandolaprilat but not trandolapril increase in proimrtion with dose. Plasma concentrations of trandolaprilat decline in a triphasic manner. The more prolonged terminal elimination phase probably represents a small fraction of dose saturably bound to ACE. After an oral radiolabeled dose of trandolapril, excretion of trandolapril and metabolites account for 33% of the dose in the urine and about 66% in the feces. Less than 1% of the dose is excreted in the urine as unchanged drug. Serum pro¬

tein binding of trandolapril is about 80%, and is indepen¬ dent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration. Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in pa¬ tients with creatinine clearance below 30 mlVmin and in pa¬ tients on hemodialysis. Dosage adjustment is recommended in renally impaired patients (see DOSAGE AND ADMIN¬ ISTRATION). Following oral administration in patients with mild to mod¬ erate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be con¬ sidered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION). Pharmacodynamics TARKA Verapamil does not interfere with ACE inhibition by trandolapril. Trandolapril does not alter the effect of verapamil on intra-cardiac conduction, Verapamil Component Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a po¬ tent inhibitor of coronary artery spasm. This property in¬ creases myocardial oxygen delivery in patients with coro¬ nary artery spasm, and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Verapamil regularly reduces the total systemic resistance (afterload) by dilating peripheral arterioles. By decreasing the influx of calcium, verapamil prolongs the effective re¬ fractory period within the AV node and slows AV conduction in a rate-related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with si¬ nus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in pa¬ tients without preexisting conduction defects (see WARN¬ INGS). Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses ampli¬ tude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been re¬ ported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following adminis¬ tration of verapamil (see WARNINGS). Hemodynamics and Myocardial Metabolism: Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with cor¬ onary heart disease has also been observed with verapamil therapy. In most patients, including those with organic car¬ diac disease, the negative inotropic action of verapamil is countered by a reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure about 20 mmHg or ejection fraction less than 30%), or in pa¬ tients taking beta-adrenergic blocking agents or other cardio-depressant drugs, deterioration of ventricular func¬ tion may occur (see PRECAUTIONS • Drug Interactions: Pulmonary Function: Verapamil does not induce bronchoconstriction and hence, does not impair ventilatory function. Trandolapril Component After a single 2 mg dose of trandolapril, inhibition of ACE activity reaches a maximum (70-85%) at 4 hours with about 10% decline at 24 hours. Eight days after dosing, ACE inhi¬ bition is still 40%. Four placebo-controlled dose response studies were con¬ ducted using once daily oral dosing of trandolapril in doses from 0.25 to 16 mg per day in 827 black and non-black pa¬ tients with mild to moderate hypertension. The minimal ef¬ fective once daily dose was 1.0 mg in non-black patients and 2.0 mg in black patients. Further decreases in trough su¬ pine diastolic blood pressure were obtained in non-black pa¬ tients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing inter¬ val. During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Follow¬ ing 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 2 to 4 mg lowered supine or standing systolic/ diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black pa¬ tients. Once daily doses of 2 to 4 mg lowered blood pressures 4-6Z3-4 mmHg below placebo responses in black patients.

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Look for PDR drug information and services in your EHR CLINICAL STUDIES In controlled clinical trials, once daily doses of TARKA. trandolapril 4 mg/verapamil HC1 ER 240 mg or trandolapril 2 mg/verapamil HCI ER 180 mg, decreased placebocorrected seated pressure (systolic/diastolicl 24 hours after dosing by about 7-12/6-8 mmHg. Each of the components of TARKA added to the antihypertensive effect. Treatment ef¬ fects were consistent across age groups (65 years', and gender (male, female). Blood pressure reductions were significantly greater for the TARKA 4/240 combination than for either of the compo¬ nents used alone. The antihypertensive effects of TARKA have continued dur¬ ing therapy for at least 1 year. INDICATIONS AND USAGE TARKA is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINIS¬ TRATION). In using TARKA, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captupril, has caused agranulocytosis, particularly in patients with re¬ nal impairment or collagen vascular disease, and that avail¬ able data are insufficient to show that trandolapril does not have similar risk (see WARNINGS - Neutropenia/Agranu¬ locytosis >. CONTRAINDICATIONS TARKA is contraindicated in patients who are hypersensi¬ tive to any ACE inhibitor or verapamil. Because of the verapamil component. TARKA is contraindi¬ cated in: 1. Severe left ventricular dysfunction (see WARNINGS 2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock. 3. Sick sinus syndrome (except in patients with a function¬ ing artificial ventricular pacemaker). 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). 5. Patients with atrial flutter or atrial fibrillation and an ac¬ cessory bypass tract (e g. Wolff-Parkinson-White. LownGanong-Levine syndromes) (see WARNINGS'. Because of the trandolapril component, TARKA is contrain¬ dicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor. Do not co-administer aliskiren with TARKA in patients with diabetes (see PRECAUTIONS, Drug Interactions'. WARNINGS Heart Failure Verapamil Component Verapamil has a negative inotropic effect which, in most pa¬ tients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net im¬ pairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8$) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction le.g., ejection fraction less than 3(Ki. pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure' and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see PRECAU¬ TIONS - Drug Interactions). Patients with milder ventricu¬ lar dysfunction should, if possible, be controlled with opti¬ mum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRE¬ CAUTIONS! Trandolapril Component Trandolapril, as an ACE inhibitor, may cause excessive hy¬ potension in patients with congestive heart failure (see WARNINGS - Hypotension) Hypotension Verapamil Component Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. Trandolapril Component Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril has only rarely been as¬ sociated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who are salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating treatment with trandolapril (see PRECAUTIONS - Drug Interactions and ADVERSE REACTIONS', In controlled studies, hypotension was observed in 0.6‘I of patients receiving any combination of trandolapril and ve¬ rapamil HCI ER. In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be as¬ Free

TARKA • ABBV1E/587 sociated with oliguria or azotemia, and, rarely, with acute renal failure and death (see DOSAGE AND ADMINIS¬ TRATION'. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal sa¬ line may be administered intravenously. A transient hypo¬ tensive response is not a contraindication to further doses: however, lower doses of verapamil HCI ER and/or trandolapril or reduced concomitant diuretic therapy should be considered. Elevated Liver Enzymes/Hepatic Failure Verapamil Component Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge: half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain> in addition to elevations of SGOT, SGPT. and alkaline phosphatase. Trandolapril Component ACE inhibitors rarely have been associated with a syn¬ drome of cholestatic jaundice, fulminant hepatic necrosis, and death. The mechanism of this syndrome is not under¬ stood. Patients receiving ACE inhibitors who develop jaun¬ dice should discontinue the ACE inhibitor and receive ap¬ propriate medical follow-up. Liver abnormalities were noted in 3.27i of patients taking any of several combinations of trandolapril/verapamil doses. Periodic monitoring of liver function in patients tak¬ ing TARKA is therefore prudent. Accessory Bypass Tract (Wolff-Parkinson-White or LownGanong-Levine Syndromes) Verapamil Component Some patients with paroxysmal and/or chronic atrial fibril¬ lation or atrial flutter and a coexisting accessory AV path¬ way have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Al¬ though a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil mav be at risk and its use in these patients is contraindi¬ cated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil. Atrioventricular Block Verapamil Component The effect of verapamil on AV conduction and the SA nixie may lead to asymptomatic first-degree AV block and tran¬ sient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8' 6.00 mEq/L) occurred in approximately 0.4 percent of hy¬ pertensive patients receiving trandolapril and in 0.8% of pa¬ tients receiving a dose of trandolapril (0.5-8 mg) in combi¬ nation with a dose of verapamil SR (120-240 mg). In most cases, elevated serum potassium levels were isolated val¬ ues, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperka¬ lemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with trandolapril (see PRECAUTIONS - Drug Interactions). Cough Presumably due to the inhibition of the degradation of en¬ dogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving af¬ ter discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose. Surgery/anesthesia Trandolapril Component In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be

due to this mechanism, it can be corrected by volume expan¬ sion (see PRECAUTIONS - Use in Patients with Attenu¬ ated (Decreased) Neuromuscular Transmission). Drug Interactions In vitro metabolic studies indicate that verapamil is metab¬ olized by cytochrome P450 including CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g. erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g. rifampin) have caused a lowering of plasma levels of verapamil. Therefore, patients receiving inhibitors or inducers of the cytochrome P450 system should be mon¬ itored for drug interactions. Digitalis Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can in¬ crease serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digoxin toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce to¬ tal body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or under-digitalization. Whenever overdigitalization is sus¬ pected, the daily dose of digoxin should be reduced or tem¬ porarily discontinued. Upon discontinuation of any verapamil-containing regime including TARKA (trandolapril/verapamil hydrochloride ER), the patient should be reassessed to avoid underdigitalization. No clini¬ cally significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and digoxin. Lithium Verapamil Component Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lith¬ ium levels. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. TARKA and lithium should be coadministered with caution, and fre¬ quent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Clarithromycin Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent clarithromy¬ cin. Erythromycin Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent erythromy¬ cin ethylsuccinate. Cimetidine The interaction between cimetidine and chronically admin¬ istered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. No clinically significant pharmacokinetic inter¬ action has been found between trandolapril (or its metabo¬ lites) and cimetidine. Antiarrhythmic Agents Verapamil Component Disopyramide Phosphate Data on possible interactions between verapamil and diso¬ pyramide phosphate are not available. Therefore, disopyra¬ mide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have addi¬ tive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine In a small number of patients with hypertrophic cardiomy¬ opathy (IHSSl, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil sig¬ nificantly counteracted the effects of quinidine on AV con¬ duction. There has been a report of increased quinidine lev¬ els during verapamil therapy. Antihypertensive Agents Concomitant use of TARKA with other antihypertensive agents including diuretics, vasodilators, beta-adrenergic blockers, and alpha-antagonists may result in additive hy¬

potensive effects. There are reports that verapamil may re¬ sult in higher concentrations of the alpha-agonists prazosin and terazosin. Dual Blockade of the Renin-Angiotensin System (RAS) Trandolapril Component Dual blockade of the RAS with angiotensin receptor block¬ ers, ACE inhibitors, or aliskiren is associated with in¬ creased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on TARKA and other agents that affect the RAS. Do not co-administer aliskiren with TARKA in patients with diabetes. Avoid use of aliskiren with TARKA in patients with renal impairment (GFR .

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Look for PDR drug information and services in your EHR (See USP Controlled Room Temperaturel. Keep out of the reach of children. Protect from moisture. 17

PATIENT COUNSELING INFORMATION

Patients should be advised: • of the potential benefits and risks of TRICOR. • not to use TRICOR if there is a known hypersensitivity to fenofibrate or fenofibric acid. • of medications that should not be taken in combination with TRICOR. • that if they are taking coumarin anticoagulants, TRICOR may increase their anti-coagulant effect, and increased monitoring may be necessary. • to continue to follow an appropriate lipid-modifying diet while taking TRICOR. • to take TRICOR once daily, without regard to food, at the prescribed dose, swallowing each tablet whole. • to return for routine monitoring. • to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking TRICOR. • to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. Manufactured for AbbVie Inc., North Chicago, IL 60064, U.S.A. by Fournier Laboratories Ireland Limited, Anngrove, Carrigtwohill Co. Cork, Ireland. 03-A774-R8, Revised: February, 2013 Shown in Product Identification Guide, page 304

TRILIPIX®

$

[try-lip-iks\ (fenofibric acid) capsule, delayed release for oral use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRILIPIX safely and effectively. See full prescribing information for TRILIPIX. TRILIPIX® (fenofibric acid) capsule, delayed release for oral use Initial U.S. Approval: 2008 -RECENT MAJOR CHANGESIndications and Usage, Combination With a Statin - removal (1) Dosage and Administration, Combination With a Statin - removal (2)

4/2015 4/2015

-INDICATIONS AND USAGETrilipix is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as adjunctive therapy to diet to: • Reduce TG in patients with severe hypertriglyceridemia (1.1). • Reduce elevated LDL-C, Tbtal-C, TG and Apo B, and to increase HDL-C in patients with primary hypercholester¬ olemia or mixed dyslipidemia (1.2). Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of Trilipix did not reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1). -DOSAGE AND ADMINISTRATION• Hypertriglyceridemia: 45 to 135 mg once daily (2.2). • Primary hypercholesterolemia or mixed dyslipide¬ mia: 135 mg once daily (2.3). • Renally impaired patients: 45 mg once daily (2.4). • Maximum dose: 135 mg once daily (2.1). • May be taken without regard to food (2.1). -DOSAGE FORMS AND STRENGTHSOral Delayed Release Capsules:

45 mg and 135 mg (3).

-CONTRAINDICATIONS• Severe renal dysfunction, including patients receiving di¬ alysis (4, 12.3). • Active liver disease (4, 5.3). • Gallbladder disease (4, 5.5). • Nursing mothers (4, 8.3). • Known hypersensitivity to fenofibric acid or fenofibrate 14. 5.9) -WARNINGS AND PRECAUTIONS• Myopathy and rhabdomyolysis have been reported in pa¬ tients taking fenofibrate. The risks for myopathy and rhabdomyolysis are increased in elderly patients; patients with diabetes, renal failure, or hypothyroidism; and pa¬ tients being treated with a statin (5.2).

TRILIPIX • ABBVIE/595 • Trilipix can increase serum transaminases. Liver tests should be monitored periodically (5.3). • Trilipix can reversibly increase serum creatinine levels (5.4). Renal function should be monitored periodically in patients with renal insufficiency (8.6). • Trilipix increases cholesterol excretion into the bile, lead¬ ing to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.5). • Exercise caution in concomitant treatment with oral cou¬ marin anticoagulants. Adjust the dosage of coumarin an¬ ticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications (5.6). -ADVERSE REACTIONSThe most common adverse events reported during clinical trials with fenofibrate (> 2% and at least 1% greater than placebo) were abnormal liver tests, increased AST, in¬ creased ALT, increased CPK, and rhinitis (6.1). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -DRUG INTERACTIONS• Coumarin Anticoagulants: (7.1). • Bile Acid Binding Resins: (7.2). • Immunosuppressants: (7.3). -USE IN SPECIFIC POPULATIONS• Geriatric Use: Dose Selection for the elderly should be made on the basis of renal function (8.5). • Renal Impairment: Trilipix should be avoided in pa¬ tients with severe renal impairment. Dose adjustment is required in patients with mild to moderate renal impair¬ ment (8.6). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 4/2015 FULL PRESCRIBING INFORMATION. CONTENTS* 1 INDICATIONS AND USAGE 1.1 Treatment of Severe Hypertriglyceridemia 1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia 1.3 Limitations of Use 1.4 General Considerations for Treatment 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations 2.2 Severe Hypertriglyceridemia 2.3 Primary Hypercholesterolemia or Mixed Dys¬ lipidemia 2.4 Impaired Renal Function 2.5 Geriatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Mortality and Coronary Heart Disease Mor¬ bidity 5.2 Skeletal Muscle 5.3 Liver Function 5.4 Serum Creatinine 5.5 Cholelithiasis 5.6 Coumarin Anticoagulants 5.7 Pancreatitis 5.8 Hematological Changes 5.9 Hypersensitivity Reactions 6.10 Venothromboembolic Disease 5.11 Paradoxical Decreases in HDL Cholesterol Levels 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Coumarin Anticoagulants 7.2 Bile Acid Binding Resins 7.3 Immunosuppressants 7.4 Colchicine 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Severe Hypertriglyceridemia 14.2 Primary Hypercholesterolemia (Heterozy¬ gous Familial and Nonfamilial) and Mixed Dyslipidemia

16 17

HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION 17.1 Patient Counseling * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Treatment of Severe Hypertriglyceridemia Trilipix is indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceride¬ mia. Improving glycemic control in diabetic patients show¬ ing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Trilipix therapy on reducing this risk has not been adequately studied. 1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia Trilipix is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Tbtal-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein choles¬ terol (HDL-C) in patients with primary hypercholesterol¬ emia or mixed dyslipidemia. 1.3 Limitations of Use Fenofibrate at a dose equivalent to 135 mg of Trilipix did not reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus /see Warnings and Precautions (5.1)}. 1.4 General Considerations for Treatment Laboratory studies should be performed to establish that lipid levels are abnormal before instituting Trilipix therapy. Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothy¬ roidism that may be contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet. Drug therapy is not indicated for patients who have eleva¬ tions of chylomicrons and plasma triglycerides, but who have normal levels of VLDL. 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving Trilipix and should continue this diet during treatment. Trilipix delayed release capsules can be taken without regard to meals. Patients should be advised to swallow Trilipix capsules whole. Do not open, crush, dis¬ solve, or chew capsules. Serum lipids should be monitored periodically. 2.2 Severe Hypertriglyceridemia The initial dose of Trilipix is 45 to 135 mg once daily. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid deter¬ minations at 4 to 8 week intervals. The maximum dose is 135 mg once daily. 2.3 Primary Hypercholesterolemia or Mixed Dyslipide¬ mia The dose of Trilipix is 135 mg once daily. 2.4 Impaired Renal Function

•

Treatment with Trilipix should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose. The use of Trilipix should be avoided in patients with se¬ verely impaired renal function /see Use in Specific Popula¬ tions (8.6) and Clinical Pharmacology (12.3)1. 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function /see Use in Specific Populations (8.5)]. 3

DOSAGE FORMS AND STRENGTHS

• 45 mg capsules with a reddish-brown cap imprinted in white ink the “a" logo and a yellow body imprinted in black ink the number “45*. • 135 mg capsules with a blue cap imprinted in whit*- ink the *a’ logo and a yellow body imprinted in black ink the number “135".

Information on the AbbVie, Inc products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110

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596/ABBVIE • TRILIPIX

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

4 CONTRAINDICATIONS Trilipix is contraindicated m: • patients with severe renal impairment, including those re¬ ceiving dialysis I see Clinical Pharmacology (12.3)1. • patients with active liver disease, including those with pri¬ mary biliary cirrhosis and unexplained persistent liver function abnormalities Isee Warnings anil Precautions (5.3)). • patients with preexisting gallbladder disease /see Warn¬ ings and Precautions 3% of pa¬ tients taking Trilipix alone Gastrointestinal Disorders: Diarrhea, dyspepsia General Disorders and Administration Site Condi tions: Pain Infections and Infestations: Nasopharyngitis, sinusitis, upper respiratory tract infection

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Look for PDR drug information and services in your EHR Musculoskeletal and Connective Tissue Disorders: Ar¬ thralgia. myalgia, pain in extremity Nervous System Disorders: Dizziness 6.2 Postmarketing Experience The following adverse events have been identified during poetapproval use of fenofibrate: rhabdomyolysis. pancreati¬ tis, renal failure, muscle spasms, acute renal failure, hepa¬ titis, cirrhosis, anemia, asthenia, and severely depressed HDL-cholesterol levels. Because these events are reported voluntarily from a popu¬ lation of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 7 DRUG INTERACTIONS 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR. Caution should be exercised when oral coumarin anticoagu¬ lants are given in conjunction with Trilipix. The dosage of the anticoagulant should be reduced to maintain the PT/ INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized lsee Warnings and Precautions (5.6)1. 7.2 Bile Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take Trilipix at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid imped¬ ing its absorption. 7.3 Immunosuppressants Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of drugs of the fibrate class including Trilipix, there is a risk that an inter¬ action will lead to deterioration of renal function. The ben¬ efits and risks of using Trilipix with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. 7.4 Colchicine Cases of myopathy, including rhabdomyolysis, have been re¬ ported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofi¬ brate with colchicine.

8

USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category: C The safety of Trilipix in pregnant women has not been es¬ tablished. There are no adequate and well controlled stud¬ ies of Trilipix in pregnant women. Trilipix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not ob¬ served at 14 mg/kg/day (less than I times the maximum rec¬ ommended human dose (MRHD), based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD. based on body surface area comparisons; mg/m2). In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD. based on body surface area comparisons; mg/m2. 8.3 Nursing Mothers Trilipix should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discon¬ tinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of Trilipix in pediatric patients have not been established. 8.5 Geriatric Use Trilipix is substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, and the risk of adverse reactions to this drug may be greater in patients with im¬ paired renal function. Fenofibric acid exposure is not influ¬ enced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function I see Dosage and Admin¬ istration (2.5) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Trilipix.

TRIUPIX • ABBVIE/597 8.6 Renal Impairment The use of Trilipix should be avoided in patients who have severe renal impairment Isee Contraindications (4)]. Dose reduction is required in patients with mild to moderate re¬ nal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)1. Monitoring renal function in patients with renal impairment is recommended. 8.7 Hepatic Impairment The use of Trilipix has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 10

OVERDOSAGE

There is no specific treatment for overdose with Trilipix. General supportive care of the patient is indicated, includ¬ ing monitoring of vital signs and observation of clinical sta¬ tus, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric la¬ vage; usual precautions should be observed to maintain the airway. Because Trilipix is highly bound to plasma proteins, hemodialysis should not be considered. 11

DESCRIPTION

Trilipix (fenofibric acid) is a lipid regulating agent available as delayed release capsules for oral administration. Each delayed release capsule contains choline fenofibrate, equiv¬ alent to 45 mg or 135 mg of fenofibric acid. The chemical name for choline fenofibrate is ethanaminium, 2-hydroxyN,N,N-trimethyl, 2-{4-(4-chlorobenzoyl)phenoxy] -2methylpropanoate (1:1) with the following structural for¬ mula: O

O

The empirical formula is C22HWC1N05 and the molecular weight is 421.91. Choline fenofibrate is freely soluble in wa¬ ter. The melting point is approximately 210°C. Choline feno¬ fibrate is a white to yellow powder, which is stable under ordinary conditions. Each delayed release capsule contains enteric coated mini¬ tablets comprised of choline fenofibrate and the following inactive ingredients: hvpromellose, povidone, water, hydroxvlpropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer, talc, triethyl cit¬ rate. The capsule shell of the 45 mg capsule contains the following inactive ingredients! gelatin, titanium dioxide, yellow iron bxide, black iron oxide, and red iron oxide. The capsule shell of the 135 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, yellow iron oxide, and FD&C Blue #2. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of Trilipix is fenofibric acid. The pharma¬ cological effects of fenofibric acid in both animals and hu¬ mans have been extensively studied through oral adminis¬ tration of fenofibrate. The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII Ian inhibitor of lipoprotein lipase activity). Activation of PPARa also induces an increase in the synthe¬ sis of HDL-C and Apo AI and AIT. 12.3 Pharmacokinetics Trilipix contains fenofibric acid, which is the only circulat¬ ing pharmacologically active moiety in plasma after oral ad¬ ministration of Trilipix. Fenofibric acid is also the circulat¬ ing pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid. Plasma concentrations of fenofibric acid after administra¬ tion of one 135 mg Trilipix delayed release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions. Absorption Fenofibric acid is well absorbed throughout the gastrointes¬ tinal tract. The absolute bioavailability of fenofibric acid is approximately 81r*. Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of Trilipix capsule under fasting conditions. Fenofibric acid exposure in plasma, as measured by C_ and AUC, is not significantly different when a single 135 mg dose of Trilipix is administered under fasting or nonfasting conditions.

Distribution Upon multiple dosing of Trilipix. fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum pro¬ tein binding is approximately 99'? in normal and dyslipidemic subjects. Metabolism Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabo¬ lite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data after fenofibrate administration in¬ dicate that fenofibric acid does not undergo oxidative me¬ tabolism (e.g., cytochrome P450) to a significant extent. Elimination After absorption, Trilipix is primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide. Fenofibric acid is eliminated with a half-life of approxi¬ mately 20 hours, allowing once daily administration of Trilipix. Specific Populations Geriatrics In five elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 IVh in young adults. This indicates that an equivalent dose of Trilipix can be used in elderly subjects with normal renal function, with¬ out increasing accumulation of the drug or metabolites Isee Use in Specific Populations (8.5)]. Pediatrics The pharmacokinetics of Trilipix has not been studied in pe¬ diatric populations. Gender No pharmacokinetic difference between males and females has been observed for Trilipix. Race The influence of race on the pharmacokinetics of Trilipix has not been studied; however, fenofibric acid is not metab¬ olized by enzymes known for exhibiting inter-ethnic vari¬ ability. Renal Impairment The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomeru¬ lar filtration rate [eGFR] 5

i’° S

5

om 0

I-1-1-1-1-1-1 05 1 2 3

4

Fresh Gas Flow Rate. L/mln

Since the reaction of carbon dioxide with absorbents is exo¬ thermic. the temperature increase will be determined by quantities of C02 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic sta¬ tus of the patient, and ventilation. The relationship of temperature produced by varying levels of C02 and Compound A production is illustrated in the following in vitro simulation where C02 was added to a circle ab¬ sorber system

Compound A concentration in a circle absorber system in¬ creases as a function of increasing C02 absorbent tempera¬ ture and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A in¬ creases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased sevoflurane concentrations and duration of anesthesia. In a clinical study in which sevoflurane was administered to patients under low flow conditions for > 2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A lev¬ els produced. The relationship between Compound A level? and sevoflurane exposure are shown in Figure 2a. Figure 2a. ppm-hr versus MAC-hr at Row Rate of 1 L/min

Sevoflurane is an inhalational anesthetic agent for use in induction and maintenance of general anesthesia. Mini¬ mum alveolar concentration (MAC) of sevoflurane in oxygen for a 40-year-old adult is 2.1%. The MAC of sevoflurane de¬ creases with age (see DOSAGE ANI) ADMINISTRATION for details). Pharmacokinetics Uptake and Distribution Solubility

Because of the low solubility of sevoflurane in blood (blood/ gas partition coefficient @ 37°C = 0.63-0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. Therefore there is a rapid rate of increase in the alveolar (end-tidal) copcentration (FA) toward the inspired concentration (F|) during induc¬ tion. Induction of Anesthesia

In a study in which seven healthy male volunteers were ad¬ ministered 70% N20/30%02 for 30 minutes followed by 1.0% sevoflurane and 0.6% isoflurane for another 30 minutes the Fa/F| ratio was greater for sevoflurane than isoflurane at all time points. The time for the concentration in the alveoli to reach 50% of the inspired concentration was 4-8 minutes for isoflurane and approximately 1 minute for sevoflurane. Fa/F| data from this study were compared with Fa/F, data of other halogenated anesthetic agents from another study. When all data were normalized to isoflurane, the uptake and distribution of sevoflurane was shown to be faster than isoflurane and halothane, but slower than desflurane. The results are. depicted in Figure 3. Recovery from Anesthesia

Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentra¬ tion of up to 270 ppm for one hour. Sporadic single cell ne¬ crosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 10501090 ppm (male-female) and, at 3 hours, 350-490 ppm (male-female). An experiment was performed comparing sevoflurane plus 75 or 100 ppm Compound A with an active control to eval¬ uate the potential nephrotoxicity of Compound A in non¬ human primates. A single 8-hour exposure of Sevoflurane in the presence of Compound A produced single-cell renal tu¬ bular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent. At a fresh gas flow rate of 1 L/min, mean maximum concen¬ trations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The levels of Compound A at which toxicity occurs in humans is not known. The second pathway for degradation of sevoflurane occurs primarily in the presence of desiccated C02 absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIPl and formaldehyde. HF1P is inactive, nongenotoxic, rapidly glucuronidated and cleared by the liver. Formaldehyde is present during normal metabolic pro¬ cesses. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and for¬ mate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature that can be associated with desiccated Baralyme*. Methanol can react with Compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimi¬ nation to form Compounds C, D, and E.

The low solubility of sevoflurane facilitates rapid elimina¬ tion via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration follow ing termination of anesthesia (FA), relative to the last alveolar concentration (Fa()) measured immediately before discontinuance of the anesthetic. In the healthy volunteer study described above, rate of elimination of sevoflurane was similar compared with desflurane, but faster compared with either halothane or isoflurane. These results are de¬ picted in Figure 4. Figure 3. Ratio of Concentration of Anesthetic in Alveolar Gas to Inspired Gas Fa*T

[See figure 4 at top of next column! Yasuda N, Lockhart S, Eger El II. et ah Comparison of ki¬ netics of sevoflurane and isoflurane in humans. Anesth Analg 72:316, 1991. Protein Binding

The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated. Other fluorinated volatile anesthetics have been shown to displace drugs from serum and tissue proteins in vitro. The clinical significance of this is unknown. Clinical studies have shown no untoward effects when sevoflurane is admin¬ istered to patients taking drugs that are highly bound and have a small volume of distribution (e.g.. phenytoin).

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Table 1. Fluoride Ion Estimates in Special Populations Following Administration of Sevoflurane

PEDIATRIC PATIENTS Anesthetic Sevoflurane-02 Sevoflurane-02 Sevoflurane/N.,0 Sevoflurane/N>0 Sevoflurane/N20 ELDERLY RENAL HEPATIC OBESE

n

Age (yr)

Duration Ihr)

Dose (MAC*hr)

Cm„ IpNI)

76 40 25 42 40 33 21 8 35

0-11 1-11 5-13 0-18 1-11 65-93 29-83 42-79 24-73

0.8 2.2 1.9 2.4 2.0 2.6 2.5 3.6 3.0

1.1 3.0 2.4 2.2 2.6 1.4 1.0 2.2 1.7

12.6 16.0 21.3 18.4 15.5 25.6 26.1 30.6 38.0

hours of the end of anesthesia and are less than 25 pM (475 ng/mL) for the majority of the population after 10 hours. The half-life is in the range of 15;23 hours. It has been reported that following administration of meth¬ oxyflurane, serum inorganic fluoride concentrations > 50 pM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical tri¬ als with sevoflurane, there were no reports of toxicity asso¬ ciated with elevated fluoride ion levels. Figure 6. Fluoride Ion Concentrations Following Administration of Sevoflurane (mean MAC = 1.27, mean duration = 2.06 hr) Mean Fluoride Ion Concentrations (n = 48)

n = number of patients studied.

Table 2. Induction and Recovery Variables for Evaluable Pediatric Patients in Two Comparative Studies: Sevoflurane versus Halothane Time to End-Point (min) Induction Emergence Response to command First analgesia Eligible for recovery discharge

Sevoflurane Mean ± SEM

Halothane Mean ± SEM

2.0 ± 0.2 (n = 294) 11.3 ± 0.7 (n -= 293) 13.7 ± 1.0 (n = 271) 52.2 ± 8.5 (n = 216) 76.5 ±2.0 (n = 292)

2.7 ± 0.2 (n = 252) 15.8 ± 0.8 (n = 252) 19.3 ±1.1 (n = 2301 67.6 ± 10.6 (n = 150) 81.1 ± 1.9 (n = 246)

n = number of patients with recording of events.

Table 3. Recovery Variables for Evaluable Adult Patients in Two Comparative Studies: Sevoflurane versus Isoflurane Time to Parameter: (min) Emergence Response to command First analgesia Eligible for recovery discharge

Sevoflurane Mean ± SEM

Isoflurane Mean ± SEM

7.7 ± 0.3 (n = 395) 8.1 ± 0.3 (n = 395) 42.7 ± 3.0 (n = 269) 87.6 ± 5.3 (n = 244)

9.1 ± 0.3 (n = 348) 9.7 ± 0.3 (n = 345) 52.9 ± 4.2 (n = 228) 79.1 ± 5.2 (n = 252)

n = number of patients with recording of recovery events.

not inducible by barbiturates. As shown in Figure 5, inor¬ ganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentra¬ tions within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimina¬ tion of sevoflurane minimizes the amount of anesthetic available for metabolism.

Figure 4. Concentration of Anesthetic in Alveolar Gas Following Termination of Anesthesia FAFao

Figure 5. Serum Inorganic Fluoride Concentrations for Sevoflurane and Other Volatile Anesthetics

Fluoride Concentrations After Repeat Exposure and in Spe¬ cial Populations

Fluoride concentrations have been measured after single, extended, and repeat exposure to sevoflurane in normal sur¬ gical and special patient populations, and pharmacokinetic parameters were determined. Compared with healthy individuals, the fluoride ion halflife waS prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impair¬ ment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 houra (range 21-61 hours) as compared to a mean of approximately 21 hours (range 10-48 hours) in normal healthy individuals. The mean half-life in the el¬ derly (greater than 65 years) approximated 24 hours (range 18-72 hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16-47 hours). Mean maxi¬ mal fluoride values (CmalI) determined in individual studies of special populations are displayed below. (See table 1 abovel Pharmacodynamics

Changes in the depth of sevoflurane anesthesia rapidly fol¬ low changes in the inspired concentration. In the sevoflurane clinical program, the following recovery variables were evaluated: 1. Time to events measured from the end of study drug:

• Time to removal of the endotracheal tube (extubation time) • Time required for the patient to open his/her eyes on verbal command (emergence time) • Time to respond to simple command (e.g., squeeze my hand) or demonstrates purposeful movement (response to command time, orientation time) 2. Recovery of cognitive function and motor coordination was evaluated based on:

• psychomotor performance tests (Digit Symbol Substitu¬ tion lest 1DSSTJ, Treiger Dot Test i • the results of subjective (Visual Analog Scale |VAS) i and objective (objective pain-discomfort scale 10PDS1 > inea sure men ts • time to administration of the first post-anesthesia anal¬ gesic medication • assessments of post-anesthesia patient status 3. Other recovery times were:

. .. Anesth

Days Post-anesthesia '

Minutes of Elimination Cousins M.J., Greenstein L.R., Hitt B.A., et al: Metabo¬ lism and renal effects of enflurane in man. Anesthesiology 44:44; 1976* and Sevo-93-044’. Metabolism

Legend:

Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIPi with release of inorganic flu¬ oride and C03. Once formed HF1P is rapidly conjugated with glucuronic acid and eliminated as a urinary metabo¬ lite. No other metabolic pathways for sevoflurane have bten identified In vivo metabolism studies suggest that approx¬ imately 5T of the sevoflurane dose may be metabolized. Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isontazid and ethanol. This is similar to the me¬ tabolism of isoflurane and enflurane and is distinct from that of methoxyflurane w hich is metabolized via a variety of cytochrome P450 isoforms. The metabolism of sevoflurane is

Pre-Anesth. = Pre-anesthesia Elimination Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluonde. Studies on fluoride indicate that up to 50'»' of fluonde clearance is nonrenal (via fluoride being taken up into bone). Pharmacokinetics of Fluoride Ion Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of sevoflurane adminis¬ tered. and the composition of the anesthetic gas mixture. In studies where anesthesia was maintained purely with sevoflurane for periods ranging from 1 to 6 hours, peak flu¬ onde concentrations ranged between 12 pM and 90 pM. As shown in Figure 6. peak concentrations occur within 2

• time to achieve an Aldrcte Score of > 8 • time required for the patient to.be eligible for discharge from the recovery area, per standard criteria at site • time when the patient was eligible for discharge from the hospital • time when the patient was able to sit up or stand with¬ out dizziness Some of these variables are summarized as follows: |See table 2 above) ISee table 3 abovel |See table 4 at top of next pagel Cardiovascular Effects

Sevoflurane was studied in 14 healthy volunteers (18-35 years old) comparing sevoflurane-02 (Sevo/Oj) to sevoflurane-NjO/Oj (Seva/N20/02> during 7 hours of anes¬ thesia. During controlled ventilation, hemodynamic param¬ eters measured are shown in Figures 7-10-

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Table 4. Meta-Analyses for Induction and Emergence Variables for Evaluable Adult Patients in Comparative Studies: Sevoflurane versus Propofol

Figure 7. Heart Rate

No. of Studies

Sevoflurane Mean ± SEM

Propofol Mean * SEM

Mean maintenance anesthesia exposure

3

Time to induction: (min)

1

Time to emergence: (min)

3

Time to respond to command: (min)

3

Time to first analgesia: (min)

3

Time to eligibility for recovery discharge: (min)

3

1.0 MAC'hr. ± 0.8 (n = 259) 3.1 ±0.18* (n = 93) 8.6 ± 0.57 (n = 255) 9.9 ± 0.60 (n = 257) 43.8 ± 3.79 (n = 177) 116.0 ± 4.15 (n = 257)

7.2 mg/kg/hr ± 2.6 (n = 258) 2.2 ± 0.18** (n = 93) 11.0 ± 0.57 (n = 260) 12.1 ± 0.60 (n = 260) 57.9 ± 3.68 (n = 179) 115.6 ± 3.98 (n = 261)

Parameter

Figure 8. Mean Arterial Pressure

* Propofol induction of one sevoflurane group = mean of 178.8 mg ± 72.5 SD (n = 165) ** Propofol induction of all propofol groups = mean of 170.2 mg ± 60.6 SD (n = 245) n = number of patients with recording of events.

Table 6. Recovery Parameters in Two Outpatient Surgery Studies: Least Squares Mean s SEM

Mean Maintenance Anesthesia Exposure ± SD Time to Emergence (min)

Figure 9. Systemic Vascular Resistance

Time to Respond to Commands (min) Time to First Analgesia (min) Time to Eligibility for Discharge from Recovery Area (min)

Sevoflurane/N20

lsoflurane/N20

Sevoflurane/N20

Propofol/N20

0.64 ± 0.03 MAC* hr. (n = 245) 8.2 ± 0.4 (n = 246) 8.5 ± 0.4 (n = 246) 45.9 ± 4.7 (n = 160) 87.6 ± 5.3 (n = 244)

0.66 ± 0.03 MAC* hr. (n = 249) 9.3 ± 0.3 (n = 251) 9.8 ± 0.4 (n = 248) 59.1 ± 6.0 (n = 252) 79.1 ± 5.2 (n = 252)

0.8 ± 0.5 MAC* hr. (n = 166) 8.3 ± 0.7 (n = 137) 9.1 ± 0.7 (n = 139) 46.1 ± 5.4 (n = 83) 103.1 ± 3.8 (n = 139)

7.3 dt 2.3 mg/kg/hr. (n = 166) 10.4 ± 0.7 (n = 142) 11.5 ± 0.7 (n = 143) 60.0 ±4.7 (n =: 88) 105.1 ±3.7 (n = 143)

n = number of patients with recording of recovery events.

Table 7. Recovery Parameters in Two Inpatient Surgery Studies: Least Squares Mean ± SEM Figure 10. Cardiac Index

O A - Sevo/C>2 A C-Sevo/CyNgO CM

E

Mean Maintenance Anesthesia Exposure ± SD Time to Emergence (min)

5

£ E

Time to Respond to Commands (min) Time to First Analgesia (min)

--*1 1 BASELINE

1.5

Time to Eligibility for Discharge from Recovery Area (min)

2

MAC LEVEL

Sevoflurane/N20

soflurane/N20

Sevoflurane/N20

Propofo!/N20

1.27 MAC*hr. ± 0.05 (n = 271) 11.0 ± 0.6 (n = 270) 12.8 ± 0.7 (n = 270) 46.1 ± 3.0 (n = 233) 139.2 ± 15.6 (n = 268)

1.58 MAC*hr. ± 0.06 (n = 282) 16.4 ± 0.6 (n = 281) 18.4 ± 0.7 (n = 281) 55.4 ± 3.2 (n = 242) 165.9 ± 16.3 (n = 282)

1.43 MAC*hr. ±0.94 (n = 93) 8.8 ± 1.2 (n = 92) 11.0 ± 1.20 (n = 92) 37.8 ± 3.3 (n = 82) 148.4 ± 8.9 (n = 92)

7.0 mg/kg/hr ± 2.9 (n = 92) 13.2 ± 1.2 (n = 92) 14.4 ± 1.21 (n = 91) 49.2 ± 3.3 (n = 79) 141.4 ± 8.9 (n = 92)

n = number of patients with recording of recovery events. Sevoflurane is a dose-related cardiac depressant. Sevoflurane does not produce increases in heart rate at doses less than 2 MAC. A study investigating the epinephrine induced arrhythmogenic effect of sevoflurane versus isoflurane in adult pa¬ tients undergoing transsphenoidal hypophysectomy demon¬ strated that the threshold dose of epinephrine (i.e., the dose at which the first sign of arrhythmia was observed) produc¬ ing multiple ventricular arrhythmias was 5 mcg/kg with both sevoflurane and isoflurane. Consequently, the interac¬ tion of sevoflurane with epinephrine appears to be equal to that seen with isoflurane. Clinical Trials Sevoflurane was administered to a total of 3185 patients prior to sevoflurane NDA submission. The types of patients are summarized as follows: Table 5. Patients Receiving Sevoflurane in Clinical Trials Type of Patients ADULT Cesarean Delivery Cardiovascular and patients at risk of myocardial ischemia Neurosurgical Hepatic impairment Renal impairment PEDIATRIC

Number

Studied

2223 29 246 22 8 35 962

Clinical experience with these patients is described below.

Adult Anesthesia The efficacy of sevoflurane in comparison to isoflurane, enflurane, and propofol was investigated in 3 outpatient and 25 inpatient studies involving 3591 adult patients. Sevoflurane was found to be comparable to isoflurane, enflurane, and propofol for the maintenance of anesthesia in adult patients. Patients administered sevoflurane showed shorter times (statistically significant) to some recovery events (extubation, response to command, and orientation) than patients who received isoflurane or propofol. Mask Induction

Sevoflurane has a nonpungent odor and does not cause res¬ piratory irritability. Sevoflurane is suitable for mask induc¬ tion in adults. In 196 patients, mask induction was smooth and rapid, with complications occurring with the following frequencies: cough, 6%; breathholding, 6%; agitation, 6%; laryngospasm, 5%. Ambulatory Surgery

Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N20 in two studies involving 786 adult (18-84 years of age) ASA Class I, II, or III patients. Shorter times to emergence and response to commands (statistically significant) were observed with sevoflurane compared to isoflurane and propofol. (See table 6 above) Inpatient Surgery

Sevoflurane was compared to isoflurane and propofol for maintenance of anesthesia supplemented with N20 in two multicenter studies involving 741 adult ASA Class I, II or III (18-92 years of age) patients. Shorter times to emer-

gence, command response, and first post-anesthesia analgesia (statistically significant) were observed with sevoflurane compared to isoflurane and propofol. [See table 7 above] Pediatric Anesthesia The concentration of sevoflurane required for maintenance of general anesthesia is age-dependent (see DOSAGE AND ADMINISTRATION). Sevoflurane or halothane was used to anesthetize 1620 pediatric patients aged 1 day to 18 years, and ASA physical status I or II (948 sevoflurane, 672 halothane). In one study involving 90 infants and children, there were no clinically significant decreases in heart rate compared to awake values at 1 MAC. Systolic blood pres¬ sure decreased 15-20% in comparison to awake values fol¬ lowing administration of 1 MAC sevoflurane; however, clin¬ ically significant hypotension requiring immediate intervention did not occur. Overall incidences of bradycar¬ dia [more than 20 beats/min lower than normal (80 beats/ min)) in comparative studies was 3% for sevoflurane and 7% for halothane. Patients who received sevoflurane had slightly faster emergence times (12 vs. 19 minutes), and a higher incidence of post-anesthesia agitation (14% vs. 10%). Sevoflurane (n = 91) was compared to halothane (n = 89) in a single-center study for elective repair or palliation of con¬ genital heart disease. The patients ranged in age from 9 days to 11.8 years with an ASA physical status of II, III, and IV (18%, 68%, and 13% respectively). No significant differ¬ ences were demonstrated between treatment groups with respect to the primary outcome measures: cardiovascular

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Look for PDR drug information and services in your EHR decompensation and severe arterial desaturation. Adverse event data was limited to the study outcome variables col¬ lected during surgery and before institution of cardiopulmo¬ nary bypass. Mask Induction

Sevoflurane has a non pungent odor and is suitable for mask induction in pediatric patients. In controlled pediatric stud¬ ies in which mask induction was performed, the incidence of induction events is shown below (see ADVERSE REAC¬ TIONS*. Table 8. Incidence of Pediatric Induction Events Sevoflurane (n = 836)

Halothane In = 660)

14% 6% 5% 3% 2% .< 1%

11% 10% 6%

Agitation Cough Breathholding Secretions Laryngospasm Bronchospasm

3% 2% 0%

n = number of patients.

Ambulatory Surgery

Sevoflurane (n = 518) was compared to halothane (n = 382) for the maintenance of anesthesia in pediatric outpatients. All patients received N20 and many received fentanyl, mid¬ azolam, bupivacaine, or lidocaine. The time to eligibility for discharge from post-anesthesia care units was similar be¬ tween agents (see CLINICAL, PHARMACOLOGY and ADVERSE REACTIONS). Cardiovascular Surgery Coronary Artery Bypass Graft ICABGI Surgery

Sevoflurane was compared to isoflurane as an adjunct with opioids in a multicenter study of 273 patients undergoing CABG surgery. Anesthesia was induced with midazolam (0.1-0.3 mg/kg); vecuronium (0.1-0.2 mg/kg), and fentanyl (5-15 mcg/kg). Both isoflurane and sevoflurane were admin¬ istered at loss of consciousness in doses of 1.0 MAC and ti¬ trated until the beginning of cardiopulmonary bypass to a maximum of 2.0 MAC. The total dose of fentanyl did not exceed 25 mcg/kg. The average MAC dose was 0.49 for sevoflurane and 0.53 for isoflurane. There Were no signifi¬ cant differences in hemodynamics, cardioactive drug use, or ischemia incidence between the two groups. Outcome was also equivalent. In this small multicenter study, sevoflurane appears to be as effective and as safe as isoflurane for sup¬ plementation of opioid anesthesia for coronary bypass grafting. Non-Cardiac Surgery Patients at Risk for Myocardial Ischemia

Sevoflurane-N20 was compared to isoflurane-N20 for main¬ tenance of anesthesia in a multicenter study in 214 pa¬ tients, age 40-87 years who were at mild-to-moderate risk for myocardial ischemia and were undergoing elective noncardiac surgery. Forty-six percent (46%) of the operations were cardiovascular, with the remainder evenly divided be¬ tween gastrointestinal and musculoskeletal and small num¬ bers of other surgical procedures. The average duration of surgery was less than 2 hours. Anesthesia induction usually was performed with thiopental (2-5 mg/kg) and fentanyl (1-5 mcg/kg). Vecuronium (0.1-0.2 mg/kg) was also adminis¬ tered to facilitate intubation, muscle relaxation or immobil¬ ity during surgery. The average MAC dose was 0.49 for both anesthetics. There was no significant difference between the anesthetic regimens for intraoperative hemodynamics, car¬ dioactive drug use, or ischemic incidents, although only 83 patients in the sevoflurane group and 85 patients in the isoflurane group were succi>ssfu!ly monitored for ischemia. The outcome was also equivalent in terms of adverse events, death, and postoperative myocardial infarction. Within the limits of this small multicenter study in patients at mild-tomoderate risk for myocardial ischemia, sevoflurane was a satisfactory equivalent to isoflurane in providing supple¬ mental inhalation anesthesia to intravenous drugs. Cesarean Section Sevoflurane (n = 29) was compared to isoflurane (n = 27) in ASA Class I or 11 patients for the maintenance of anesthesia during cesarean section. Newborn evaluations and recovery events were recorded. With both anesthetics, Apgar scores averaged 8 and 9 at 1 and 5 minutes, respectively. Use of sevoflurane as part of general anesthesia for elective cesarean section produced no untoward effects in mother or neonate. Sevoflurane and isoflurane demonstrated equiva¬ lent recovery characteristics. There was no difference be¬ tween sevoflurane and isoflurane with regard to the effect on the newborn, as assessed by Apgar Score and Neurolog¬ ical and Adaptive Capacity Score (average = 29.5). The safety of sevoflurane in labor and vaginal delivery has not been evaluated.

Neurosurgery trol (N = 90) administered for a 2 hours at a fresh gas flow rate of < 1 Liter/minute. Per study defined criteria (Hou et Three studies compared sevoflurane to isoflurane for main¬ tenance of anesthesia during neurosurgical procedures. In a I al.) one patient in the sevoflurane group developed eleva¬ tions of creatinine, in addition to glycosoria and protein¬ study of 20 patients, there was no difference between uria. This patient received sevoflurane at fresh gas flow¬ sevoflurane and isoflurane with regard to recovery from an¬ rates of < 800 mL/minute. Using these same criteria, there esthesia. In 2 studies, a total of 22 patients with intracra¬ were no patients in the active control group who developed nial pressure (ICP) monitors received either sevoflurane or treatment emergent elevations in serum creatinine. isoflurane. There was no difference between sevoflurane Sevoflurane may present an increased risk in patients with and isoflurane with regard to ICP response to inhalation of known sensitivity to volatile halogenated anesthetic agents. 0.5, 1.0, and 1.5 MAC inspired concentrations of volatile KOH containing C02 absorbents are not recommended for agent during N20-02-fentanyl anesthesia. During progres¬ use with sevoflurane. sive hyperventilation from PaC02 = 40 to PaC02 = 30, ICP Reports of QT prolongation, associated with torsade de response to hypocarbia was preserved with sevoflurane at pointes (in exceptional cases, fatal), have been received. both 0.5 and 1.0 MAC concentrations. In patients at risk for Caution should be exercised when administering elevations of ICP, sevoflurane should be administered cau¬ sevoflurane to susceptible patients (e.g. patients with con¬ tiously in conjunction with ICP-reducing maneuvers such as genital Long QT Syndrome or patients taking drugs that hyperventilation. can prolong the QT interval). Hepatic Impairment Malignant Hyperthermia A multicenter study (2 sites) compared the safety of In susceptible individuals, potent inhalation anesthetic sevoflurane and isoflurane in 16 patients with mild-toagents, including sevoflurane, may trigger a skeletal muscle moderate hepatic impairment utilizing the lidocaine MEGX hypermetabolic state leading to high oxygen demand and assay for assessment of hepatocellular function. All patients the clinical syndrome known as malignant hyperthermia. received intravenous propofol (1-3 mg/kg) or thiopental Sevoflurane can induce malignant hyperthermia in geneti¬ (2-7 mg/kg) for induction and succinylcholine, vecuronium, cally susceptible individuals, such as those with certain in¬ or atracurium for intubation. Sevoflurane or Isoflurane was herited ryanodine receptor mutations. The clinical syn¬ administered in either 100% 02 or up to 70% N20/02. Nei¬ drome is signaled by hypercapnia, and may include muscle ther drug adversely affected hepatic function. No serum in¬ rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, organic fluoride level exceeded 45 pM/L, but sevoflurane pa¬ and/or unstable blood pressure. Some of these nonspecific tients had prolonged terminal disposition of fluoride, as signs may also appear during light anesthesia, acute hy¬ evidenced by longer inorganic fluoride half-life than pa¬ poxia, hypercapnia, and hypovolemia. tients with normal hepatic function (23 hours vs. 10-48 In clinical trials, one case of malignant hyperthermia was hours). reported. In addition, there have been postmarketing re¬ Renal Impairment ports of malignant hyperthermia. Some of these cases have Sevoflurane was evaluated in renally impaired patients been fatal. with baseline serum creatinine > 1.5 mg/dL. Fourteen pa¬ Treatment of malignant hyperthermia includes discontinu¬ tients who received sevoflurane were compared with 12 pa¬ ation of triggering agents (e.g., sevoflurane), administration tients who received isoflurane. In another study, 21 patients of intravenous dantrolene sodium (consult prescribing infor¬ who received sevoflurane were compared with 20 patients mation for intravenous dantrolene sodium for additional in¬ who received enflurane. Creatinine levels increased in 7% of formation on patient management), and application of sup¬ patients who received sevoflurane, 8% of patients who re¬ portive therapy. Supportive therapy may include efforts to ceived isoflurane, and 10% of patients who received enfturestore body temperature, respiratory and circulatory sup¬ rane. Because of the small number of patients with renal port as indicated, and management of electrolyte-fluid-acidinsufficiency (baseline serum creatinine greater than base abnormalities. Renal failure may appear lator, and 1.5 mg/dL) studied, the safety of sevoflurane administration urine flow should be monitored and sustained if possible. in this group has not yet been fully established. Therefore, Perioperative Hyperkalemia sevoflurane should be used with caution in patients with re¬ Use of inhaled anesthetic agents has been associated with nal insufficiency (see WARNINGS). rare increases in serum potassium levels that have resulted INDICATIONS AND USAGE in cardiac arrhythmias and death in pediatric patients dur¬ Sevoflurane is indicated for induction and maintenance of ing the postoperative period. Patients with latent as well as general anesthesia in adult and pediatric patients for inpa¬ overt neuromuscular disease, particularly Duchenne mus¬ tient and outpatient surgery. cular dystrophy, appear to be most vulnerable. Concomitant Sevoflurane should be administered only by persons trained use of succinylcholine has been associated with most, but in the administration of general anesthesia. Facilities for not all, of these cases. These patients also experienced sig¬ maintenance of a patent airway, artificial ventilation, oxy¬ nificant elevations in serum creatine kinase levels and, in gen enrichment, and circulatory resuscitation must be im¬ some cases, changes in urine consistent with myoglobin¬ mediately available. Since level of anesthesia may be al¬ uria. Despite the similarity in presentation to malignant tered rapidly, only vaporizers producing predictable hyperthermia, none of these patients exhibited signs or concentrations of sevoflurane should be used. symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and CONTRAINDICATIONS resistant arrhythmias is recommended; as is subsequent Sevoflurane can cause malignant hyperthermia. It should evaluation for latent neuromuscular disease. not be used in patients with known sensitivity to PRECAUTIONS sevoflurane or to other halogenatod agents nor in patients with known or suspected susceptibility to malignant hyper¬ During the maintenance of anesthesia, increasing the con¬ centration of sevoflurane produces dose-dependent de¬ thermia. creases in blood pressure. Due to sevoflurane's insolubility WARNINGS in blood, these hemodynamic changes may occur more rap¬ Although data from controlled clinical studies at low flow idly than with other volatile anesthetics. Excessive de¬ rates are limited, findings taken from patient and animal creases in hlood pressure or respiratory depression may be studies suggest that there is a potential for renal injury related to depth of anesthesia and may be corrected by de¬ which is presumed due to Compound A. Animal and human creasing the inspired concentration of sevoflurane. studies demonstrate that sevoflurane administered for more Rare cases of seizures have been reported in association than 2 MAO hours and at fresh gas flow rates of < 2 17min with sevoflurane use (see PRECAUTIONS - Pediatric Use may be associated with proteinuria and glycosuria. and ADVERSE REACTIONS). While a level of Compound A exposure at which clinical The recovery from general anesthesia should be assessed nephrotoxicity might be expected to occur has not been es¬ carefully before a patient is discharged from the post¬ tablished, it is prudent to consider all of the factors leading anesthesia care unit. to Compound A exposure in humans, (■specially duration of Drug Interactions exposure, fresh gas flow rate, and concentration of In clinical trials, no significant adverse reactions occurred sevoflurane. During sevoflurane anesthesia the clinician with other drugs commonly used in the perioperative pe¬ should adjust inspired concentration and fresh gas flow rate riod, including: central nervous system depressants, auto¬ to minimize exposure to Compound A. Tb minimize exposure nomic drugs, skeletal muscle relaxants, anti-infective to Compound A, sevoflurane exposure should not exceed agents, hormones and synthetic substitutes, blood deriva2 MAC‘hours at flow rates of 1 to < 2 I7min Fresh gas flow j tives, and cardiovascular drugs rates < 1 L/min are not recommended. Intravenous Anesthetics Because clinical experience in administering sevoflurane to Sevoflurane administration is compatible with barbiturates, patients with renal insufficiency (creatinine > 1.5 mg/dL) is propofol, and other commonly used intravenous anesthetics. limited, its safety in these patients has not been estab¬ lished. Sevoflurane may be associated with glycosuria and protein¬ Information on the AbbVie, Inc. products listed on these uria when used for long procedures at low flow rates. The pages is from the prescribing information in use as safety of low flow sevoflurane on renal function was evalu¬ of July 31, 2015 For more information, please visit ated in patients with normal preoperative renal function. rxabbvie com or call 1-800-633-9110 One study compared sevoflurane (N = 98) to an active con¬

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604/ABBVIE • ULTANE Benzodiazepines and Opioids Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as with other inhalational anesthetics. Sevoflurane administration is compatible with benzodiazepines and opioids as commonly used in surgical practice. Nitrous Oxide As with other halogenated volatile anesthetics, the anes¬ thetic requirement for sevoflurane is decreased when ad¬ ministered in combination with nitrous oxide. Using 50% N20, the MAC equivalent dose requirement is reduced ap¬ proximately 50% in adults, and approximately 25% in pedi¬ atric patients (see DOSAGE AND ADMINISTRATION). Neuromuscular Blocking Agents As is the case with other volatile anesthetics, sevoflurane increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. When used to supplement alfentanil-N20 anesthesia, sevoflurane and isoflurane equally potentiate neuromuscu¬ lar block induced with pancuronium, vecuronium or atracurium. Therefore, during sevoflurane anesthesia, the dosage adjustments for these muscle relaxants are similar to those required with isoflurane. Potentiation of neuromuscular blocking agents requires equilibration of muscle with delivered partial pressure of sevoflurane. Reduced doses of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation. Among available nondepolarizing agents, only vecuronium, pancuronium and atracurium interactions have been stud¬ ied during sevoflurane anesthesia. In the absence of specific guidelines: 1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants. 2. During maintenance of anesthesia, the required dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N20/opioid anesthesia. Adminis¬ tration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation. The effect of sevoflurane on the duration of depolarizing neuromuscular blockade induced by succinylcholine has not been studied. Hepatic Function Results of evaluations of laboratory parameters (e.g., ALT, AST, alkaline phosphatase, and total bilirubin, etc.), as well as investigator-reported incidence of adverse events relat¬ ing to liver function, demonstrate that sevoflurane can be administered to patients with normal or mild-to-moderately impaired hepatic function. However, patients with severe hepatic dysfunction were not investigated. Occasional cases of transient changes in postoperative he¬ patic function tests were reported with both sevoflurane and reference agents. Sevoflurane was found to be comparable to isoflurane with regard to these changes in hepatic func¬ tion. Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences. Clini¬ cal judgement should be exercised when sevoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction (see ADVERSE REACTIONS). It has been reported that previous exposure to halogenated hydrocarbon anesthetics may increase the potential for he¬ patic injury. Desiccated C02 Absorbents An exothermic reaction occurs when sevoflurane is exposed to C02 absorbents. This reaction is increased when the C02 absorbent becomes desiccated, such as after an extended pe¬ riod of dry gas flow through the C02 absorbent canisters. Rare cases of extreme heat, smoke, and/or spontaneous fire in the anesthesia breathing circuit have been reported dur¬ ing sevoflurane use in conjunction with the use of desiccated C02 absorbent, specifically those containing potassium hy¬ droxide (e.g. Baralyme). KOH containing C02 absorbents are not recommended for use with sevoflurane. An unusu¬ ally delayed rise or unexpected decline of inspired sevoflurane concentration compared to the vaporizer setting may be associated with excessive heating of the C02 absor¬ bent and chemical breakdown of sevoflurane. As with other inhalational anesthetics, degradation and production of degradation products can occur when sevoflurane is exposed to desiccated absorbents. When a cli¬ nician suspects that the C02 absorbent may be desiccated, it should be replaced. The color indicator of most C02 absor¬ bents may not change upon desiccation. Therefore, the lack of significant color change should not be taken as an assur¬ ance of adequate hydration. C02 absorbents should be re¬ placed routinely regardless of the state of the color indica¬ tor. Carcinogenesis. Mutagenesis, Impairment of Fertility Studies on carcinogenesis have not been performed for ei¬ ther sevoflurane or Compound A. No mutagenic effect of

sevoflurane was noted in the Ames test, mouse micronu¬ cleus test, mouse lymphoma mutagenicity assay, human lymphocyte culture assay, mammalian cell transformation assay, 32P DNA adduct assay, and no chromosomal aberra¬ tions were induced in cultured mammalian cells. Similarly, no mutagenic effect of Compound A was noted in the Ames test, the Chinese hamster chromosomal aberra¬ tion assay and the in vivo mouse micronucleus assay. How¬ ever, positive responses were observed in the human lym¬ phocyte chromosome aberration assay. These responses were seen only at high concentrations and in the absence of metabolic activation (human S-9). Pregnancy Category B Reproduction studies have been performed in rats and rab¬ bits at doses up to 1 MAC (minimum alveolar concentration) without C02 absorbent and have revealed no evidence of im¬ paired fertility or harm to the fetus due to sevoflurane at 0.3 MAC, the highest nontoxic dose. Developmental and re¬ productive toxicity studies of sevoflurane in animals in the presence of strong alkalies (i.e., degradation of sevoflurane and production of Compound A) have not been conducted. There are no adequate and well-controlled studies in preg¬ nant women. Because animal reproduction studies are not always predictive of human response, sevoflurane should be used during pregnancy only if clearly needed. Labor and Delivery Sevoflurane has been used as part of general anesthesia for elective cesarean section in 29 women. There were no unto¬ ward effects in mother or neonate (see PHARMACODY¬ NAMICS - Clinical Trials). The safety of sevoflurane in labor and delivery has not been demonstrated. Nursing Mothers The concentrations of sevoflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, sevoflurane concentrations in milk are pre¬ dicted to be below those found with many other volatile an¬ esthetics. Geriatric Use MAC decreases with increasing age. The average concentra¬ tion of sevoflurane to achieve MAC in an 80 year old is ap¬ proximately 50% of that required in a 20 year old. Pediatric Use Induction and maintenance of general anesthesia with sevoflurane have been established in controlled clinical tri¬ als in pediatric patients aged 1 to 18 years (see PHARMA¬ CODYNAMICS - Clinical Trials and ADVERSE REAC¬ TIONS). Sevoflurane has a nonpungent odor and is suitable for mask induction in pediatric patients. The concentration of sevoflurane required for maintenance of general anesthesia is age dependent. When used in com¬ bination with nitrous oxide, the MAC equivalent dose of sevoflurane should be reduced in pediatric patients. MAC in premature infants has not been determined (see PRECAU¬ TIONS - Drug Interactions and DOSAGE AND ADMINIS¬ TRATION for recommendations in pediatric patients 1 day of age and older). The use of sevoflurane has been associated with seizures (see PRECAUTIONS and ADVERSE REACTIONS). The majority of these have occurred in children and young adults starting from 2 months of age, most of whom had no predisposing risk factors. Clinical judgement should be ex¬ ercised when using sevoflurane in patients who may be at risk for seizures. ADVERSE REACTIONS Adverse events are derived from controlled clinical trials conducted in the United States, Canada, and Europe. The reference drugs were isoflurane, enflurane, and propofol in adults and halothane in pediatric patients. The studies were conducted using a variety of premedications, other an¬ esthetics, and surgical procedures of varying length. Most adverse events reported were mild and transient, and may reflect the surgical procedures, patient characteristics (in¬ cluding disease) and/or medications administered. Of the 5182 patients enrolled in the clinical trials, 2906 were exposed to sevoflurane, including 118 adults and 507 pediatric patients who underwent mask induction. Each pa¬ tient was counted once for each type of adverse event. Ad¬ verse events reported in patients in clinical trials and con¬ sidered to be possibly or probably related to sevoflurane are presented within each body system in order of decreasing frequency in the following listings. One case of malignant hyperthermia was reported in pre-registration clinical trials. Adverse Events During the Induction Period (from Onset of Anesthesia by Mask Induction to Surgical Incision) Inci¬ dence > 1% Adult Patients IN = 118) Cardiovascular Bradycardia 5%, Hypotension 4%, Tachycardia 2% Nervous System Agitation 7%

Respiratory System Laryngospasm 8%, Airway obstruction 8%, Breathholding 5%, Cough Increased 5% Pediatric Patients (N = 507) Cardiovascular Tachycardia 6%, Hypotension 4% Nervous System Agitation 15% Respiratory System Breathholding 5%,.Cough Increased 5%, Laryngospasm 3%, Apnea 2% Digestive System Increased salivation 2% Adverse Events During Maintenance and Emergence Peri¬ ods, Incidence > 1% IN = 2906) Body as a whole Fever 1%, Shivering 6%, Hypothermia 1%, Movement 1%, Headache 1% Cardiovascular Hypotension 11%, Hypertension 2%, Bradycardia 5%, Tachycardia 2% Nervous System Somnolence 9%, Agitation 9%, Dizziness 4%, Increased sal¬ ivation 4% Digestive System Nausea 25%, Vomiting 18% Respiratory System Cough increased 11%, Breathholding 2%, Laryngospasm 2% Adverse Events, All Patients in Clinical Trials (N = 2906), All Anesthetic Periods, Incidence 65, apart from an increased tendency of the elderly to develop constipation. However, because the elderly may be more sensitive to the renal and gastrointestinal effects of non¬ steroidal anti-inflammatory agents as well as possible in¬ creased risk of respiratory depression with opioids, extra caution and reduced dosages should be used when treating the elderly with VICOPROFEN. ADVERSE REACTIONS VICOPROFEN was administered to approximately 300 pain patients in a safety study that employed dosages and a duration of treatment sufficient to encompass the recom¬ mended usage (see DOSAGE AND ADMINISTRATION). Adverse event rates generally increased with increasing daily dose. The event rates reported below are from approx¬ imately 150 patients who were in a group that received one tablet of VICOPROFEN an average of three to four times daily. The overall incidence rates of adverse experiences in the trials were fairly similar for this patient group and those who received the comparison treatment, acetamino¬ phen 600 mg with codeine 60 mg. The following lists adverse events that occurred with an in¬ cidence of 1% or greater in clinical trials of VICOPROFEN, without regard to the causal relationship of the events to the drug, lb distinguish different rates of occurrence in clin¬ ical studies, the adverse events are listed as follows: name of adverse event = less than 3% adverse events marked with an asterisk * = 3% to 9% adverse event rates over 9% are in parentheses. Body as a Whole Abdominal pain*; Asthenia*; Fever; Flu syndrome; Head¬ ache (27911; Infection*; Pain. Cardiovascular Palpitations; Vasodilation.

VICOPROFEN • ABBVIE/609 Central Nervous System Anxiety*; Confusion; Dizziness (14%); Hypertonia; Insom¬ nia*; Nervousness*; Paresthesia; Somnolence (22%); Think¬ ing abnormalities. Digestive Anorexia; Constipation (22%); Diarrhea*; Dry mouth*; Dyspepsia (12%); Flatulence*; Gastritis; Melena; Mouth ul¬ cers; Nausea (21%); Thirst; Vomiting*. Metabolic and Nutritional Disorders Edema*. Respiratory Dyspnea; Hiccups; Pharyngitis; Rhinitis. Skin and Appendages Pruritus*; Sweating*. Special Senses Tinnitus. Urogenital Urinary frequency. Incidence less than 1% Body as a Whole Allergic reaction. Cardiovascular Arrhythmia; Hypotension; Tachycardia. Central Nervous System Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo. Digestive Chalky stool; “Clenching teeth”; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver en¬ zyme elevation. Metabolic and Nutritional Weight decrease. Musculoskeletal Arthralgia; Myalgia. Respiratory Asthma; Bronchitis; Hoarseness; Increased cough; Pulmo¬ nary congestion; Pneumonia; Shallow breathing; Sinusitis. Skin and Appendages Rash; Urticaria. Special Senses Altered vision; Bad taste; Dry eyes. Urogenital Cystitis; Glycosuria; Impotence; Urinary incontinence; Uri¬ nary retention.

Signs and Symptoms Hydrocodone Component Serious overdose with hydrocodone is characterized by res¬ piratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis) extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycar¬ dia and hypotension. In severe overdosage, apnea, circula¬ tory collapse, cardiac arrest and death may occur. Ibuprofen Component Symptoms include gastrointestinal irritation with erosion and hemorrhage or perforation, kidney damage, liver dam¬ age, heart damage, hemolytic anemia, agranulocytosis, thrombocytopenia, aplastic anemia, and meningitis. Other symptoms may include headache, dizziness, tinnitus, confu¬ sion, blurred vision, mental disturbances, skin rash, stoma¬ titis, edema, reduced retinal sensitivity, corneal deposits, and hyperkalemia. Treatment Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a pa¬ tent airway and the institution of assisted or controlled ven¬ tilation. Naloxone, a narcotic antagonist, can reverse respi¬ ratory depression and coma associated with opioid overdose or unusual sensitivity to opioids, including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered intravenously with simultaneous ef¬ forts at respiratory resuscitation. Since the duration of ac¬ tion of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Supportive mea¬ sures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug. In cases where consciousness is impaired it may be inadvisable to perform gastric lavage. If gastric lavage is performed, little drug will likely be recovered if more than an hour has elapsed since ingestion. Ibuprofen is acidic and is excreted in the urine: therefore, it may be beneficial to administer alkali and in¬ duce diuresis. In addition to supportive measures the use of oral activated charcoal may help to reduce the absorption and reabsorption of ibuprofen. Dialysis is not likely to be effective for removal of ibuprofen because it is very highly bound to plasma proteins.

DRUG ABUSE AND DEPENDENCE Misuse Abuse and Diversion of Opioids VICOPROFEN contains hydrocodone, an opioid agonist, and is a Schedule II controlled substance. VICOPROFEN, and other opioids used in analgesia can be abused and are subject to criminal diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: im¬ paired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable dis¬ ease utilizing a multidisciplinary approach, but relapse is common. “Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo ap¬ propriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping" to obtain ad¬ ditional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physical dependence usually as¬ sumes clinically significant dimensions only after several weeks of continued opioid use, although a mild degree of physical dependence may develop after a few days of opioid therapy. Tblerance, in which increasingly large doses are re¬ quired in order to produce the same degree of analgesia, is manifested initially by a shortened duration of analgesic ef¬ fect, and subsequently by decreases in the intensity of an¬ algesia. The rate of development of tolerance varies among patients. Physicians should be aware that abuse of opioids can occur in the absence of true addiction and is character¬ ized by misuse for non-medical purposes, often in combina¬ tion with other psychoactive substances. VICOPROFEN, like other opioids, may be diverted for non-medical use. Record-keeping of prescribing information, including quan¬ tity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing prac¬ tices, periodic re-evaluation of therapy, and proper dispens¬ ing and storage are appropriate measures that help to limit abuse of opioid drugs.

Carefully consider the potential benefits and risks of VICOPROFEN and other treatment options before deciding to use VICOPROFEN. Use the lowest effective dose for the shortest duration consistent with individual patient treat¬ ment goals (see WARNINGS). After observing the response to initial therapy with VICOPROFEN, the dose and frequency should be adjusted to suit an individual patient's needs. For the short-term (generally less than 10 days) manage¬ ment of acute pain, the recommended dose of VICOPROFEN is one tablet every 4 to 6 hours, as neces¬ sary. Dosage should not exceed 5 tablets in a 24-hour period. It should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of unto¬ ward effects is dose related. The lowest effective dose or the longest dosing interval should be sought for each patient (see WARNINGS), espe¬ cially in the elderly. After observ ing the initial response to therapy with VICOPROFEN, the dose and frequency of dos¬ ing should be adjusted to suit the individual patient's need, without exceeding the total daily dose recommended.

OVERDOSAGE Following an acute overdosage, toxicity may result from hydrocodone and/or ibuprofen.

DOSAGE AND ADMINISTRATION

HOW SUPPLIED VICOPROFEN tablets are available as: White film-coated round convex tablets, engraved with “VP” over “a” logo on one side and plain on the other side. Bottles of 100-NDC 0074-2277-14 Bottles of 500-NDC 0074-2277-54 Hospital Unit Dosage Package-100 tablets (4 x 25 tabletsPNDC 0074-2277-12 Storage Store at 25°C (77°F); excursions permitted to 15*-30°C (59°-86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. A Schedule II Controlled Substance. © Abb Vie Inc. 2014 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDsj (See the end of this Medication Guide for a list of prescription NS AID medicines.)

Information on the AbbVie, Inc. products listed on these pages is from the prescribing information in use as of July 31, 2015. For more information, please visit rxabbvie.com or call 1-800-633-9110.

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610/ABBVIE • VICOPROFEN What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases: • with longer use of NSAID medicines • in people who have heart disease • NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft ICABG)." NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ul¬ cers and bleeding: • can happen without warning symptoms • may cause death The chance of a person getting an ulcer or bleeding in¬ creases with: • taking medicines called “corticosteroids” and “anticoagu¬ lants” • longer use ' , • smoking • drinking alcohol • older age • having poor health NSAID medicines should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAID medicines are used to treat pain and redness, swell¬ ing, arid heat (inflammation1 from medical conditions such as: • different types of arthritis • menstrual cramps and other types of short-term pain Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)? Do not take an NSAID medicine: • if you had an asthma attack, hives, or other allergic reac¬ tion with aspirin nr any other NSAID medicine • for pain right before or after heart bypass surgery ' ' Tell your healthcare provider: • about all your medical conditions, • about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause se¬ rious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist. • if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. • if you are breastfeeding Talk to your doctor. What are the possible side effects of Non-Steroidal AntiInflammatory Drugs (NSAIDs)? Serious side effects include: • heart attack • stroke • high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • bleeding and ulcers in the stomach and intestine • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma

Other side effects include: • stomach pain • constipation • diarrhea • gas • heartburn • nausea • vomiting • dizziness

Generic Name

Tradename

Celecoxib

Celebrex

Diclofenac

Cataflam, Voltaren, Arthrotec (combined with misoprostol)

---INDICATIONS AND USAGEVIEKIRA PAK with or without ribavirin is indicated for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cir¬ rhosis. VIEKIRA PAK includes ombitasvir, a hepatitis C vi¬ rus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, ritonavir, a CYP3A inhibitor and dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor. (1) Limitation of Use: VIEKIRA PAK is not recommended for use in patients with decompensated liver disease. (1) -DOSAGE AND ADMINISTRATION• Recommended dosage: Two ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets once daily (in the morningl and one dasabuvir 250 mg tablet twice daily (morning and evening) with a meal without regard to fat or calorie con¬ tent. (2.1) Treatment Regimen and Duration by Patient Population Patient Population

Diflunisal

Dolobid

Etodolac

Lodine, Lodine XL

Fenoprofen

Nalfon, Nalfon 200

Flurbirofen

Ansaid

Ibuprofen

Motrin, Tab-Profen, Vicoprofen* * (combined with hydrocodone),' Combunox (combined with oxycodone) Indocin, Indocin SR, Indo-Lemmon, Indomethagan

Ketoprofen

Oruvail

Ketorolac

Toradol

Mefenamic Acid

Ponstel

Meloxicam

Mobic

Nabumetone

Relafen

Naproxen

Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)

Oxaprozin

Daypro

Piroxicam

Feldene'

Sulindac

Clinoril 1 ‘ •

Treatment*

Duration

Genotype la. without cirrhosis

MEKIRA PAK + ribavirin

12 weeks

Genotype la, with cirrhosis

MEKIRA PAK + ribavirin

24 weeks**

VIEKIRA PAK

12 weeks

MEKIRA PAK + ribavirin

12 weeks

Genotype 1b, without cirrhosis

Indomethacin

Tolmotin

Genotype 1b, with cirrhosis

*Note:- Follow the genotype la dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. ** VIE KIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history /See Clinical Studies (14.3)]. • HCV/HTV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the ta¬ ble above. (2.1) • Liver Transplant Recipients: In liver transplant recipi¬ ents with normal hepatic function and mild fibrosis 'Metavir fibrosis score £2), the recommended duration of VIEKIRA PAK with ribavirin is 24 weeks. (2.2) -DOSAGE FORMS AND STRENGTHSTablets: • Ombitasvir, paritaprevir, ritonavir: 12.5/75/50 mg (3) • Dasabuvir: 250 mg (3) -CONTRAINDICATIONS• If VIEKIRA PAK is administered with ribavirin, the con¬ traindications to ribavirin also apply to this combination regimen. (4) • Patients with severe hepatic impairment. (4, 8.6, 12.3) • Co-administration with drugs that are: highly depen¬ dent on CYP3A for clearance: moderate or strong inducers of CYP3A and strong inducers of CYP2C8; and strong in¬ hibitors of CYP2C8. (4) • Known hypersensitivity to ritonavir te.g. toxic epidermal necrolysis, Stevens-Johnson syndrome). (4)

Tblectin, Tolectin DS, Tblectin 600

* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

-WARNINGS AND PRECAUTIONS~

. y

Get emergency help right away if you have any of the fol¬ lowing symptoms: • shortness of breath or • slurred speech trouble breathing • swelling of the face or • chest pain throat • weakness in one part or side of your body Stop your NSAID medicine and call your healthcare pro¬ vider right away if you have any of the following symp¬ toms: • nausea • more tired or weaker than usual • itching • your skin or eyes look yellow • stomach pain • flu-like symptoms • vomit blood

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more in¬ formation about NSAID medicines. Call your doctor for medical advice about side effects. You may report side ef¬ fects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ul¬ cers in the stomach and intestines. • Some of these NSAID medicines are sold in lower doses without a prescription (over the counter). Talk to your healthcare provider before using over the counter NSAIDs for more than 10 days. NSAID medicines that need a prescription

• there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet

Manufactured by Halo Pharmaceutical Inc. Whippany, NJ 07981 U.S.A. for AbbVie Inc. North Chicago, IL 60064 U.SA. This Medication Guide has been approved by the U-S. Food and Drug Administration. Ref. 03-B024-R6-Rev. August, 2014 Shown in Prwluct Identification Guide, page 304

VIEKIRA PAK™

IJ

(ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) co-packaged for oral use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VIEKIRA PAK safely and effectively. See full prescrib¬ ing information for VIEKIRA PAK VIEKIRA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets), co-packaged for oral use Initial U S. Approval: 2014 -RECENT MAJOR CHANGESDosage and Administration, Recommended Dosage in Adults (2.11 Contraindications (4)

3/2015 7/2015

• ALT Elevations: Discontinue ethinyl c.-lradiolcontaining medications prior to starting VIEKIRA PAK (alternative contraceptive methods are recommended). Perform hepatic laboratory testing on all patients during the first 4 weeks of treatment. For ALT elevations on ME KIRA PAK, monitor closely and follow recommenda¬ tions in full prescribing information. (5.1) • Risks Associated With Ribavirin Combination Treat¬ ment: If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen. (5.2) • Drug Interactions: The concomitant use of MEKIRA PAK and certain other drugs may result in known or po¬ tentially significant drug interactions, some of which maylead to loss of therapeutic effect of VIEKIRA PAK. (5.3) -ADVERSE REACTIONSIn subjects receiving VIEKIRA PAK with ribavirin, the most commonly reported adverse reactions (greater than 10*1 of subjects) were fatigue, nausea, pruritus, other skin reac¬ tions, insomnia and asthenia. In subjects receiving MEKIRA PAK without ribavirin, the most commonly re¬ ported adverse reactions (greater than or equal to 5% of subjects) were nausea, pruritus and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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VIEKIRAPAK • ABBVIE/611

-DRUG INTERACTIONSCo-administration of VIEKIRA PAK can alter the plasma concentrations of some drugs and some drugs may alter the plasma concentrations of VIEKIRA PAK. The potential for drug interactions must be considered before and during treatment. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.3, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 7/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults 2.2 Use in Liver Transplant Recipients 2.3 Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Increased Risk of ALT Elevations 5.2 Risks Associated With Ribavirin Combination Treatment 5.3 Risk of Adverse Reactions or Reduced Thera¬ peutic Effect Due to Drug Interactions 5.4 Risk of HIV-1 Protease Inhibitor Drug Resis¬ tance in HCWHIV-1 Co-infected Patients 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Adverse Reactions 7 DRUG INTERACTIONS 7.1 Potential for VIEKIRA PAK to Affect Other Drugs 7.2 Potential for Other Drugs to Affect One or More Components of VIEKIRA PAK 7.3 Established and Other Potential Drug Inter¬ actions 7.4 Drugs without Clinically Significant Interac¬ tions with VIEKIRA PAK 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Other HCV Genotypes 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Description of Clinical Trials 14.2 Clinical Trial Results in Adults with Chronic HCV Genotype la and lb Infection without Cirrhosis 14.3 Clinical Trial Results in Adults with Chronic HCV Genotype la and lb Infection and Compen¬ sated Cirrhosis 14.4 Effect of Ribavirin Dose Reductions on SVR12 14.5 Clinical Trial of Selected Liver Transplant Recipients (CORAL-I) 14.6 Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I) 14.7 Durability of Response 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

VIEKIRA PAK with or without ribavirin is indicated for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cir¬ rhosis. Limitation of Use: VIEKIRA PAK is not recommended for use in patients with decompensated liver disease/see Use in Specific Populations (8.61, and Clinical Pharmacology (12.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.

Table 2. Drugs that are Contraindicated with VIEKIRA PAK Drug(s) within Class that are Contraindicated

Drug Class

Clinical Comments

Alphal-adrenoreceptor antagonist

Alfuzosin HCL

Potential for hypotension.

Anticonvulsants

Carbamazepine, phenytoin, phenobarbital

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK

Antihyperlipidemic agent

Gemfibrozil

Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation.

Antimycobacterial

Rifampin

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK

Ergot derivatives

Ergotamine, dihydroergotamine, ergonovine, methylergonovine

Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine.

Ethinyl estradiol-containing products

Ethinyl estradiol-containing medications such as combined oral contraceptives

Potential for ALT elevations [see Warnings and Precautions (5.1)].

Herbal Product

St. John’s Wort (Hypericum perforatum)

Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK.

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis.

Neuroleptics

Pimozide

Potential for cardiac arrhythmias.

Non-nucleoside reverse transcriptase inhibitor

Efavirenz

Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations.

Phosphodiesterase-5 (PDE5) inhibitor

Sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension (PAH)

There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.

Sedatives/hypnotics

Triazolam Orally administered midazolam

Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with VTEKIRA PAK may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content /see Clinical Pharmacology (12.3)]. VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When adminis¬ tered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, re¬ fer to the ribavirin prescribing information. For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antivi¬ ral drugs. Monitor liver chemistry tests before initiating and during therapy [see Warnings and Precautions (5.1)]. Table 1 shows the recommended VIEKIRA PAK treatment regimen and duration based on patient population. Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naive or Interferon-Experienced) Patient Population

Treatment*

Duration

Genotype la. without cirrhosis

VIEKIRA PAK + ribavirin

12 weeks

Genotype la. with cirrhosis

VIEKIRA PAK -iribavirin

24 weeks**

Genotype 1b, without cirrhosis

VIEKIRA PAK

12 weeks

Genotype 1b, with cirrhosis

VIEKIRA PAK + ribavirin

’Note: Follow the genotype la dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. •’VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies (14.3)].

2.2 Use in Liver Transplant Recipients In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the rec¬ ommended duration of VIEKIRA PAK with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype /see Clinical Studies (14.6)]. When VIEKIRA PAK is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed /see Drug In¬ teractions (7)]. 2.3 Hepatic Impairment No dosage adjustment of VIEKIRA PAK is required in pa¬ tients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in patients with moder¬ ate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C) /see Contraindications (4), Use in Specific Populations (8.6), and Clinical Pharmacology 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to Placebo for 12 Weeks SAPPHIRE-I and -II VIEKIRA PAK + RBV 12 Weeks N = 770 %

Placebo 12 Weeks N = 255 %

Fatigue

34

26

Nausea

22

15

Pruritus"

.18

Skin reactions5

16

9

Insomnia

14

8

Asthenia

14

7

.

. 7

^Grouped term ‘pruritus' included the preferred terms pruritus and pruritus generalized. Grouped teems: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermntitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria.

j

VIEKIRA PAK with and without Ribavirin in Regiment’untrolled Trials VIEKIRA PAK with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection, respec¬ tively, in three clinical trials (PEARL-II, PEARL-111 and PEARL TV) (see Clinical Studies (14.1. 14.2)1. Pruritus, nau¬ sea. insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with VIEKIRA PAK in combination with ribavirin (see Table 4). The majority of adverse events were mild to moderate in

severity. The proportion of subjects who permanently dis¬ continued treatment due to adverse events was less than 1% for both VIEKIRA PAK in combination with ribavirin and VIEKIRA PAK alone. Table 4. Adverse Events with >5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to VIEKIRA PAK for 12 Weeks PEARL-II, III and -IV VIEKIRA PAK + RBV 12 Weeks N = 401 %

VIEKIRA PAK 12 Weeks N = 509 %

Nausea

16

8

Pruritus*

13

7

Insomnia

12

5

Asthenia

9

4

*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. VIEKIRA PAK with Ribavirin in Subjects with Compen¬ sated Cirrhosis VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II) [see Clini¬ cal Studies (14.1, 14.3)1. The type and severity of adverse events in subjects with compensated cirrhosis was compa¬ rable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of adverse events occurred during the first 12 weeks of dosing in both treatment arms. Most of the adverse events were mild to moderate in severity. The proportion of subjects treated with VIEKIRA PAK for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of subjects perma¬ nently discontinued treatment due to adverse events in each treatment arm. Skin Reactions In PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 1091 of subjects receiving VIEKIRA PAK with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving VIEKIRA PAK with ribavirin and 9% of subjects receiving placebo re¬ ported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks reported skin reactions. The majority of events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as Stevens Johnson Syn¬ drome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash with eosinophilia and sys¬ temic symptoms (DRESS). Laboratory Abnormalities Serum ALT Elevations Approximately 1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treat¬ ment. The incidence increased to 25% (4/16) among women taking a concomitant ethinyl estradiol containing medica¬ tion Isee Contraindications (4) and Warnings and Precau¬ tions (5.1)1. The incidence of clinically relevant ALT eleva¬ tions among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy was 3% (2/59). ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations were assessed as drug-related liver injury. Elevations in ALT were gener¬ ally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT /see Warnings and Precau¬ tions (5.1)1. Serum Bilirubin Elevations Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving VIEKIRA PAK with ribavirin compared to 2% in those receiving VIEKIRA PAK alone. These bilirubin increases were predominately indi¬ rect and related to the inhibition of the bilirubin transport¬ ers OATP1B1/1B3 by paritaprevir and ribavirin-induced he¬ molysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associ¬ ated with serum ALT elevations. Anemia /Decreased Hemoglobin Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with VIEKIRA PAK in combination with ribavirin was -2.4 g/dL and the mean

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VIEKIRA PAR • ABBVIE/613

Table 5 Established Drug Interactions Based on Drug Interaction Trials Concomitant Drug Class: Drug Name

Effect on Concentration

Clinical Comments

ANTIPSYCHOTIC quetiapine

T quetiapine

• Initiation of VIEKIRA PAK in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to l/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for the recommendations on adverse reaction monitoring. • Initiation of quetiapine in patients taking VIEKIRA PAK Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

T antiarrhythmics

Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK.

ketoconazole

T ketoconazole

When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.

voriconazole

i voriconazole

Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.

ANTIARRHYTHMICS amiodarone , bepridil , disopyramide , flecainide , lidocaine (systemic) , mexiletine , propafenone’, quinidine ANTIFUNGALS

CALCIUM CHANNEL BLOCKERS amlodipine

T amlodipine

Consider dose reduction for amlodipine. Clinical monitoring is recommended.

CORTICOSTEROIDS (INHALED/NASAL) t fluticasone

Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.

t furosemide (Cmal)

Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.

atazanavir/ritonavir once daily

t paritaprevir

When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning.

darunavir/ritonavir

1 darunavir (Clrough)

Co-administration of VIEKIRA PAK with darunavir/ ritonavir is not recommended.

lopinavir/ritonavir

T paritaprevir

Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended.

rilpivirine

T rilpivirine

Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.

fluticasone

DIURETICS furosemide

HIV-ANTIVIRAL AGENTS

HMG CoA REDUCTASE INHIBITORS rosuvastatin

T rosuvastatin

When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.

pravastatin

T pravastatin

When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day. (Table continued on next page)

change in subjects treated with VIEKIRA PAK alone was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment ) Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post¬ treatment Week 4. Less than 15 of subjects treated with VIEKIRA PAK with ribavirin had hemoglobin levels de¬ crease to less than 8.0 g/dL during treatment. Seven per¬ cent of subjects treated with VIEKIRA PAK in combination with ribavirin underw ent a ribavirin dose reduction due to a

decrease in hemoglobin levels; three subjects received a blood transfusion and five required erythropoietin. One pa¬ tient discontinued therapy due to anemia. No subjects treated with VIEKIRA PAK alone had a hemoglobin level less than 10 g/dL. VIEKIRA PAK in HCV/HIV-1 Co-infected Subjects VIEKIRA PAK with ribavirin was assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable antiretro¬ viral therapy. The most common adverse events occurring in

at least 10% of subjects were fatigue 500 pg/mL

CKD Stage 5 Dose in micrograms is based on baseline iPTH level (pg/mL)/80. Dose three times a week (e.g. every other day).

2 meg daily or 4 meg three times a week (e.g. every other day)

What are the ingredients in VIEKIRA PAK? Ombitasvir, paritaprevir, and ritonavir tablets:

Dose Titration CKD Stages 3, 4 Dosing Recommendation iPTH l,evel Relative to Baseline Increase dose by 1 meg daily or Decreased by < 30'/) 2 meg three times a week (e.g. every other day)

Decreased bv ^ 30% and < 60% Decreased by > 60'S or iPTH < 60 pg/mL

"Who should not take VIEKIRA PAK?"

• have HIV infection • have had a liver transplant If you take the medicines tacrolimus iPrograf®! or cyclosporine (Gengraf®, Neoral®, Sandimmune®) to help prevent rejection of your trans¬ planted liver, the amount of these medicines in your blood may increase during treatment with VIEKIRA PAK. o Your healthcare provider should check the level of tacrolimus or cyclosporine in your blood, and if needed may change your dose of these medicines or how often you take them. c When you finish taking VIEKIRA PAK or if you have to stop VIEKIRA PAK for any reason, your healthcare pro¬ vider should tell you what dose of tacrolimus or cyclo¬ sporine you should take and how often you should take it. • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if VIEKIRA PAK will harm your unborn baby. When tak¬ ing VIEKIRA PAK in combination with ribavirin you should also read the ribavirin Medication Guide for important pregnancy information. Pregnancy Registry: There is a registry for females who take antiretroviral medicines during pregnancy. The pur¬ pose of this registry is to collect information about the health of the pregnant mother and her baby. If you are a pregnant female and have both HCV and HIV infection, talk with your healthcare provider about enrolling in this registry. • are breastfeeding or plan to breastfeed. It is not known if VIEKIRA PAK passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take VIEKIRA PAK. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medi¬ cines. vitamins, and herbal supplements. Some medicines interact with VIEKIRA PAK Keep a list of your medicines to show your healthcare provider and pharmacist. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with VIEKIRA PAK. • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take VIEKIRA PAK with other medicines. • When you finish treatment with VIEKIRA PAK: • If your doctor changed the dose of any of your usual medicines during treatment with VIEKIRA PAK: Ask vour doctor about when you should change back to your original dose after you finish treatment with VIEKIRA PAK » If your doctor told you to stop taking any of your usual medicines during treatment with VIEKIRA PAK: Ask your doctor if you should start taking these medicines again after you finish treatment with VIEKIRA PAK.

• Each of the 4 smaller cartons contains enough child resis¬ tant daily dose packs of medicine to last for 7 days (1 week). • Each daily dose pack contains all of your VIEKIRA PAK medicine for 1 day (4 tablets). Follow the instructions on each daily dose pack about how to remove the tablets. • Take VIEKIRA PAK tablets with a meal as follows: ° take the 2 pink tablets (ombitasvir, paritaprevir, and ritonavir), with 1 of the beige tablets (dasabuvir), at about the same time every morning. »take the second beige tablet (dasabuvir), at about the same time every evening. • If you miss a dose of the pink tablets, and it is less than 12 hours from the time you usually take your dose, take the missed dose with a meal as soon as possible. Then take your next dose at your usual time with a meal. • If you miss a dose of the pink tablets, and it is more than 12 hours from the time you usually take your dose, do not take the missed dose. Take your next dose at your usual time with a meal. • If you miss a dose of the beige tablet, and it is less than 6 hours from the time you usually take your dose, take the missed dose with a meal as soon as possible. Then take your next dose at your usual time with a meal. • If you miss a dose of the beige tablet, and it is more than 6 hours from the time you usually take your dose, do not take the missed dose. Take your next dose at your usual time with a meal. • Do not take more than your prescribed dose of VIEKIRA PAK to make up for a missed dose. • If you take too much VIEKIRA PAK, call your healthcare provider or go to the nearest emergency room right aw'ay. What are the possible side effects of VIEKIRA PAK?

See "What is the most important information I should know about VIEKIRA PAK?" Common side effects of VIEKIRA PAK when used with riba¬ virin include:

• • • • • •

Inactive ingredients: copovidone, K value 28, vitamin E

polyethylene glycol succinate, propylene glycol monolaurate Type I, sorbitan monolaurate, colloidal silicon dioxide/colloi¬ dal anhydrous silica, sodium stearyl fumarate, polyvinyl al¬ cohol, polyethylene glycol 3350/macrogoI 3350, talc, tita¬ nium dioxide, and red iron oxide.

Dose in micrograms is based on most recent iPTH level (pg/mL)/80 with adjustments based on serum calcium and phosphorous levels. Dose three times a week (e.g. every other day).

Maintain dose Decrease dose by 1 meg daily or 2 meg three times a week (e.g. every other day)

• have liver problems other than hepatitis C infection. See

How should I take VIEKIRA PAK?

Active ingredients: ombitasvir, paritaprevir, and ritonavir

CKD Stage 5

tiredness nausea itching skin reactions such as redness or rash sleep problems feeling weak

Common side effects of VIEKIRA PAK when used without ribavirin include:

• nausea • itching • sleep problems Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of VIEKIRA PAK. For more information, ask your healthcare provider or phar¬ macist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Take V IEKIRA PAK exactly as your healthcare provider How should I store VIEKIRA PAK? tells you to take it. Do not change your dose unless vour • Store VIEKIRA PAK at or below 86°F (30°C). healthcare provider tells you to. Keep VIEKIRA PAK and all medicines out of the reach of • Do not stop taking VIEKIRA PAK without first talking ! children. with your healthcare provider. General information about the safe and effective use of • When you receive your VIEKIRA PAK prescription, you | VIEKIRA PAK will gt t a monthly carton that contains enough medicine It is not known if treatment with VIEKIRA PAK will pre¬ for 28 days vent you from infecting another person with the hepatitis C • h e h monthly carton of V 1KKIRA PAK contains 4 smaller virus during your treatment. Talk with vour healthcare procartons \ ider about ways to prevent spreading the hepatitis C virus.

Dasabuvir tablets: Active ingredients: dasabuvir Inactive ingredients: microcrystalline cellulose (D50-100

um), microcrystalline cellulose (D50-50 um), lactose mono¬ hydrate, copovidone, croscarmellose sodium, colloidal sili¬ con dioxide/anhydrous colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350/macrogol 3350, talc and iron oxide yellow, iron oxide red and iron oxide black. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by AbbVie Inc., North Chicago, IL 60064. Revised: July 2015 VIEKIRA PAK and NORVIR are trademarks of AbbVie Inc. All other brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. © 2015 AbbVie Inc. All rights reserved. 03-B188 Shown in Product Identification Guide, page 304

ZEMPLAR®

ft

[z$m-phr\ (paricalcitol) capsules HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZEMPLAR safely and effectively. See full prescribing information for ZEMPLAR. ZEMPLAR (paricalcitol) capsules Initial U.S. Approval: 1998

-RECENT MAJOR CHANGESWarnings and Precautions, Laboratory tests (5.3) 8/2014 -INDICATIONS AND USAGEZemplar is a vitamin D analog indicated for the prevention and treatment of secondary hyperparathyroidism associ¬ ated with • Chronic kidney disease (CKD) Stages 3 and 4 (1.1). • CKD Stage 5 in patients on hemodialysis (HD) or perito¬ neal dialysis (PD) (1.2).

---DOSAGE AND ADMINISTRATION• CKD Stages 3 and 4: Zemplar Capsules may be admin¬ istered once daily or every other day, three times a week (2.1). • CKD Stage 5: Zemplar Capsules are dosed every other day, three times a week (2.2). To minimize the risk of hy¬ percalcemia patients should be treated only after their baseline serum calcium has been reduced to 9.5 mg/dL or lower. ISee first table abovel ISee second table above)

-DOSAGE FORMS AND STRENGTHSCapsules:

1 meg, 2 meg, and 4 meg (3).

-CONTRAINDICATIONSEvidence of hypercalcemia or vitamin D toxicity (4).

-WARNINGS AND PRECAUTIONS• Hypercalcemia: Excessive administration of Zemplar Capsules can cause over suppression of PTH, hypercalce¬ mia. hvpercalciuria, hyperphosphatemia, and adynamic bone disease. Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treat¬ ment (5.1). • Digitalis toxicity: Potentiated by hypercalcemia of any cause. Use caution when Zemplar Capsules are prescribed concomitantly with digitalis compounds (5.2). • Laboratory tests: Monitor serum calcium, serum phos¬ phorus, and serum or plasma iPTH during initial dosing or following any dose adjustment. Zemplar Capsules may increase serum creatinine and therefore decrease the esti¬ mated GFR leGFR) (5.3). • Aluminum overload and toxicity: Avoid excessive use of aluminum containing compounds (5.4).

Sign up at PDR net/registration to receive PDR Safety Communicati

Look for PDR drug information and services in your EHR -ADVERSE REACTIONSThe most common adverse reactions (> 5% and more fre¬ quent than placebo) include diarrhea, hypertension, dizzi¬ ness and vomiting. To report SUSPECTED ADVERSE REACTIONS, contact

ZEMPLAR CAPSULES • ABBVIE/623 Dose Titration Dosing must he individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus The following is a suggested approach to dose titration.

AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

-DRUG INTERACTIONS• Strong CYP3A inhibitors (e.g. ketoconazole) will increase the exposure of paricalcitol. Use with caution (7.1). • Cholestyramine, Mineral Oil: Intestinal absorption of Zemplar may be reduced if administered simultaneously with mineral oil or cholestyramine (7.2,7.3). See 17 for PATIENT COUNSELING INFORMATION. Revised: 09/2014 FULL PRESCRIBING INFORMATION: CONTENTS*

1

INDICATIONS AND USAGE 1.1 1.2

2

DOSAGE AND ADMINISTRATION 2.1 2.2

3 4 5

Clinical Trials Experience Postmarketing Experience

DRUG INTERACTIONS 7.1 7.2 7.3

8

Hypercalcemia Digitalis Toxicity Laboratory Tests Aluminum Overload and Toxicity

ADVERSE REACTIONS 6.1 6.2

7

Chronic Kidney Disease Stages 3 and 4 Chronic Kidney Disease Stage 5

DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 5.2 5.3 5.4

6

Chronic Kidney Disease Stages 3 and 4 Chronic Kidney Disease Stage 5

CYP3A Inhibitors Cholestyramine Mineral Oil

USE IN SPECIFIC POPULATIONS 8.1 8.3 8.4 8.5

Pregnancy Nursing Mothers Pediatric Use Geriatric Use

10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 12.2 12.3

Mechanism of Action Pharmacodynamics Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 13.1

Carcinogenesis, Mutagenesis and Impairment of Fertility

14 CLINICAL STUDIES 14.1 14.2

Chronic Kidney Disease Stages 3 and 4 Chronic Kidney Disease Stage 5

16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION ‘Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE 1.1 Chronic Kidney Disease Stages 3 and 4 Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4. 1.2 Chronic Kidney Disease Stage 5 Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peri¬ toneal dialysis (PD). 2 DOSAGE AND ADMINISTRATION 2.1 Chronic Kidney Disease Stages 3 and 4 Zemplar Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered not more frequently than every other day. The total weekly doses for both daily and three times a week dosage regimens are similar [see Clinical Studies (14.1)). Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment. Initial Dose The initial dose of Zemplar Capsules for CKD Stages 3 and 4 patients is based on baseline intact parathyroid hormone liPTH) levels.

Baseline iPTH Level

Daily Dose

Three Times a Week Dose*

< 500 pg/ml, 1 meg 2 meg > 500 pg/mL 2 meg 4 meg lb be administered not more often than every other day

Dose Adjustment at 2 to 4 Week Intervals iPTH Level

Zemplar

Daily

Three Times a

Relative to

Capsule

Dosage

Week Dosage*

Baseline

Dose

Increase 1 meg 2 meg The same, increased or dose by decreased by 30% and < 60% dose Decreased by Decrease 1 meg 2 meg > 60% or iPTH dose by < 60 pg/mL * To be administered not more often than every other day If a patient is taking the lowest dose, 1 meg, on the daily regimen and a dose reduction is needed, the dose can be de¬ creased to 1 meg three times a week. If a further dose re¬ duction is required, the drug should be withheld as needed and restarted at a lower dosing frequency. If a patient is on a calcium-based phosphate binder, the phosphate-binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hyper¬ calcemia is observed, the dose of Zemplar should be reduced or withheld until these parameters are normalized. Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar Capsules, during dose titration periods and during co-administration with strong CYP3A inhibitors [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)}. 2.2 Chronic Kidney Disease Stage 5 Zemplar Capsules are to be administered three times a week, not more frequently than every other day. Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment. Initial Dose The initial dose of Zemplar Capsules in micrograms is based on a baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower [see Clinical Pharmacology (12.2) and Clinical Stud¬ ies (14.2)]. Dose Titration Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of Zemplar Capsules is based on the following formula: Titration dose (micrograms) = most recent iPTH level (pg/ml )/80 Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If serum calcium is el¬ evated, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of paricalcitol capsules should be reduced or withheld until these param¬ eters are normalized. As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH. Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH/100) may be war¬ ranted.

5.1

Hypercalcemia

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emer¬ gency attention [see Overdosage (10)]. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and sei¬ zures and may potentiate the action of digitalis. Chronic hy¬ percalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Concomitant administra¬ tion of high doses of calcium-containing preparations or thi¬ azide diueretics with Zemplar may increase the risk of hy¬ percalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be in¬ formed about the symptoms of elevated calcium, which in¬ clude feeling tired, difficulty thinking clearly, loss of appe¬ tite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss. Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hy¬ percalcemia. 5.2

Digitalis Toxicity

Digitalis toxicity is potentiated by hypercalcemia of any cause. Use caution when Zemplar Capsules are prescribed concomitantly with digitalis compounds. 5.3

Laboratory Tests

During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for 3 months, then monthly for 3 months, and every 3 months thereafter. In pre-dialysis patients, Zemplar Capsules may increase serum creatinine and therefore decrease the estimated GFR (eGFR). Similar effects have also been seen with calcitriol. 5.4

Aluminum Overload and Toxicity

Aluminum-containing preparations le.g., antacids, phos¬ phate binders) should not be administered chronically with Zemplar, as increased blood levels of aluminum and alumi¬ num bone toxicity may occur. 6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience CKD Stages 3 and 4

The safety of Zemplar Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebocontrolled, multicenter clinical studies involving 220 CKD Stages 3 and 4 patients. Six percent (6%) of Zemplar Capsules treated patients and 4% of placebo treated pa¬ tients discontinued from clinical studies due to an adverse event. Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are presented in Table 1: Table 1. Treatment-Emergent Adverse Events by Body System Occurring in 2 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stages 3 and 4 Studies; All Treated Patients Number (%) of Subjects Zemplar Placebo Capsules = 113)

Adverse Event*

(n = 107) Overall Ear and Labyrinth Disorders Vertigo

88

(82%)

86

(76%)

5

(4.7%)

0

(0.0%)

4

(3.7%)

1

(0.9%)

4 7 6 5

(3.7%) (6.5%) (5.6%) (4.7%)

4 5 4 5

(3.5%) ) (4.4%) (0.9%)

0

(0.0%)

2 0

(1.8%) (0.0%)

3 1 0

(2.7%) (0.9%) (0.0%)

4 (3.5%) 3 (2.7%) Zemplar

The following adverse reactions, with a causal relationship to Zemplar, occurred in

5 3 2 2

(8.2% i (4.9%) (3.3%) ij.3%)

2 0 0 0

(7.4%) 0.M (0.0% I (0.0%)

Metabolism and Nutrition Disorders (4.9%) 3 Fluid Overload (3.3%) 2 Hypoglycemia Nervous System Disorders (6.6%) 4 Dizziness (3.3%) 2 Headache Psychiatric Disorders (3.3%) 2 Anxiety (4.9%) 3 Insomnia Renal and Urinary Disorders 2 (3.3%) Renal Failure Chronic a. Includes only events more common in the treatment group.

0 0

(0.0%) (0.0%)

0 0

(0.0%) (0.0%)

0 0

(0.0%) ' (0.0%)

0

(0.0%)

10

Zemplar

The following adverse reactions, with a causal relationship to Zemplar, occurred in 60 beats per minute cannot achieve a target heart rate < 60 beats per minute, and these patients were excluded from clinical trials/see Clinical Studies (14)1. The use of Corlanor is not recommended in patients with de-’ mand pacemakers set to rates > 60 beats per minute.

teratogenic effects. Increased, intrauterine and post-natal mortality and cardiac malformations were observed at doses > 2.3 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC„ Mhr). Teratogenic effects including in¬ terventricular septal defect and complex anomalies of major arteries were observed at doses 5 4 6 mg/kg/day (approxi¬ mately 3 times the human exposure at the MRHD based on AUC0.24hr)In pregnant rabbits, oral administration of ivabradine dur¬ ing the period of organogenesis (gestation day 6-18) at doses of 7, 14, or 28 mg/kg/day resulted in fetal toxicity and tera¬ togenicity. Treatment with all doses >7 mg/kg/day-(equiva¬ lent to the human exposure at the MRHD based on AUC0.24hr* caused an increase in post-implantation loss. At the high dose of 28 mg/kg/day (approximately 15 times the human exposure at the MRHD based on AUC0.24hr), reduced fetal and placental weights were observed, and evidence of teratogenicity (ectrodactylia observed in 2 of 148 fetuses from 2 of 18 litters) was demonstrated. In the pre- and postnatal study, pregnant rats received oral administration of ivabradine at doses of 2.5, 7, or 20 mg/kg/day from gestation day 6 to lactation day 20. In¬ creased postnatal mortality associated with cardiac terato¬ genic findings was observed in the FI pups, delivered by dams treated at the high dose (approximately 15 times the human exposure at the MRHD based on AUC0.24hP 8.2 Lactation Risk Summary There is no information regarding the presence of ivabradine in human milk, the effects of ivabradine on the breastfed infant, or the effects of the drug on milk produc¬ tion. Animal studies have shown, however, that ivabradine is present in rat milk [see Dalai. Because of the potential risk to breastfed infants from exposure to Corlanor, breast¬ feeding is not recommended. Data Lactating rats received daily oral doses of [l4C]-ivabradine (7 mg/kg) on post-parturition days 10 to 14; milk and ma¬ ternal plasma were collected at 0.5 and 2.5 hours post-dose on day 14. The ratios of total radioactivity associated with 1,4C1* ivabradine or its metabolites in milk vs. plasma were 1.5 and 1.8, respectively, indicating that ivabradine is trans¬ ferred to milk after oral administration. 8.3 Females and Males of Reproductive Potential Contraception Females Corlanor may cause fetal harm, based on animal data. Ad¬ vise females of reproductive potential to use effective con¬ traception during Corlanor treatment [see Use in Specific Populations (8.1)1. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No pharmacokinetic differences have been observed in el¬ derly (> 65 years) or very elderly (> 75 years) patients com¬ pared to the overall population. However. Corlanor has only been studied in a limited number of patients > 75 vears of age. 8.6 Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. Corlanor is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as it has not been studied in this population and an increase in systemic exposure is anticipated /see Contraindications (4) and Clinical Pharmacology (12.3)1. 8.7 Renal Impairment No dosage adjustment is required for patients with creati¬ nine clearance 15 to 60 ml ,/nun. No data are available for patients with creatinine clearance below 15 mL/min [see Clinical Pharmacology (12.3)].

Figure 1. Chemical Structure of Ivabradine

Corlanor tablets are formulated as salmon-colored, filmcoated tablets for oral administration in strengths of 5 mg and 7.5 mg of ivabradine as the free base equivalent. Inactive Ingredients Core Lactose monohydrate, maize starch, maltodextrin, magne¬ sium stearate, colloidal silicon dioxide Film Coating Hypromeilose, titanium dioxide, glycerol, magnesium stea¬ rate, polyethylene glycol 6000, yellow iron oxide, red iron oxide 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker /, current, which regulates heart rate. In clinical electrophysiology studies, the cardiac effects were most pro¬ nounced in the sinoatrial (SA) node, but prolongation of the AH interval ha,s occurred on the surface ECG, as has PR interval prolongation. There was no effect oh ventricular re¬ polarization and no effects on myocardial contractility [see Clinical Pharmacology (12.2)]. Corlanor can also inhibit the retinal current 7h. /his involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e g., rapid changes in luminosity), partial inhibition of lh by Corlanor may underlie the lumi¬ nous phenomena experienced by patients. Luminous phe¬ nomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field [see Adverse Reactions (6.1)]. 12.2 Pharmacodynamics Corlanor causes a dose-dependent reduction in heart rate. The size of the effect is dependent on the baseline heart rate (i.e., greater heart rate reduction occurs in subjects with higher baseline heart rate). At recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. Analysis of heart rate reduction vs. dose indicates a plateau effect at doses > 20 mg twice daily. In a study of subjects with preexisting conduction system disease (firstor second-degree AV block or left or right bundle branch block) requiring electrophysiologic study, IV ivabradine (0.20 mg/kg) administration slowed the overall heart rate by approximately 15 bpm, increased the PR interval (29 msec), and increased the AH interval (27 msec). Corlanor does not have negative inotropic effects. Ivabradine increases the uncorrected QT interval with heart rate slowing but does not cause rate-corrected prolon¬ gation of QT. 12.3 Pharmacokinetics Absorption and Bioavailability Following oral administration, peak plasma ivabradine con¬ centrations are reached in approximately 1 hour under fast¬ ing conditions. The absolute oral bioavailability of ivabradine is approximately 40% because of first-pass elim¬ ination in the gut and liver. Food delays absorption by approximately 1 hour and in¬ creases plasma exposure by 20% to 409. Corlanor should be taken with meals [see Dosage and Administration (2)]. Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approxi¬ mately 100 L. Metabolism and Excretion

H. USE IN SPECIFIC POF’UIATIONS 8 1 Pregnancy Risk Summary Based on findings in animals, Corlanor may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Corlanor in preg¬ nant women to inform any drug-associated risks. In animal reproduction studies, oral administration of ivabradine to pregnant rats during organogenesis at a dosage providing 1 to 3 times the human exposure (AUC,,^) at the MRHD resulted in embryo-fetal toxicity and teratogenicity mani¬ fested as abnormal shape of the heart, interventricular sep¬ tal defect, and complex anomalies of primary arteries. In¬ creased postnatal mortality was associated with these teratogenic effi-cts in rats In pregnant rabbits, increased post implantation loss was noted at an exposure 1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3- | substrates, inducers, and other concomitantly administered Animal Data benzazepin-2-one, hydrochloride The molecular formula is drugs) on the pharmacokinetics of Corlanor were studied in In pregnant rat*, oral administration of ivabradine during * .';H isN.jO.,. HCI, and the molecular weight (free base + several single- and multiple-dose studies. Pharmacokinetic the period of organogenesis ‘gestation day 6 151 at doses of IK I1 is 505.1 i468.6 + 36.5) The chemical structure of measures indicating the magnitude of these interactions are 2.3, 4 6. 9 3, or 19 mg/kg/d ay resulted in fetal toxicity and ivabradine is shown in Figure 1. presented in Figure 2.

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR Change Due to

PK Measures

Fold Change and 90% Confidence Intervals

Strong CYP3A4 inhibrtors

KeKeoeazole200mgQO Moderate CYP3A4 inhibitors

Mtatem 120 mg BID

c*.

Verapaml 120 mg BID

AUC C AUC

Grapefruit xce

Cm*i

CYP3A4 Inducer

w

CffHJ AUC

Other Sridenotl MX) mg

LacdpnermgOO

Cesai

LansopnuaeWmjOO

AUC Ctrax AX

No Dose Adjustment No Dose Adjustment No Dose Adjustment

W

Omeprazole 40 mg OD

WarlamlloSmgQO

Avod Use

Iw

AX C*w AX

Smvastatm20rrgQD

AvodUse

tr

CfllD

No Dose Adjustment No Dose Adjustment

w m

AX Ctr*» AX 0-25

Endpoint

Avoid Use

05 I 2 4 Change relatre to itaMAne alone

No Dose Adjustment

%

% PY

n

%

% PY

Hazard Ratio

[95% Cl!

p-value

793

24.5

14.5

937

28.7

17.7

0.82

[0.75.0.90]

65 years) or very elderly (2 75 years) patients and the overall patient population /see Use in Specific Populations (8.5)1. Hepatic Impairment In patients with mild (Child-Pugh A) and moderate (ChildPugh B) hepatic impairment, the pharmacokinetics of Corlanor were similar to that in patients with normal he¬ patic function. No data are available in patients with severe hepatic impairment (Child-Pugh C) Isee Contraindications (4)1. Penal Impairment Renal impairment (creatinine clearance from 15 to 60 mlVmin) has minimal effect on the pharmacokinetics of Corlanor. No data are available for patients with creatinine clearance below 15 mlVmin. Pediatrics The pharmacokinetics of Corlanor have not been investi¬ gated in patients < 18 years of age.

13.

Primary composite endpoint: Time to first hospitalization for worsening heart failure or cardiovascular death" Hospitalization for worsening heart failure Cardiovascular death as first event

»

Placebo (N = 3264

n

AredUse

Ta w )*(

AX

Corlanor (N = 3241)

COTianacaieo

m

l-H

AUC

Table 3. SHIFT - Incidence of the Primary Composite Endpoint and Components

Recommendation

l-H

SUNw's wotl 300 mg TID

CORLANOR • AMGEN/631

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility There was no evidence of carcinogenicity when mice and rats received ivabradine up to 104 weeks by dietary admin¬ istration. High doses in these studies were associated with mean ivabradine exposures of at least 37 times higher than the human exposure (AUC(,.21hr) at the MRHD. Ivabradine tested negative in the following assays: bacterial reverse mutation (Ames) assay, in vivo bone mar¬ row micronucleus assay in both mouse and rat, in vivo chro¬ mosomal aberration assay in rats, and in vivo unscheduled DNA synthesis assay in rats. Results of the in vitro chromo¬ somal aberration assay were equivocal at concentrations approximat4‘ly 1,500 times the human C^, at the MRHIl. Ivabradine tested positive in the mouse lymphoma assays and in vitro unscheduled DNA synthesis assay in rat hepatocytes at concentrations greater than 1,500 times the human CmBI at the MRHD. Reproduction toxicity studies in animals demonstrated that ivabradine did not affect fertility in male or female rats at exposures 46 to 133 times the human exposure (AUC0.W|U.) at the MRHD 13.2 Animal Toxicology and/or Pharmacology Reversible changes in retinal function were observed in dogs administered oral ivabradine at total doses of 2, 7, or 24 mg/kg/day (approximately 0.6 to 50 times the human ex¬ posure at the MRHD based on AUC0.24hr) for 52 weeks Ret¬ inal function assessed by electroretinography demonstrated reductions in cone system responses, which reversed within a week post-dosing, and were not associated with damage to ocular structures as evaluated by light microscopy These data are consistent with the pharmacological effect of ivabradine related to its interaction with hvperpolarizationactivated /h currents in the retina, which share homology with the cardiac pacemaker I, current.

“Subjects who died on the same calendar day as their first hospitalization for worsening heart failure are counted under cardiovascular death. b Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity. N: number of patients at risk; n: number of patients having experienced the endpoint; %: incidence rate - (n/Nl y 100; % PY: annual incidence rate = (n/number of patient-years) x 100; Cl: confidence interval The hazard ratio between treatment groups (ivabradine /placebo) was estimated based on an adjusted Cox proportional hazards model with beta-blocker intake at randomization (yes/no) as a covariate; p-value: Wald test

14.

CLINICAL STUDIES

SHIFT The Systolic Heart failure treatment with the If inhibitor ivabradine TrTal (SHIFT) was a randomized, double-blind trial comparing Corlanor and placebo in 6558 adult patients with stable NYHA class II to IV heart failure, left ventricu¬ lar ejection fraction < 35%, and resting heart rate > 70 bpm. Patients had to have been clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and di¬ uretics, with fluid retention and symptoms of congestion minimized. Patients had to have been hospitalized for heart failure within 12 months prior to study entry. The underlying cause of CHF was coronary artery disease in 68% of patients. At baseline, approximately 49% of ran¬ domized subjects were NYHA class II, 50% were NYHA class III, and 2% were NYHA class IV. The mean left ven¬ tricular ejection fraction was 29% All subjects were initi¬ ated on Corlanor 5 mg (or matching placebo) twice daily and the dose was increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily to maintain the resting heart rate be¬ tween 50 and 60 bpm, as tolerated. The primary endpoint was a composite of the first occurrence of either hospitaliza¬ tion for worsening heart failure or cardiovascular death. Most patients (89% ) were taking beta-blockers, with 26% on guideline-defined target daily doses. The main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decom¬ pensation (9%), and bradycardia (6%). For the 11%’ of pa¬ tients not receiving any beta-blocker at baseline, the main reasons were chronic obstructive pulmonary disease, hypo¬ tension, and asthma. Most patients were also taking ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60% >. Few patients had an implantable cardioverter-defibrillator (ICD) (3.2%) or a cardiac resynchronization therapy (CRT) device (11%). Me¬ dian follow-up was 22.9 months. At 1 month, 63%. 26%, and 8% of Corlanor-treated patients were taking 7.5, 5. and 2.5 mg BID, whereas 3% had withdrawn from the drug, pri¬ marily for bradycardia. SHIFT demonstrated that Corlanor reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82. 95% confidence interval |CI|: 0.75, 0.90, p < 0.0001) (Table 3). The treatment effect re¬ flected only a reduction in the risk of hospitalization for worsening heart failure; there was no favorable effect on the mortality component of the primary endpoint. In the overall treatment population, Corlanor had no statistically signifi¬ cant benefit on cardiovascular death ISee table 3 above] The Knplan-Meier curve (Figure 3) shows time to first oc¬ currence of the primary composite endpoint of hospitaliza¬ tion for worsening heart failure or cardiovascular death in the overall study. [See figure 3 at top of next column] A wide range of demographic characteristics, baseline dis¬ ease characteristics, and baseline concomitant medications were examined for their influence on outcomes Many of these results are shown in Figure 4. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the results show effects consistent with the overall study result. Corlanor’s benefit on the primary endpoint in

Time from randomization (months) Number ol Subjects at Risk: Placebo 1264 2868 Corlanor 3241 2928

2489 2600

2061 2173

1089 1191

439 447

17 16

Figure 3. SHIFT: Time to First Event of Primary Composite Endpoint

SHIFT appeared to decrease as the dose of beta-blockers in creased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers. [See figure 4 at top of next pagel Note: The figure above presents effects in various sub¬ groups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. BEAIT1FUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart failure BEAUTIFUL was a randomized, double-blind, placebocontrolled trial in 10.917 adult patients with coronary ar¬ tery disease, impaired left ventricular systolic function (ejection fraction < 40% t and resting heart rate St 60 bpm. Patients had stable symptoms of heart failure and/or angina for at least 3 months, and were receiving conventional car diovascular medications at stable doses for at least 1 month. Beta-blocker therapy was not required, nor was there a pro¬ tocol mandate to achieve any specific dosing targets finr pa¬ tients who were taking beta-blockers Patients were ran domized 1:1 to Corlanor or placebo at an initial dose of 5 mg twice daily with the dose increased to 7 5 mg twice daily de¬ pending on resting heart rate and tolerability. The primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure Most patients were NYHA class 11 (61.4%) or class III (23.2%) - none were class IV. Through a median follow-up of 19 months. Corlanor did not significantly affect the primary composite endpoint (HR 1.00, 95%- Cl = 0.91, 1.10). SIGNIFY was a randomized, double-blind trial administe-r ing Corlanor or placebo to 19,102 adult patients with stable coronary artery disease but without clinically evident heart failure (NYHA class l>. Beta-blocker therapy was not re quired. Corlanor was initiated at a dose of 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5.0 mg twice daily to achieve a target heart rate of 55 to 60 bpm The primary endpoint was a composite of the first occurrence of either cardiovas¬ cular death or myocardial infarction Through a median follow-up of 24.1 months. Corlanor did not significantly af¬ fect the primary composite endpoint

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632/AMGEN • CORLANOR 16.

Corlanor 5 mg tablets are formulated as salmon-colored, oval-shaped, film-coated tablets scored on both edges, marked with “5” on one face and bisected on the other face. They are supplied as follows: • Bottles of 60 tablets (NDC 55513-800-60). • Bottles of 180 tablets (NDC 5551-3-800-80) Corlanor 7.5 mg tablets are formulated as salmon-colored, triangular-shaped, film-coated tablets debossed with “7.5” on one face and plain on the other face. They are supplied as follows: . Bottles of 60 tablets (NDC 55513-810-60) . Bottles of 180 tablets (NDC 55513-810-80) Storage Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) Isee USP Controlled Room Temperature]. 17.

% of Total Population

HOW SUPPLIED/STORAGE AND HANDLING

PATIENT COUNSELING INFORMATION

Age >-65 years >*75 years Age quartile 19 to 53 to 60 to 6§4 to 79.6 to 91 ing (Medication Guide). Basejjje heart rate quartile 30.1% 199(20.1% 211 (21.8%) • Fetal Toxicity 0 91 075-1.11 >73 to 77 to 84 343(41.6%) Advise females of reproductive potential to use effective NYHA Class contraception and to notify their healthcare provider with 48.7% 300 (18.9%) 356 (22.5%) NYHA Class II 0 81 (0 69-0 94) a known or suspected pregnancy [see Warnings and Pre¬ 49.5% 470 (29.3% NYHA Class III 542 (33.5% NYHA Class IV 1.7% 38 (62.3%) 23 (46.0%) cautions (5.1) and Use in Specific Populations (8.1, 8.3)1. Basehne LV ejection fraction quartile • Low Heart Rate 27.6% 303 (33.9% 335 37.1%| 087 0 75-1.02! 25.3% > 26 to 0.5 xl09/L, continue at the same dose level • For subsequent drops to < 0.5 xl09/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis"

• Platelets 10 xl09/L and/or bleeding is controlled, continue at the same dose level • For subsequent drops to < 10 xl09/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis"

Renal Toxicity

Recommended Action

• Serum creatinine > 2 x baseline, or • Creatinine clearance < 15 mL/min or creatinine clearance decreases to 10%) [see Dosage and Administration (2) and Adverse Reactions The adverse events in the first 12 cycles of therapy that (6) |. occurred at a rate of 10% or greater in the KRd arm are 5.12 Thrombotic Thrombocytopenic Purpura/Hemolytic presented in Table 5. Uremic Syndrome [See table 5 at top of previous pagel Cases of thrombotic thrombocytopenic purpura/hemolytic There were 274(709!) patients in the KRd arm who received uremic syndrome (TTP/HUS) including fatal outcome have treatment beyond Cycle 12. There were no new clinically been reported in patients who received Kyprolis. Monitor relevant AEs that emerged in the later treatment cycles. for signs and symptoms of TTP/HUS. If the diagnosis is sus¬ Adverse Reactions Occurring at a Frequency o( < 10% pected, stop Kyprolis and evaluate. If the diagnosis of TTP/ • Blood and lymphatic system disorders: febrile neutro¬ HUS is excluded, Kyprolis may be restarted. The safety of penia, lymphopenia reinitiating Kyprolis therapy in patients previously experi¬ • Cardiac disorders: cardiac arrest, cardiac failure, car¬ encing TTP/HUS is not known. diac failure congestive, myocardial infarction, myocardial 5.13 Posterior Reversible Encephalopathy Syndrome ischemia • Eye disorders: cataract, vision blurred Cases of PRES have been reported in patients receiving • Gastrointestinal disorders: abdominal pain, abdominal Kyprolis. Posterior reversible encephalopathy syndrome pain upper, dyspepsia, toothache (PRES), formerly termed Reversible Posterior Leukoen• General disorders and administration site condi¬ cephalopathy Syndrome 'RPLS), is a neurological disorder tions: chills, infusion site reaction, multi-organ failure, which can present with seizure, headache, lethargy, confu¬ pain sion, blindness, altered consciousness, and other visual and • Infections and infestations: influenza, sepsis, urinary neurological disturbances, along With hypertension, and the tract infection, viral infection diagnosis is confirmed by neuro-radiological imaging i MRI). • Metabolism and nutrition disorders: dehydration, hy¬ Discontinue Kyprolis if PRES is suspected and evaluate. , perkalemia. hyperuricemia, hypoalbuminemia, hyponaThe safety of reinitiating Kyprolis therapy in patients pre¬ trrmia, tumor lysis syndrome viously experiencing PRES is not known. ’ • Musculoskeletal and connective tissue disorders: mus¬ 5.14 Embryo-fetal Toxicity cular weakness, mvRlgia Kyprolis can cause fetal harm when administered to a preg¬ • Nervous system disorders: hvpoesthesia, paresthesia, I nant woman based on its mechanism of action and findings deafness in animals There a re no adequate and well-controlled stud¬ • Psychiatric disorders: anxiety, delirium ies in pregnant women using Kvprohs (’.nrtilzomib caused • Renal and urinary disorders: renal fnilure. renal failure i embryo-fetal toxicity in pregnant rabbits at doses that were acute, renal impairment lower than m patients receiving the recomnumded dose Respiratory, thoracic and mediastinal disorders: dysFemales of reproductive potential should be advised to phonia, epistaxis. oropharyngeal pain, pulmonary embo- l avoid becoming pregnant while being rivaled with Kyprolis lism. pulmonary edema

• Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus • Vascular disorders: deep vein thrombosis, hypotension Grade 3 and higher adverse reactions that occurred during Cycles 1-12 with a substantial difference (> 2%) between the two arms were neutropenia, thrombocytopenia, hypokale¬ mia, and hypophosphatemia. Laboratory Abnormalities

Table 6 describes Grade 3-4 laboratory abnormalities re¬ ported at a rate of >10% in the KRd arm for patients who received combination therapy. Table 6: Grade 3-4 Laboratory Abnormalities (2 10%) in Cycles 1-12 (Combination Therapy) Laboratory Abnormality

KRd (N = 392)

Rd (N = 389)

Decreased Lymphocytes

182 (46%)

119(31%)

Decreased Absolute Neutrophil Count

152 (39%)

140 (36%)

Decreased Phosphorus

122 (31%)

106 (27%)

Decreased Platelets

101 (26%)

59(15%)

Decreased Total White Blood Cell Count

97 (25%)

71 (18%)

Decreased Hemoglobin

58 (15%)

68 (18%)

Decreased Potassium

41 (11%)'

23 (6%)

KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; Rd = lenalidomide and low-dose dexamethasone 6.1.2 Safety Experience with Kyprolis in Patients with Mul¬ tiple Myeloma who Received Monotherapy The safety of Kyprolis was evaluated in clinical trials in which 598 patients with relapsed and/or refractory my¬ eloma received Kyprolis monotherapy starting with the 20 mg/m2 dose in Cycle 1 Day 1 and escalating to 27 mg/m2 on Cycle 1 Day 8 or Cycle 2 Day 1. The median age of these patients was 64 years (range 32-87). The patients received a median of 5 (range 1-20) prior regimens. Approximately 57% of the patients were male. The median number of cycles initiated was 4. (range 1-35), Serious adverse events were reported, regardless of causal¬ ity, in 50% of patients in the pooled Kyprolis monotherapy studies (n = 598). The most common serious adverse events were: pneumonia (8%), acute renal failure (5%), disease pro¬ gression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%). anemia (2%), and dyspnea (2%). In patients treated with Kyprolis, the in¬ cidence of serious adverse events was higher in those > 65 years old and in those > 75 years old [see Geriatric Use (8.5)). Deaths due to adverse events within 30 days of the last dose of Kyprolis occurred in 30/598 (59!) patients receiving Kyprolis monotherapy. These adverse events were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other ad¬ verse events in 8 (1%) patients. In a randomized trial com¬ paring Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the con¬ trol arm in the subgroup of 48 patients 275 years of age. The most common cause of discontinuation due to an ad¬ verse event was acute renal failure (2%). The common ad¬ verse events occurring at a rate of 10% or greater with Kyprolis monotherapy are presented in Table 7. Table 7: Most Commonly Reported Adverse Events (2 10%) with Kyprolis Monotherapy Kyprolis Monotherapy 20/27 mg/m2 (N = 598) System Organ Class

Any Grade

2 Grade3

Blood and Lymphatic System Disorders Anemia

291 (49%)

141 (24%)

Throm bocytopenia

220 (37%)

152 (25%)

Neutropenia

113 (19%)

63(11%)

Lymphopenia

85(14%)

73(12%)

Leukopenia

61 (10%)

26(4%)

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KYPROLIS • AMGEN/637

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Table 9: Demographics and Baseline Disease Characteristics in Study 1 (Combination Therapy for Relapsed Multiple Myeloma)

Gastrointestinal Disorders Nausea

211 (35%)

7(1%)

Diarrhea

160 (27%)

8 (1%)

Vomiting

104 (17%)

4 (1%)

Constipation

90(15%)

1 (0%)

KRd Combination Therapy

Characteristic Age, Median Years (min. max) Age Group, > 75 Years, n (%)

General Disorders and Administration Site Conditions

KRd Arm (N = 396)

Rd Arm IN = 396)

64.0 (38, 87)

65.0t31.91i

43(11)

53 (13)

215(54)

232 (59)

Fatigue

238(40%)

25 (4%)

Males, n (%)

Pyrexia

177 (30%)

11 (2%)

Race, n (%)

Edema Peripheral

118 (20%)

1 (0%)

White

377 (95)

377(95)

Chills

73 (12%)

1 (0%)

Black

12 (3)

11 (3)

Asthenia

71 (12%)

9 (2%)

Other3

7(2)

8(2)

1

184 (46%)

157 3 x upper limit of normal (ULN) and bilirubin > 2 x ULN [see Clinical Pharmacology (12.3)].

DESCRIPTION

Kyprolis (carfilzomib) is an antineoplastic agent available for intravenous use only. Kyprolis is a sterile, white to offwhite lyophilized powder and is available as a single-dose vial. Each vial of Kyprolis contains 60 mg of carfilzomib, 3000 mg sulfobutyl ether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5). Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S )-N-( (S)-1-( (S )-4-methy 1- l-((R)-2-methyloxiran-2-yl)-1oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:

Table 10: Efficacy Outcomes in Study 1 (Combination Therapy for Relapsed Multiple Myeloma) KRd Combination Therapy

PFS Months Median (95% Cl)

KRd Arma (INI = 396)

(N = 396)

26.3 (23.3, 30.5)

17.6 (15.0, 20.6)

HR (95% Cl); 2-sided p-valueb

Rd Arm*

0.69 (0.57, 0.83); 0.0001

ORR n (%) sCR

345 (87)

264 (67)

56(14)

17(41

CR

70 (18)

20 (5)

VGPR

151 (38)

123 (31)

PR

68 (17)

104 (26)

(I - confidence interval; OR = complete response; EBMT = European Blood and Marrow Transplantation; IMWG = International Myeloma Working Group; KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; ORR = overall response rate; PFS = progression-free survival; Rd = lenalidomide and low-dose dexamethasone; sCR = stringent complete response; VGPR = very good partial response “ As determined by an Independent Review Committee using standard objective IMWG/EBMT response criteria. Statistically significant.

The doses of 0.4 and 0.8 mg/kg/day in rabbits are approxi¬ mately 20'? and 40%. respectively, of the recommended dose in humans of 27 mg/m" based on body surface area. 8.2

Lactation

Risk Summary There is no information regarding the presence of Kyprolis in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Kyprolis and any potential ad¬ verse effects on the breastfed infant from Kyprolis or from the underlying maternal condition. 8.3

Females and Males of Reproductive Potential

Contraception Kyprolis can cause fetal harm when administered to preg¬ nant women I see Use in Specific Populations 75 years of age |see Warnings and Precau¬ tions - Cardiac Toxicities (5.1) 1. In Study 2 (n = 266), no overall differences in effectiveness were observed between these and younger patients. Of 392 patients treated with Kyprolis in combination with lenalidomide and dexamethasone, 185 patients (47%) were 2 65 years of age and 43 patients (11%) were > 75 years of age. The median age was 64 years. No overall diffbrences in effectiveness were observed between these and younger pa¬ tients. The incidence of serious adverse events was 50% in patients < 65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients > 75 years of age (see Warnings and Precautions - Cardiac Toxicities (5.1)).

Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C4nH57N507. Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions. 12 CLINICAL PHARMACOLOGY 12.1

Mechanism of Action

Carfilzomib is a tetrapeptide epoxyketone proteasome in¬ hibitor that irreversibly binds to the N-terminal threoninecontaining active sites of the 20S proteasome, the proteo¬ lytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and de¬ layed tumor growth in models of multiple myeloma, hema¬ tologic, and solid tumors. 12.2 Pharmacodynamics Intravenous carfilzomib administration resulted in suppres¬ sion of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib > 15 mg/m2 with or without lenalidomide and dexamethasone induced a 2 80% inhibition of the CT-L ac¬ tivity of the proteasome. In addition, carfilzomib 20 mg/m2 intravenously as a single agent, resulted in a mean inhibi¬ tion of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 i.MECLl) sub¬ units of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for 2 48 hours following the first dose of carfilzomib for each w’eek of dosing. 12.3

Pharmacokinetics

The Cmii, and AUC following a single intravenous dose of 27 mg/m was 4232 ng/mL and 379 ng• hr/mL, respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m , systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure. 8.6 Renal Impairment Distribution: The mean steady-state volume of distribu¬ No starting dose adjustment is required in patients with tion of a 20 mg/m2 dose of carfilzomib was 28 L. When tested baseline mild, moderate, or severe renal impairment or pa¬ in vitro, the binding of carfilzomib to human plasma pro¬ tients on chronic dialysis. The pharmacokinetics and safety teins averaged 97% over the concentration range of 0.4 to 4 of Kyprolis were evaluated in a Phase 2 trial in patients micro molar. with normal renal function and those with mild, moderate, i Metabolism: Carfilzomib was rapidly and extensively me and severe renal impairment and patients on chronic dial¬ tabolized. The predominant metabolites measured in hu¬ ysis. In thus study, the pharmacokinetics of Kyprolis was not | man plasma and urine, and generated in vitro by human influenced by the degree of bast-line renal impairment, in¬ hepatocytes. were peptide fragments and the diol of cluding the patients on dialysis. Since dialysis clearance of carfilzomib. suggesting that peptidase cleavage and epoxide

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KYPROLIS • AMGEN/639

Look for PDR drug information and services in your EHR hydrolysis were the principal pathways of metabolism. Cy¬ tochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism The metabolites have no known biologic activity. Elimination: Following intravenous administration of doses >15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of Si hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 LThour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. In 24 hours, approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose). Age: Population pharmacokinetic analyses that included patients ranging from 35 to 87.6 years of age indicate that the pharmacokinetics of carfilzomib are not influenced by age. Gender: Population pharmacokinetic analyses indicate that the pharmacokinetics of carfilzomib are not influenced by gender. Flepatic Impairment: No dedicated studies have been com¬ pleted in patients with hepatic impairment. Renal Impairment: A pharmacokinetic study was con¬ ducted in which 50 multiple myeloma patients who had var¬ ious degrees of renal impairment and who were classified according to their creatinine clearances fCLcr) into the fol¬ lowing groups: normal function (CLcr > 80 mL/min, n = 12), mild impairment (CLcr 50-80 mL/min. n = 12), moderate impairment (CLcr 30-49 mL/min, n = 10), severe impair¬ ment (CLcr < 30 mL/min, n = 8), and chronic dialysis (n = 8). Kyprolis, as a single agent, was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three weeks (Days 1, 2. 8, 9, 15, and 16), followed bv a 12day rest period every 28 days. Patients received an initial dose of 15 mg/m2, which could lie escalated to 20 mg/m2 starting in Cycle 2 if 15 mg/nj' was well tolerated in Cycle 1. In this study, renal function status had no effect on the clearance or exposure of carfilzomib following a single or repeat-dose administration [see Use in Specific Populations

Figure 1: Kaplan-Meier Curve of Progression-Free Survival in Relapsed Multiple Myeloma in Study 1

Working Group: KRd = Kyprolis. lenalidomide. and low-dose dexamethasone: mo = months. PFS = progression-lree survival. Rd lenalidomide and low-dose dexamethasone arm Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria

(8.6/1. Cytochrome P4bC

In an in vitro study using human liver microsomes. carfilzomib showed modest direct (Ki = 1.7 mi¬ cromolar' and time-dependent inhibition (Ki = 11 micromolarl of human cytochrome CYP3A4/5. In vitro studies indi¬ cated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients us¬ ing oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by con¬ comitant carfilzomib administration. Kyprolis is not ex¬ pected to inhibit CYP3A4/5 activities and/or affect the expo¬ sure to CYP3A4/5 substrates. P-gp Carfilzomib is a P-glycoprotein (P-gp) substrate. In vitro, carfilzomib inhibited the efflux transport of P-gp sub¬ strate digoxin by 25% in a Caco-2 monolayer system. How¬ ever. given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or in¬ ducers.

13 13.1

Figure 2: Kaplan-Meier Curve of Interim Overall Survival in Relapsed Multiple Myeloma in Study 1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis. Impairment of Fer¬

tility

Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal ab¬ erration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Amesl test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-dav repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. 13.2

Animal Toxicology and/or Pharmacology

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recom¬ mended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and in¬ creased serum levels of troponin-T. The repeated bolus in travenous administration of carfilzomib at > 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (car¬ diac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necro¬ sis/hemorrhage I. renal (glomerulonephropathy, tubular ne¬ crosis, dysfunction', and pulmonary ihemorrhage/inflanv maltoni systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dnse in monkeys is approximately equivalent to the recommended dose in humans based on hody surface area

KRd * Kyprolis. lenalidomide. and low-dose dexamethasone: NE - not estimable: OS » overall survival. PFS » progression tree survival: Rd - lenalidomide and low-dose dexamethasone arm Note. The interim OS analysis did not meet the protocol-specified early stopping boundary lor OS

14 14.1

CLINICAL STUDIES In

Combination

with

Lenalidomide

and

Dexamethasone for the Treatment of Patients with Re¬ lapsed Multiple Myeloma

Study 1 was a randomized, open-label, multicenter study which evaluated the combination of Kyprolis with lenalido¬ mide and low-dose dexamethasone iKRdi versus lenalido¬ mide and low-dose dexamethasone alone of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOELi of denosumab were observed (no inhibition of RANKL). Using the highest seminal fluid concentration measured in men, and assuming 100% vaginal and placen¬ tal transfer from a 6-mL ejaculate per day, female and fetal exposure via seminal fluid would be up to 0.6 ng/mL per day. Thus, the potential amount of fetal exposure when a man treated w ith Prolia has unprotected sexual intercourse with a pregnant partner is at least 38-times lower than the NOEL in monkeys. Therefore, it is unlikely that a female partner or fetus would be exposed to pharmacologically rel¬ evant concentrations of denosumab via seminal fluid /see Clinical Pharmacology (12.3)]. Animal Data The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expres¬ sion was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in off¬ spring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, re¬ duced bone strength, reduced hematopoiesis, dental dyspla¬ sia and tooth malalignment; and decreased neonatal growth. At birth out to 1 month of age, infants had measur¬ able blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and in¬ guinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered matura¬ tion of the maternal mammary gland, leading to impaired lactation /see Use in Specific Populations (8.3) and Nonclinical Tbxicology (13.2)]. 8.3 Nursing Mothers It is not known whether Prolia is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (< 0.5% milk:serum ratio). Because many drugs are excreted in human milk and be¬ cause of the potential for serious adverse reactions in nurs¬ ing infants from Prolia, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Prolia during pregnancy may impair mammary gland development and lactation based on ani¬ mal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lacta¬ tion postpartum. However in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammarv gland development was normal, with no impaired lac¬ tation. Mammary gland histopathology at 6 months of ago was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated /see Use in Specific Populations (8.1) and Nonclirucal Tbxicology (13.2)].

Cynomolgus monkeys exposed in utero to denosumab exhib¬ ited bone abnormalities, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hemato¬ poiesis, tooth malalignment, and decreased neonatal growth. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth /see Use in Specific Populations (8.1)]. 8.5

Geriatric Use

Of the total number of patients in clinical studies of Prolia, 9943 patients (76%) were > 65 years old, while 3576 (27%) were > 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were > 65 years old, while 39 patients (16%) were > 75 years old No overall differences in safety or efficacy were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the el¬ derly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6

Renal Impairment

No dose adjustment is necessary in patients with renal im¬ pairment. In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Prolia to pa¬ tients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phospho¬ rus and magnesium) is highly recommended. Adequate in¬ take of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. 8.7

Hepatic Impairment

No clinical studies have been conducted to evaluate the ef. feet of hepatic impairment on the pharmacokinetics of Prolia. 10

OVERDOSAGE

There is no experience with overdosage with Prolia. 11

DESCRIPTION

Prolia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor ac¬ tivator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is pro¬ duced in genetically engineered mammalian (Chinese ham¬ ster ovary) cells. Prolia is a sterile, preservative-free, clear, colorless to pale yellow solution. Each 1 mL single-use prefilled syringe of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2. Each 1 mL single-use vial of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM ace¬ tate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2. 12 12.1

CLINICAL PHARMACOLOGY Mechanism of Action

taneously administered Prolia dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (CIIiax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tnutx) was 10 days (range: 3 to 21 days). After Cmux, serum denosumab concentrations de¬ clined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-theconcentration-time curve up to 16 weeks (AUC0 W w„,ks) of denosumab was 316 mcg*day/mL (SD = 101 meg* day/m I.1 No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg sub¬ cutaneously administered once every 6 months. Prolia pharmacokinetics were not affected by the formation of binding antibodies. A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg). Seminal Fluid Pharmacokinetic Study Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 i± 81.91 ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The me¬ dian (range) Tmux values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respec¬ tively. Amongst the subjects, the highest denosumab con¬ centration in seminal fluid was 301 ng/mL at 22 days post¬ dose. On the first day of measurement (10 days post-dose >, nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post¬ dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (±36.5) ng/mL across all subjects (n = 12). [see Use in Specific Populations (8.1)1. Drug Interactions In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneous injection i, which approximates the Tnmx of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indi¬ cates that denosumab should not alter the pharmacokinet¬ ics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis. Specific Populations Gender: Mean serum denosumab concentration-time pro¬ files observed in a study conducted in healthy men > 50 years were similar to those observed in a Study conducted in postmenopausal women using the same dose regimen. Age: The pharmacokinetics of denosumab were not af¬ fected by age across all populations studied whose ages ranged from 28 to 87 years. Race: The pharmacokinetics of denosumab were not af¬ fected by race.

Prolia binds to RANKL, a transmembrane or soluble pro¬ tein essential for the formation, function, and survival of os¬ teoclasts, the cells responsible for bone resorption. Prolia prevents RANKL from activating its receptor. RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast forma¬ tion, function, and survival, thereby decreasing bone resorp¬ tion and increasing bone mass and strength in both cortical and trabecular bone.

Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharma¬ cokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary. Hepatic Impairment: No clinical studies have been con¬ ducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.

12.2

13 NONCLINICAL TOXICOLOGY

Pharmacodynamics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ In clinical studies, treatment with 60 mg of Prolia resulted tility in reduction in the bone resorption marker serum type 1 Carcinogenicity C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were The carcinogenic potential of denosumab has not been eval¬ uated in long-term animal studies. below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% ol patients 1 to 3 months after dosing of Prolia. At Mutagenicity the end of each dosing interval, CTX reductions were par¬ The genotoxic potential of denosumab has not I teen evalu¬ ated. tially attenuated from a maximal reduction of > 87% to > 45% (range: 45% to 80%), as serum denosumab levels di¬ Impairment of Fertility 84 Pediatric Use minished, reflecting the reversibility of the effects of Prolia Denosumab had no effect on female fertility or male repro¬ Prolia is not recommended in pediatric patients The safety on bone remodeling. These effects were sustained with con¬ ductive organs in monkeys at doses that were 13- to 50-lold and effectiveness of Prolia in pediatric patients have not tinued treatment. Upon reinitiation, the degree of inhibition higher than the recommended human dose of 60 mg subcu¬ been established. of CTX by Prolia was similar to that observed in patients taneously administered once every 6 months, based on body Treatment with Prolia may impair bone growth in children initiating Prolia treatment. weight (mg/kg). with open growth plates and may inhibit eruption of denti¬ Consistent with the physiological coupling of bone forma¬ 13.2 Animal Toxicology and/or Pharmacology tion. In neonatal rats, inhibition of RANKL (the target of tion and resorption in skeletal remodeling, subsequent re¬ Denosumab is an inhibitor of osteoclastic bone resorption Prolia therapy i with a construct of osteoprotogerin bound to ductions in bone formation markers (i.e. osteocalcin and via inhibition of RANKL. rc (OPti-Fc) at doses < It) mg/kg was associated with inhi- ! procollagen type 1 N-terminal peptide [P1NP]) were ob¬ In ovariectomized monkeys, once-monthly treatment with bition of bone growth and tooth eruption. Adolescent pri¬ served starting 1 month after the first dose of Prolia. After denosumab suppressed bone turnover and increased bone mates treated with denosumab at doses 10 and 50 times 110 discontinuation of Prolia therapy, markers of bone resorp- ! mineral density (BMD) and strength of cancellous and cor¬ and •>() mg/kg dose' higher than the recommended human tion increased to levels 40% to 60% above pretreatment val¬ tical bone at doses 50-fold higher than the recommeruled dose of 60 mg administered every 6 months, based on body ues but returned to baseline levels within 12 months. human dose of 60 mg administered once every 6 months, weight mg/kg i, had abnormal growth plates, considered to i 12.3 Pharmacokinetics based on body weight t mg/kg). Bone tissue was normal with b«* consistent with the pharmacological activity of | In a study conducted in healthy male and female volunteers denosumab. no evidence of mineralization defects, accumulation of oste¬ n = 73. age range: 18 to 64 years) following a single subcu¬ oid. or woven bone.

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically en¬ gineered (“knockout”) mice or use of other biological inhibi¬ tors of the RANK/RANKL pathway, namely OPG-Fc, pro¬ vided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice ex¬ hibited absence of lymph node formation, as well as an ab¬ sence of lactation due to inhibition of mammary gland mat¬ uration (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhib¬ ited reduced bone growth and lack of tooth eruption. A cor¬ roborative study in 2-week-old rats given the RANKL inhib¬ itor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.

14

PROLIA • AMGEN/645 Table 2. The Effect of Prolia on the Incidence of New Vertebral Fractures in Postmenopausal Women

*

Proportion of Women With Fracture (%)* Placebo

Prolia

Absolute

Relative

N = 3691

Risk Reduction

(%)

N = 3702 1%)

l%)'|95% Cl)

Risk Reduction (%)’(95% Cl)

0-1 Year

2.2

0.9

1.4 (0.8, 1.9)

61 (42, 74)

0-2 Years

5.0

1.4

3.5 (2.7, 4.3)

71 (61, 79)

0-3 Years

7.2

2.3

4.8 (3.9, 6.8)

68 (59, 74)

* Event rates based on crude rates in each interval. t Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable.

CLINICAL STUDIES

14.1 Postmenopausal Women with Osteoporosis

The efficacy and safety of Prolia in the treatment of post¬ menopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other dis¬ eases (such as rheumatoid arthritis, osteogenesis imper¬ fecta, and Paget’s disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Over¬ all, the mean baseline lumbar spine BMD T-score was -2.8, and 23% of women had a vertebral fracture at baseline. Women were randomized to receive subcutaneous injections of either placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg cal¬ cium and 400 IU vitamin D supplementation daily. The primary efficacy variable was the incidence of new mor¬ phometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years. Effect on Vertebral Fractures Prolia significantly reduced the incidence of new morpho¬ metric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral frac¬ tures at year 3 was 7.2% in the placebo-treated women com¬ pared to 2.3% for the Prolia-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3. [See table 2 above] Prolia was effective in reducing the risk for new morpho¬ metric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis. Effect on Hip Fractures The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).

Table 3. The Effect of Prolia on the Incidence of Nonvertebral Fractures at Year 3

1 Proportion of Women With Fracture (%)*

Nonvertebral fracture*

Placebo N = 3906

Prolia

Absolute Risk

N = 3902

Reduction (%)

Relative Risk Reduction (%)

(%)

(%l

(95% Cl)

(95% Cl)

8.0

6.5

1.5 (0.3, 2.7)

20 (5, 33)>

* Event rates based on Kaplan-Meier estimates at 3 years. t Excluding those of the vertebrae (cervical, thoracic, and lumbar!, skull, facial, mandible, metacarpus, and finger and toe phalanges, t p-value = 0.01.

6.4% at the total hip, and 5.2% at the femdral neck. Consis¬ tent effects on BMD were observed at the lumbar Spine/re¬ gardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover After Prolia discontinuation, BMD returned to approxi¬ mately baseline levels within 12 months. Bone Histology and Uistomorphometry A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Prolia group, 62 specimens in placebo group). Of the biopsies ob¬ tained, 115 (100% i were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments showed normal architec¬ ture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia. The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Prolia, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-trested patients had double label present at both time points. When compared to placebo, treatment with Prolia resulted in virtually absent activa¬ tion frequency and markedly nduced bone formation rates. However, the long-term consequences of this degree of sup¬ pression of bone remodeling are unknown 14.2 Treatment to Increase Bone Mass in Men with Os¬ teoporosis

N • number of subjects randomized

Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years

Effect on Nonvertebral Fractures Treatment with Prolia resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3). [See table 3 above] Effect on Bone Mineral Density (BMD) Treatment with Prolia significantly increased BMD at all anatomic sites measured at 3 years. The treatment differ¬ ences in BMD at 3 years were 8.8% at the lumbar spine.

The efficacy and safety of Prolia in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history* of prior fra¬ gility fracture1. Men with other diseases (such as rheuma¬ toid arthritis, osteogenesis imperfecta, and Paget s disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age,of 65 years. Men were randomized to receive St) injections of either placebo (n= 121) or Prolia 60 mg (n = 1211 once every 6 months All men received at least 1000 mg calcium and at least 800 ID vitamin D supplementation daily. Effect on Bone Mineral Density 1 BMD1 The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1 year. Secondary efficacy vari¬ ables included percent change in total hip, and femoral neck BMD from baseline to 1 year Treatment with Prolia significantly increased BMD at 1 year. The treatment differences in BMD at 1 year wen- 4 8% I (+0.9% placebo, +5.7% Prolia; (95% Cl 4.0. 5.6); p < O.OOOU at the lumbar spine, 2.0% 1+0.3% placebo. +2 4% Prolia' .it the total hip, and 2.2% (0.0% placebo, +2.1% Prolia) at feni

oral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testos¬ terone concentrations and level of bone turnover. Bone Histology and H i s to morphometry A total of 29 transiliac crest bone biopsy specimens were ob¬ tained from men with osteoporosis at 12 months (17 speci¬ mens in Prolia group, 12 specimens in placebo group). Of the biopsies obtained. 29 1100%) were adequate for qualita¬ tive histology* and, in Prolia patients, 6(35%) were adequate for frill quantitative histomorphometry assessment. Quali¬ tative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia. The presence of double tetracycline labeling in a bi¬ opsy specimen provides an indication of active bone remod¬ eling, while the absence of tetracycline label suggests sup¬ pressed bone formation. In patients treated with Prolia, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with Prolia resulted in markedly reduced bone formation rates. How¬ ever, the long-term consequences of this degree of suppres¬ sion of bone remodeling are unknown. 14.3 Treatment of Bone Loss in Men with Prostate Cancer

The efficacy and safety of Prolia in the treatment of bone loss in men with , nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had ei¬ ther a BMD T-score at the lumbar spine, total hip. or femo¬ ral neck between -1.0 and -4.0, or a history of(an osteopor¬ otic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at base¬ line. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Prolia 60 mg 'n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age (< 70 years vs. J 70 years) and duration of ADT at trial entry (S 6 months vs. > 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementa¬ tion dailv. I Effict on Bone Mineral Density (BMP) I The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key ' secondary efficacy variable was the incidence of new verte; bra! fracture through 'month 36 diagnosed based on x-ray | evaluation fry two independent radiologists. Lumbar spine BMD was* higher at 2 years in Prolia-treated patients as compared to placebo-treated patients I-1.0% placebo, +5.6% Prolia; treatment difference 6 7% (95% Cl; 6.2, 7.1); p < 0 00011 With approximately 62% of patients followed for 3 yeare, treatment differences in BMI) at 3 years were 7.9% (-1.2% placebo. +6 8% Prolia l at the lumbar spine, 6.7% 1-2.6% pla¬ cebo,+3.2% Prolia) at the total hip, and 4 9% (-1.8% placebo.

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646/AMGEN • PROLIA

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Table 4 The Effect of Prolia on the Incidence of New Vertebral Fractures in Men with Nonmetastatic Prostate Cancer Proportion of Men With Fracture (%)* Placebo N = 673

Prolia

Absolute Risk Reduction (%|f

Relative Risk Reduction (%)’

N = 679

(95% Cl)

(95% Cl)

6 months). Sixty-two percent of patients re¬ ceived adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily. Effect on Bone Mineral Density (BMD) The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Prolia-treated patients as com¬ pared to placebo-treated patients [-0.7% placebo, +4.8% Prolia; treatment difference 5.5% (95% Cl: 4.8, 6.3); p < 0.0001). With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% Prolia) at the lumbar spine, 4.7 % (-1.0% pla¬ cebo, +3.8% Prolia) at the total hip, and 3.6% (-0.8% placebo, +2.8% Prolia) at the femoral neck. 16

HOW SUPPLIED/STORAGE AND HANDLING

Prolia is supplied in a single-use prefilled syringe with a safety guard or in a single-use vial. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).

60 n»g/l mL in a single-use prefilled syringe

1 per carton

NDC 55513-710-01

60 mg/1 mL in a single-use vial

1 per carton

NDC 55513-720-01

sensitivity reactions that they should not receive denosumab (Prolia or Xgeva) Isee Warnings & Precautions (5.2), Contraindications (4.3)]. 17.3

Hypocalcemia

Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Prolia [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they de¬ velop signs or symptoms of hypocalcemia. 17.4

Osteonecrosis of the Jaw

Advise patients to maintain good oral hygiene during treat¬ ment with Prolia and to inform their dentist prior to dental procedures that they are receiving Prolia. Patients should inform their physician or dentist if they experience persis; tent pain and/or slow healing of the mouth or jaw after den¬ tal surgery [see Warnings and Precautions (5.4)]. 17.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Advise patients to report new or unusual thigh, hip, or groin pain [see Warnings and Precautions (5.5)]. 17.6

Serious Infections

Advise patients to seek prompt medical attention if they de¬ velop signs or symptoms of infections, including cellulitis [see Warnings and Precautions (5.6)]. 17.7

Dermatologic Reactions

Advise patients to seek prompt medical attention if they de¬ velop signs or symptoms of dermatological reactions (der¬ matitis, rashes, and eczema) Isee Warnings and Precautions (5.7)1. 17.8

Musculoskeletal Pain

Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking Prolia. Patients should report severe symptoms if they develop /see Warn¬ ings and Precautions (5.8)]. 17.9

Embryo-Fetal Toxicity

Pregnancy Advise patients that Prolia is contraindicated in women who are pregnant and may cause fetal harm Isee Contrain¬ dications (4.2), Use in Specific Populations (8.1)]. 17.10

Nursing Mothers

Advise patients that because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Prolia, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Isee Use in Specific Populations (8.3)1. 17.11

Schedule of Administration

If a dose of Prolia is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection. [Amgen Logo] Manufactured by:

Store Prolia in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Prolia may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Prolia must not be exposed to temperatures above 25*C/77°F and must be used within 14 days. If not used within the 14 days, Prolia should be discarded. Do not use Proha after the expiry date printed on the label. Protect Prolia from direct light and heat. Avoid vigorous shaking of Prolia.

Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 Patent: http://pat.amgen.com/prolia/ © 2010-2015 Amgen Inc. All rights reserved, lxxxxxx - v9 MEDICATION GUIDE Prolia® (PRO-lee-a) (denosumab) Injection, for subcutaneous use

17

PATIENT COUNSELING INFORMATION

See FDA approved patient labeling (Medication Guide). 17 1

Drug Products with Same Active Ingredient

Advise patients that denosumab is also marketed as Xgeva. and if taking Prolia, they should not receive Xgeva I see Warnings and Precautions (5.DI. 17.2 Hypersensitivity Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise pa¬ tients who have had signs or symptoms of systemic hyper¬

Read the Medication Guide that comes with Proha before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Prolia. What is the most important information I should know about Prolia?

If you receive Prolia. you should not receive XGEVA®. Prolia contains the same medicine as Xgeva (denosumab).

Prolia can cause serious side effects including: • Serious allergic reactions. Serious allergic reactions have happened in people who take Prolia. Call your doctor or go to your nearest emer¬ gency room right away if you have any symptoms of a se¬ rious allergic reaction. Symptoms of a serious allergic re¬ action may include: • low blood pressure (hypotension) • trouble breathing • throat tightness • swelling of your face, lips, or tongue • rash • itching • hives • Low calcium levels in your blood (hypocalcemia). Prolia may lower the calcium levels in your blood. If you have low blood calcium before you start receiving Prolia, it may get worse during treatment. Your low blood calcium must be treated before you receive Prolia. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as: • Spasms, twitches, or cramps in your muscles • Numbness or tingling in your fingers, toes, or around your mouth Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you take Prolia. Take calcium and vitamin D as your doctor tells you to. • Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you take Prolia. Your doctor should examine your mouth before you start Prolia. Your doctor may tell you to see your dentist before you start Prolia. It is important for you to practice good mouth care during treatment with Prolia. Ask your doctor or dentist about good mouth care if you have any questions • Unusual thigh bone fractures. Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture include new or un¬ usual pain in your hip, groin, or thigh. • Serious infections. Serious infections in your skin, lower stomach area (abdo¬ men), bladder, or ear may happen if you take Prolia. In¬ flammation of the inner lining of the heart (endocarditis) due to an infection also may happen more often in people who take Prolia. You may need to go to the hospital for treatment if you develop an infection. Prolia is a medicine that may affect the ability of your body to fight infections. People who have weakened im¬ mune system or take medicines that affect the immune system may have an increased risk for developing serious infections. Call your doctor right away if you have any of the follow¬ ing symptoms of infection: • Fever or chills • Skin that looks red or swollen and is hot or tender to touch • Fever, shortness of breath, cough that will not go away • Severe abdominal pain • Frequent or urgent need to urinate or burning feeling when you urinate • Skin problems. Skin problems such as inflammation of your skin (derma¬ titis), rash, and eczema may happen if you take Prolia. Call your doctor if you have any of the following symptoms of skin problems that do not go away or get worse: • Redness • Itching • Small bumps or patches (rash) • Your skin is dry or feels like leather • Blisters that ooze or become crusty • Skin peeling • Bone, joint, or muscle pain. Some people who take Prolia develop severe bone, joint, or muscle pain. Call your doctor right away if you have any of these side effects. What is Prolia? Prolia is a prescription medicine used to: • Treat osteoporosis (thinning and weakening of bone) in women after menopause (“change of life”) who: ° are at high risk for fracture (broken bone) • cannot use another osteoporosis medicine or other osteo¬ porosis medicines did not work well • Increase bone mass in men with osteoporosis who are at high risk for fracture ' • Treat bone loss in men who are at high risk for fracture receiving certain treatments for prostate cancer that has not spread to other parts of the body • Treat bone loss in women who are at high risk for fracture receiving certain treatments for breast cancer that has not spread to other parts of the body is not known if Prolia is safe and effective in children.

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Look for PDR drug information and services in your EHR Who should not take Prolia? Do not take Prolia if you: • have been told by your doctor that your blood calcium level is too low. • are pregnant or plan to become pregnant • are allergic to denosumab or any of the ingredients in Prolia. See the end of this leaflet for a complete list of in¬ gredients in Prolia. What should I tell my doctor before taking Prolia? Before taking Prolia, tell your doctor if you: • Are taking a medicine called Xgeva (denosumab). Xgeva contains the same medicine as Prolia. • Have low blood calcium • Cannot take daily calcium and vitamin D • Had parathyroid or thyroid surgery (glands located in your neck) • Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome) • Have kidney problems or are on kidney dialysis • Plan to have dental surgery or teeth removed. • Are pregnant or plan to become pregnant. Prolia may harm your unborn baby. Tell your doctor right away if you become pregnant while taking Prolia. ° Pregnancy Surveillance Program: Prolia is not in¬ tended for use in pregnant women. If you become preg¬ nant while taking Prolia, talk to your doctor about en¬ rolling in Amgen’s Pregnancy Surveillance Program or call 1-800-772-6436 (1-800-77-AMGEN). The purpose of this program is to collect information about w omen who have become pregnant while taking Prolia. • Are breastfeeding-or plan to breastfeed. It is not known if Prolia passes into your breast milk. You and your doctor should decide if you wall take Prolia or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and nonprescription drugs, vitamins, and herbal supplements. Know the medicines you take. Keep a list of medicines with you to show to your doctor or pharmacist when you get a new medicine. How will I receive Prolia? • Prolia is an injection that will be given to you by a health¬ care professional. Prolia is injected under your skin (sub¬ cutaneous). • You w'ill receive Prolia 1 time every 6 months. • You should take calcium and vitamin D as your doctor tells you to while you receive Prolia. • If you miss a dose of Prolia, you should receive your injec¬ tion as soon as you can. • Take good care of your teeth and gums while you receive Prolia. Brush and floss your teeth regularly. • Tell your dentist that you are receiving Prolia before you have dental work. What are the possible side effects of Prolia? Prolia may cause serious side effects. • See "What is the most important information I should know about Prolia?" • It is not known if the use of Prolia over a long period of time may cause slow healing of broken bones. The most common side effects of Prolia in women who are being treated for osteoporosis after menopause are: • back pain • pain in vour arms and legs • high cholesterol • muscle pain • bladder infection The most common side effects of Prolia in men with osteo¬ porosis are: • back pain • joint pain • common cold (runny nose or sore throat) The most common side effects of Prolia in patients receiving certain treatments for prostate or breast cancer are: • joint pain • back pain • pain in your arms and legs • muscle pain "fell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Prolia. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report sidb effects to FDA at 1-800-FDA-1088. How should I store Prolia if I need to pick it up from a phar¬ macy? • Keep Prolia in a refrigerator at 36°F to 46“F (2* *C to 8*0 in the original carton • Do not freeze Prolia. • When you remove Prolia from the refrigerator, Prolia must be kept at room temperature (up to 77'F 5°F of patients treated with REPATHA and occurring more frequently than placebo): nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda gov/medwatch See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2015

Recommended Dosage Important Administration Instructions

3 4 5

DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

6

ADVERSE REACTIONS

5.1 6.1 6.2

8

11 12

Clinical Trials Experience Immunogenicity Pregnancy Lactation Pediatric Use Geriatric Use Renal Impairment Hepatic Impairment

DESCRIPTION CLINICAL PHARMACOLOGY 12.1 12.2 12.3

13

Allergic Reactions

USE IN SPECIFIC POPULATIONS 8.1 8.2 8.4 8.5 8.6 8.7

Mechanism of Action Pharmacodynamics Pharmacokinetics

NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology

14

CLINICAL STUDIES 14.1 Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease 14.2 Heterozygous Familial Hypercholesterolemia (HeFH) 14.3 Homozygous Familial Hypercholesterolemia

-INDICATIONS AND USAGEREPATHA is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated as an adjunct to diet and: • Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C). (1.1) • Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hy¬ percholesterolemia (HoFH) who require additional lower¬ ing of LDL-C. (1.2) Limitations of Use • The effect of REPATHA on cardiovascular morbidity and mortality has not been determined. (1.3)

Primary Hyperlipidemia Homozygous Familial Hypercholesterolemia Limitations of Use

DOSAGE AND ADMINISTRATION 2.1 2.2

R

[ri-PAth-a] (evolocumab) injection, for subcutaneous use

INDICATIONS AND USAGE

16 17

HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia REPATHA “ is indicated as an adjunct to diet and maxi¬ mally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cho¬ lesterol (LDL-C). 1.2 Homozygous Familial Hypercholesterolemia REPATHA is indicated as an adjunct to diet and other LDLlowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hy¬ percholesterolemia (HoFH) who require additional lowering of LDL-C. 1.3 Limitations of Use The effect of REPATHA on cardiovascular morbidity and mortality has not been determined.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended subcutaneous dosage of REPATHA in pa¬ tients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regi¬ men. The recommended subcutaneous dosage of REPATHA in pa¬ tients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA. since response to therapy will depend on the de¬ gree of LDL-receptor function. If an every 2 week or once monthly dose is missed, instruct the patient to: • Administer REPATHA as soon as possible if there are more than 7 days until the next scheduled dose, or, • Omit the missed dose and administer the next dos< ac¬ cording to the original schedule. 2.2 Important Administration Instructions • Tb administer the 420 mg dose, give 3 REPATHA injec¬ tions consecutively within 30 minutes • Provide proper training to patients and/or earn'ivers on how to prepare and administer REPATHA prior to use. ac¬ cording to the Instructions for Use, including aseptic tech¬ nique. Instruct patients and/or caregivers to read and fol low the Instructions for Use each time thev use REPATHA

Fre« mob/fePDR app for fast drug references on Apple or Android devices

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648/AMGEN • REPATHA • Keep REPATHA in the refrigerator. Prior to use, allow REPATHA to warm to room temperature for at least 30 minutes. Do not warm in any other way. Alternatively, for patients and caregivers, REPATHA can be kept at room temperature I up to 25“C (77°F)) in the original carton. However, under these conditions, REPATHA must be used within 30 days [see How Supplied/Storage and Handling

am. • Visually inspect REPATHA for particles and discoloration prior to administration. REPATHA is a clear to opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy or discolored or contains particles. • Administer REPATHA by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use pre¬ filled syringe or single-use prefilled autoinjector. • Do not co-administer REPATHA with other injectable drugs at the same injection site. • Rotate the injection site with each injection. 3

DOSAGE FORMS AND STRENGTHS

REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution available as follows: • Injection: 140 mg/mL solution in a single-use prefilled syringe • Injection: 140 mg/mL solution in a single-use prefilled SureClick® autoinjector 4

5.1

Adverse Reactions in Seven Pooled 12-Week Controlled Trials In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of REPATHA subcutaneously every 2 weeks and 1059 patients received 420 mg of REPATHA subcutaneously monthly. The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% were women, 85% White, 5% Black, 9%> Asian, and 5% Hispanic. Adverse reactions re¬ ported in at least 1% of REPATHA-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2. of REPATHA-treated Patients and More Frequently than with Placebo in Pooled 12-Week Studies

Allergic Reactions

ADVERSE REACTIONS

The following adverse reactions are also discussed in the other sections of the labeling: • Allergic reactions [see Warnings and Precautions (5.1)] 6.1

’ includes erythema, pain, bruising

WARNINGS AND PRECAUTIONS

Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with REPATHA, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with REPATHA, treat according to the standard of care, and monitor until signs and symptoms resolve. 6

Nasopharyngitis Back pain Upper respiratory tract infection Arthralgia Nausea Fatigue Muscle spasms Urinary tract infection Cough Influenza Contusion

Placebo

REPATHA’

(N = 1224) %

(N = 2052) %

3.9 2.2 2.0 1.6 1.2 1.0 1.2 1.2 0.7 1.1 0.5

4.0 2.3 2.1 1.8 1.8 1.6 1.3 1.3 1.2 1.2 1.0

Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients re¬ ceived 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.3)]. The mean age was 31 years (range: 13 to 57 years), 49% were women, 88% were White, 3% Asian, and 9% other. The adverse reactions that occurred in at least two (6.1%) REPATHA-treated patients, and more frequently than in placebo-treated patients, in¬ cluded: • Upper respiratory tract infection (9.1% versus 6.3%) • Influenza (9.1% versus 0%) • Gastroenteritis (6.1% versus 0%) • Nasopharyngitis (6.1% versus 0%) 6.2

Table 1 Adverse Reactions Occurring in Greater than or Equal to 3% of REPATHA-treated Patients and More Frequently than with Placebo in Study 2

Placebo (N = 302) %

(N = 599) %

9.6 6.3 6.3 6.6

10.5 9.3 7.5 6.2

REPATHA

140 mg every 2 combined

weeks

and

420 mg once

monthly

Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial) The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12-week trials. The mean and median exposure durations of REPATHA in this pool of eight trials were 20 weeks and 12 weeks, respectively Local Injection Site Reactions Injection site reactions occurred in 3.2% and 3.0% of REPATHA-treated and placebo-treated patients, respec¬ tively. The most common injection site reactions were ery¬ thema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in REPATHA-treated patients and placebo-treated patients were 0.1% and 0%, respectively. Allergic Reactions Allergic reactions occurred in 5.1% and 4.6% of REPATHAtreated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for REPATHA and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%). Neurocognitive Events In placebo-controlled trials, neurocognitive events were re¬ ported in less than or equal to 0.2% in REPATHA-treated and placebo-treated patients. Low LDL-C Levels In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1609 patients treated with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to background lipidaltering therapy were not made in response to low LDL-C values, and REPATHA dosing was not modified or inter¬ rupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by REPATHA are unknown. Musculoskeletal Events Musculoskeletal adverse reactions were reported in 14.3% of REPATHA-treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for REPATHA and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia 12.0% versus 1.8%).

Immunogenicity

As with all therapeutic proteins, there is potential for im¬ munogenicity The immunogenicity of REPATHA has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti¬ drug antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of REPATHA tested positive for binding antibody development. Patients whose sera tested positive for binding antibodies were fur¬ ther evaluated for neutralizing antibodies; none of the pa¬ tients tested positive for neutralizing antibodies. There was no evidence that the presence of anti-drug bind¬ ing antibodies impacted the pharmacokinetic profile, clini¬ cal response, or safety of REPATHA, but the long-term con¬ sequences of continuing REPATHA treatment in the presence of anti-drug binding antibodies are unknown. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to REPATHA with the incidence of antibodies to other products may be mis¬ leading.

8

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Patients with Primary Hyperlipid¬ emia and in Patients with Heterozygous Familial Hypercho¬ lesterolemia REPATHA is not indicated for use in patients without famil¬ ial hypercholesterolemia or atherosclerotic CVD [see Indica¬ tions and Usage (1.1)]. The data described below reflect exposure to REPATHA in 8 placebo-controlled trials that included 2651 patients treated with REPATHA, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks). The mean age of the population was 57 years, 49% of the population were women, 85% were White, 6% were Black, 8% were Asians, and 2% were other races. Adverse Reactions in a 52 Week Controlled Trial In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of REPATHA subcutaneously once monthly [see Clinical Studies (14.1)]. The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% were women, 80% White, 8% Black, 6% Asian, and 6% Hispanic. Adverse reactions re¬ ported in at least 3% of REPATHA-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1. Adverse reactions led to discontinua¬ tion of treatment in 2.2% of REPATHA-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to REPATHA treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).

Nasopharyngitis Upper respiratory tract infection Influenza Back pain

5.7 4.5 4.5 4.2 4.0 4.0 3.7 3.3 3.2 3.0 3.0

Table 2. Adverse Reactions Occurring in Greater than 1%

CONTRAINDICATIONS

REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA [see Warn¬ ings and Precautions (5.1)]. 5

5.0 3.6 3.6 3.0 3.6 3.0 2.6 3.0 2.3 2.6 2.0

Ipjection site reactions’ Cough Urinary tract infection Sinusitis Headache Myalgia Dizziness Musculoskeletal pain Hypertension Diarrhea Gastroenteritis

8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Risk Summary There are no data available on use of REPATHA in pregnant women to inform a drug-associated risk. In animal repro¬ duction studies, there were no effects on pregnancy or neo¬ natal/infant development when monkeys were subcutane¬ ously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month. In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses. The exposures where immune suppression occurred in infant monkeys were greater than those ex¬ pected clinically. No assessment for immune suppression was conducted with evolocumab in infant monkeys. Measur¬ able evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibod¬ ies, crosses the placental barrier. FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; how¬ ever, they are likely to cross the placenta in increasing amounts in the second and third trimester. Consider the benefits and risks of REPATHA and possible risks to the fe¬ tus before prescribing REPATHA to pregnant women. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically rec¬ ognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In cynomolgus monkeys, no effects on embryo-fetal or post¬ natal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to partu¬ rition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. No test of humoral im¬ munity in infant monkeys was conducted with evolocumab 8.2

Lactation

Risk Summary There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed in¬ fant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for REPATHA and any po¬ tential adverse effects on the breastfed infant from

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Look for PDR drug information and services in your EHR REPATHA or from the underlying maternal condition. Hu¬ man IgG is present in human milk, but published data sug¬ gest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. 8.4 Pediatric Use The safety and effectiveness of REPATHA in combination with diet and other LDL-C-lowering therapies in adoles¬ cents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebocontrolled trial that included 10 adolescents ages 13 to 17 years old with HoFH Isee Clinical Studies (14.3)]. in this trial, 7 adolescents received REPATHA 420 mg subcutane¬ ously once monthly and 3 adolescents received placebo. The effect of REPATHA on LDL-C was generally similar to that observed among adult patients with HoFH. Including expe¬ rience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with REPATHA, with a median exposure duration of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult patients with HoFH. The safety and effectiveness of REPATHA have not been es¬ tablished in pediatric patients with HoFH who are younger than 13 years old. The safety and effectiveness of REPATHA have not been es¬ tablished in pediatric patients with primary hyperlipidemia or HeFH. 8.5 Geriatric Use In controlled studies, 1420 patients treated with REPATHA were i 65 years old and 171 were > 75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in re¬ sponses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dose adjustment is needed in patients with mild to mod¬ erate renal impairment. No data are available in patients w ith severe renal impairment Isee Clinical Pharmacology (12.3)1. 8.7 Hepatic Impairment No dose adjustment is needed in patients with mild to mod¬ erate hepatic impairment (Child-Pugh A or B). No data are available in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

11

Table 3. Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg, Rosuvastatin 40 mg, or Simvastatin 40 mg (Mean % Change from Baseline to Week 12 in Study 1) Treatment Group

LDL-C

Non-HDL-C

Apo B

Total Cholesterol

7

2

5

4

-64

-56

-49

-38

Mean difference from placebo (95% Cl)

-71 (-81, -61)

-58 (-67, -49)

-55 (-62, -47)

-42 (-48, -36)

Placebo once monthly (n = 44)

5

5

3

3

-58

-47

-46

-32

-63 (-76, -50)

-52 (-63, -41)

-49 (-58, -39)’

-36 (-43, -28)

Placebo every 2 weeks (n = 42) REPATHA 140 mg every 2 weeks (n = 105)

REPATHA 420 mg once monthly* (n = 105) Mean difference from placebo (95% Cl)

Estimates based on a multiple imputation model that accounts for treatment adherence 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C

DESCRIPTION

Evolocumab is a human monoclonal immunoglobulin G2 (IgG2> directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in ge¬ netically engineered mammalian (Chinese hamster ovary) cells. REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous injection. Each 1 inL single-use prefilled syringe and single-use pre¬ filled SureClick® autoinjector contains 140 mg evolocumab, acetate 11.2 mg), polysorbate 80 (0.1 mg), proline (25 mg), in Water for Injection, USP. Sodium hydroxide may be used to adjust to a pH of 5.0.

12

REPATHA • AMGEN/649

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor i LDLRi. preventing PCSK9-mediated LDLR degra¬ dation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. 12.2 Pharmacodynamics Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 con¬ centrations returned toward baseline when evolocumab con¬ centrations decreased below the limit of quantitation. 12.3 Pharmacokinetics Evolocumab exhibits non-linear kinetics as a result of bind¬ ing to PCSK9. Administration of the 140 mg dose in healthy volunteers resulted in a Cm„, mean (standard deviation |SU]) of 18.6 (7.31 pg/mL and AUC)„, mean (SD) of 188 198.6) day*pg/mL. Administration of the 420 mg dose in healthy volunteers resulted in a C^,, mean (SD) of 59.0 (17.2) pg/mL and AUC^* mean (SD) of 924 (346) day*pg/mL. Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mlVhr. An approximate 2- to 3-fold accumulation was ob¬ served in trough serum concentrations (Cm,u [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or follow ing 420 mg doses administered subcutane¬ ously monthly 1C,*,, [SD] 11.2 (10.8)), and serum trough concentrations approached steady state by 12 weeks of dosing

-100

Pooled Statins

Atorvastatin 80 mg QD REPATHA 140 mg every 2 weeks

Rosuvastatin 40 mg QD

Simvastatin 40 mg QD

—w- REPATHA 420 mg once monthly

Figure 1. Effect of REPATHA on LDL-C in Patients with Atherosclerotic CVD When Combined with Statins (Mean % Change from Baseline to Week 12 in Study 1)

Absorption Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and es¬ timated absolute bioavailability was 12%. Distribution Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L. Metabolism and Elimination Two elimination phases were observed for REPATHA. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of REPATHA is largely through a non-saturable proteolytic pathw'ay. REPATHA was estimated to have an effective half-life of 11 to 17 days. Specific Populations The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all ap¬ proved populations /see Use in Specific Populations (8.5)]. The exposure of evolocumab decreased with increasing body weight. These differences are not clinically meaningful. Renal Impairment Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR) < 30 mL/min/1.73 m2) have not been studied. Hepatic Impairment Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 2030% lower mean ('„„ and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients. Pregnancy The effect of pregnancy on evolocumab pharmacokinetics has not been studied /see Use in Specific Populations (8.1)].

Drug Interaction Studies An approximately 20% decrease in the Cm„ and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen. This difference is not clini¬ cally meaningful and does not impact dosing recommenda¬ tions. 13 NONCLINIC AL TOXICOLOGY 13.1 Carcinogenesis. Mutagenesis, Impairment of Fer¬ tility The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks. There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. The muta¬ genic potential of evolocumab has not been evaluated; how¬ ever, monoclonal antibodies are not expected to alter DNA or chromosomes. There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embry¬ onic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC. In addition, there were no adverse evolocumab-related ef¬ fects on surrogate markers uf fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature mon¬ keys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly. The highest doae tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respec¬ tively, based on plasma AUC. 13.2 Animal Toxicology and/or Pharmacology During a 3-month toxicology' study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg

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650/AMGEN • REPATHA

daily with or without ezetimibe 10 mg daily. After stabiliza¬ tion on background therapy, patients were randomly as¬ signed to the addition of placebo or REPATHA 420 mg ad¬ ministered subcutaneously once monthly. Among these patients, the mean age at baseline was 59 years (range: 35 to 75 years), 2591 were > 65 years, 4091 were women, 80% were White, 3% were Black, 5% were Asian, and < 1% were Hispanic or Latino. After stabilization on the assigned back¬ ground therapy, the mean baseline LDL-C was 105 mg/dL. In these patients with atherosclerotic CVD on maximumdose atorvastatin therapy with or without ezetimibe, the difference between REPATHA 420 mg once monthly and placebo in mean percent change in LDUC from baseline to Week 52 was -54 % (95% Cl: -65%, -42%; p < 0.0001) (Table 4 and Figure 2). For additional results see Table 4. ISee table 4 abovel (See figure 2 above] Estimates based on a multiple imputation model that ac¬ counts for treatment adherence Error bars indicate 95% confidence intervals

Table 4 Effect of REPATHA on Lipid Parameters in Patients with Atherosclerotic CVD on Atorvastatin 80 mg with or without Ezetimibe 10 mg daily (Mean % Change from Baseline to Week 52 in Study 2) Treatment Group

LDL-C

Non-HDL-C

Apo B

Total Cholesterol

2

3

0

3

-52

-41

-40

-28

-54 (-65, -42)

-44 (-56, -32)

-40 (-50, -30)

-31 (-39, -24)

Placebo once monthly (n = 44) REPATHA 420 mg once monthly (n = 95) Mean difference from placebo (95% CI)

Estimates based on a multiple imputation model that accounts for treatment adherence

20 10 0 co

e £

14.2 (HeFH)

\

10

\

20-

-

\

§> c -30n> .c O -40-

\ \

50-

\

-*----f

-60■70-

IBaseline

Week 12

Week 24

Week 36

Week 52

Placebo once monthly Observed n: 44 -▲-

RE

Observed n: 95

38

42

36

39

86

70

79

•

monthly 82

Figure 2: Effect of REPATHA 420 mg Once Monthly on LDL-C in Patients with Atherosclerotic CVD on Atorvastatin 80 mg with or without Ezetimibe 10 mg Daily

Treatment Group

LDL-C

Non-HDL-C

po B

Total Cholesterol

-1

-1

-1

-2

-62

-56

-49

-42

Mean difference from placebo 95% CI

-61 (-67, -55)

-54 (-60, -49)

-49 (-54, -43)

-40 (-45, -36)

Placebo once monthly (n = 55)

4

4

4

2

-56

-49

-44

-37

-60 (-68, -52)

-53 (-60, -46)

-48 (-55. -41)

(-45. -33)

Placebo every 2 weeks (n = 54) REPATHA 140 mg every 2 weeks* (n = 110)

REPATHA 420 mg once monthly* (n = 110) Mean difference from placebo 95% CI

QQ

Estimates based on a multiple imputation model that accounts for treatment adherence 140 mg every 2 weeks or 420 mg once monthly yield similar reductions in LDL-C

once daily rosuvastatin in adult monkeys, there were no ef¬ fects of evolocumab on the humoral immune response to keyhole limpet hemocyanin iKLHl after 1 to 2 months ex¬ posure. The highest dose tested corresponds to exposures 54- and 21 -fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respec¬ tively, based on plasma AUC. Similarly, there were no ef¬ fects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure! in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respec¬ tively, based on plasma AUC.

who received REPATHA or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 4591 were > 65 years old, 33% were women, 9891 were White, 2% were Black, < 1 % were Asian and 591 were Hispanic or Latino. After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL.

In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -7191 (95% Cl: -8191, -6191; p < 0 0001) and -63% (9591 Cl: -76%, -5091; p < 0.0001) for the | 140 mg every 2 weeks and 420 mg once monthly dosages, 14 CLINICAL STUDIES respectively. For additional results see Table 3 and Figure 1. 14 1 Primary Hyperlipidemia in Patients with Clinical ISee table 3 at top of previous page] Atherosclerotic Cardiovascular Disease |See figure 1 at top of previous page] Study 1 was a multicenter, double-blind, randomized con- I Estimates based on a multiple imputation model that ac¬ trolled trial in which patients wen- initially randomized to counts for treatment adherence ; an open-label specific statin regimen for a 4 week lipid sta Error bars indicate 95' 1 confidence intervals bihzation period followed by random assignment to subcu- I Study 2 was a multicentcr, double-blind, randomized, taneous injections of REPATHA 140 mg every 2 weeks. placebo-controlled. 52-week trial that included 139 patients REPATHA 420 mg once monthly, or placebo for 12 weeks with atherosclerotic CVD who received protocol-determined The trial included 296 patients with atherosclerotic CVD background lipid-lowering therapy of atorvastatin 80 mg

Familial

Hypercholesterolemia

Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with het¬ erozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome cri¬ teria (1991). In Study 3, 38% of patients had clinical ather¬ osclerotic cardiovascular disease. The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were > 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on highintensity statin therapy. In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% Cl: -67%. -55%; p < 0.0001) and -60% (95% Cl: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 5. ISee table 5 abovel 14.3

Table 5: Effect of REPATHA on Lipid Parameters in Patients with HeFH (Mean % Change from Baseline to Week 12 in Study 3)

Heterozygous

Homozygous Familial Hypercholesterolemia

Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hyper¬ cholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of REPATHA once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other. The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received REPATHA. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a his¬ tory of an untreated LDL-C concentration > 500 mg/dL to¬ gether with either xanthoma before 10 years of age or evi¬ dence of HeFH in both parents. In these patients with HoFH, the difference between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% Cl: -44%, -18%; p < 0.0001). For additional results see Table 6. Patients know-n to have two LDL-receptor negative alleles (little to no residual function) did not respond to REPATHA. [See table 6 at top of next pagel

16

HOW SUPPLIED/STORAGE AND HANDLING

REPATHA is a sterile, clear to opalescent, colorless to pale yellow solution lor subcutaneous injection supplied in a single-use prefilled syringe or a single-use prefilled SureClick* autoinjector. Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of REPATHA is designed to deliver 1 mL of 140 mg/mL solution.

140 mg/mL single-use prefilled syringe

1 pack

NDO 55513-750-01

140 mg/niL single-use prefilled SureClick® autoinjector

1 pack

NDC 55513-760-01

140 mg/mL single-use prefilled SureClick® autoinjector

2 pack

NDC 55513-760-02

140 mg/mL single-use prefilled SureClick* autoinjector

3 pack

NDC 55513-760-03

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Look for PDR drug information and services in your EHR Pharmacy Store refrigerated at 2° to 8°C (36° to 46“F) in the original carton to protect from light. Do not freeze. Do not shake. For Patients/Caregivers Store refrigerated at 2° to 8°C (36° to 46°F) in the original carton. Alternatively, REPATHA can be kept at room tem¬ perature (up to 25°C (77°F)) in the original carton; however, under these conditions, REPATHA must be used within 30 days. If not used within the 30 days, discard REPATHA. Protect REPATHA from direct light and do not expose to temperatures above 25°C (77°F).

REPATHA • AMGEN/651 Table 6: Effect of REPATHA on Lipid Parameters in Patients with HoFH (Mean % Change from Baseline to Week 12 in

Study 4) Treatment Group

LDL-C

Non-HDL-C

Apo B

"Total Cholesterol

9

8

4

8

-22

-20

-31 (-44, -18)

-28 (-41, -16)

Placebo once monthly (n = 16) REPATHA 420 mg once monthly (n = 33) Mean difference from placebo 95% Cl

, -17

-17

-2l (-33, -9)

-25 (-36, -14)

Estimates based on a multiple imputation model that accounts for treatment adherence 17

PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDAapproved patient labeling [Patient Information and Instruc¬ tions for Use (IFU)] before the patient starts using REPATHA, and each time the patient gets a refill as there may be new information they need to know. Provide guidance to patients and caregivers on proper sub¬ cutaneous injection technique, including aseptic technique, and how to use the prefilled autoinjector or prefilled syringe correctly (see Instructions for Use leaflet). Inform patients that it may take up to 15 seconds to inject REPATHA. Advise latex-sensitive patients that the following compo¬ nents contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to la¬ tex; the needle cover of the glass prefilled syringe and the autoinjector. For more information about REPATHA, go to www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842). REPATHA™ (evolocumab)

Tell your healthcare provider or pharmacist about any prescription and over-the-counter medicines you are taking or plan to take, including natural or herbal remedies. .

How should I use REPATHA? • See the detailed "Instructions for Use" that comes with this patient information about the right way to prepare and give your REPATHA injections.

• Use REPATHA exactly as your healthcare provider tells you to use it. • REPATHA is given as an injection under the skin (subcutaneously), every 2 weeks or 1 time each month. • REPATHA comes as a single-use (1 time) prefilled autoinjector (SureClick* autoinjector), or as a single-use prefilled syringe. Your healthcare provider will prescribe the type and dose that is best for you.

Manufactured by:

Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License Number 1080 Patent: http://pat.amgen.com/repatha/ © 2015 Amgen Inc. All rights reserved, vl

• If your healthcare provider prescribes you the monthly dose, you will give yourself 3 separate injections in a row, using a different syringe or autoinjector for each injection. Give all of these injections within 30 minutes. • If your healthcare provider decides that you or a caregiver can give the injections of REPATHA, you or your caregiver should receive training on the right way to prepare and administer REPATHA. Do not try to inject REPATHA until you have been shown the right way by your healthcare provider or nurse.

Patient Information REPATHA™ (ri-PAth-a) (evolocumab) Injection, for Subcutaneous Injection

What is REPATHA?

REPATHA is an injectable prescription medicine called a PCSK9 inhibitor. REPATHA is used: • along with diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL) or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol. • along with diet and other LDL lowering therapies in people with homozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL), who need additional lowering of LDL cholesterol. The effect of REPATHA on heart problems such as heart attacks, stroke, or death is not known. It is not known if REPATHA is safe and effective in children with homozygous familial hypercholesterolemia (HoFH) who are younger than 13 years of age or in children who do not have HoFH. Who should not use REPATHA? Do not use REPATHA if you are allergic to evolocumab or to any of the ingredients in REPATHA. See the end of this leaflet for a complete list of ingredients in REPATHA.

What should I tell my healthcare provider before using REPATHA?

Before you start using REPATHA, tell your healthcare provider about all your medical conditions, including allergies, and if you: • are allergic to rubber or latex. The needle covers on the single-use prefilled syringes and within the needle caps on the single-use prefilled SureClick* autoinjectors contain dry natural rubber. • are pregnant or plan to become pregnant. It is not known if REPATHA will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking REPATHA. • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take REPATHA or breastfeed. You should not do both without talking to your healthcare provider first.

• Do not inject REPATHA together with other injectable medicines at the same injection site.

General information about the safe and effective use of REPATHA.

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use REPATHA for a condition for which it was not prescribed. Do not give REPATHA to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about REPATHA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about REPATHA that is written for healthcare professionals. For more information about REPATHA, go to www.REPATHA.com. or call 1-844-REPATILA (1-844-737-2842). What are the ingredients in REPATHA?

• Active Ingredient: evolocumab • Inactive Ingredients: proline, glacial acetic acid, polysorbate 80, water for injection, and sodium hydroxide. Manufactured by: Amgen Inc. One Amgen Center Drive, Thousand Oaks, California 91320-1799. Patent: http://pat.amgen.com/repatha/ ©2015 Amgen Inc. All rights reserved. This Patient Information has been approved by the U.S. Food and Drug Administration. Issue Date: August 2015 V1 Instructions for use:

• Always check the label of your autoinjector or syringe to make sure you have the correct medicine and the correct dose of REPATHA before each injection. • If you forget to use REPATHA or are not able to take the dose at the regular time, iqject your missed dose as soon as you remember, as long as there are more than 7 days until the next scheduled dose. If there are 7 days or less until your next scheduled dose, administer the next dose according to the original schedule. This will put you back on your original schedule. If you are not sure when to take REPATHA after a missed dose, ask your healthcare provider or pharmacist.

REPATHA™ (ri-PAth-a) (evolocumab) Single-Use Prefilled SureClick® Autoinjector

Guide to parts Before use

After use

Gray start button

• If you use more REPATHA than you should, talk to your healthcare provider or pharmacist. • Do not stop using REPATHA without talking with your healthcare provider. If you stop using REPATHA, your cholesterol levels can increase.

What are possible side effects of REPATHA?

REPATHA can cause side effects including: • allergic reactions. REPATHA may cause allergic reactions. Call your healthcare provider or go to the nearest hospital emergency room right away if you have any symptoms of an allergic reaction including a severe rash, redness, severe itching, a swollen face, or trouble breathing. The most common side effects of REPATHA include: runny nose, sore throat, symptoms of the common cold, flu or flu-like symptoms, back pain, and redness, pain, or bruising at the injection site. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of REPATHA. j Ask your healthcare provider or pharmacist for more information. 1 Call your healthcare provider for medical advice about side effects Yon may report side effects to FDA at I 1-800-FDA-1088.

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Yekow window (rjecfor complete) Window

Medone Yekow safety guard

Orange capon

Needle is inside

t

Orange up ok

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652/AMGEN • REPATHA

Important Before you use a Single-Use REPATHA SureClick autoinjector, read this important information:

• It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. • The orange cap on the REPATHA SureClick autoinjector contains a needle cover (located inside the cap) that contains dry natural rubber, which is made from latex. Tell your healthcare provider if you are allergic to latex. Storage of REPATHA:

• Keep the REPATHA SureClick autoinjector in the original carton to protect from light during storage. • Keep the REPATHA SureClick autoiryector in the refrigerator between 36°F to 46°F (2°C to 8°C). • If removed from the refrigerator, the REPATHA SureClick autoinjector should be kept at room temperature up to 77°F (25°C) in the original carton and must be used within 30 days. • Do not freeze the REPATHA SureClick autoinjector or use a REPATHA SureClick autoinjector that has been frozen.

Do not use the autoinjector if any part appears cracked or broken. Do not use the autoinjector if the autoinjector has been dropped. Do not use the autoinjector if the orange cap is missing or not securely attached. In all cases, use a new autoinjector, and call 1-844-REPATHA (1-844-737-2842).

1

c

2 B

Stretch or pinch your injection site to create a firm surface.

Thigh. Stretch method

Gather all materials needed for your injection.

Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the: • 1 new autoinjector • Alcohol wipes • Cotton ball or gauze pad • Adhesive bandage • Sharps disposal container (see Step 4: Finish)

Stretch skin firmly by moving your thumb and fingers in opposite directions, creating an area about 2 inches wide. or Stomach or upper arm: Pinch method

Do not: • Do not shake the REPATHA SureClick autoinjector. • Do not remove the orange cap from the REPATHA

SureClick autoinjector until you are ready to inject. • Do not use the REPATHA SureClick autoinjector if it

has been dropped on a hard surface. Part of the REPATHA SureClick autoinjector may be broken even if you cannot see the break. Use a new REPATHA SureClick autoinjector, and call 1-844-REPATHA (1-844-737-2842). • Do not use the REPATHA SureClick autoinjector after the expiration date. A healthcare provider who knows how to use the REPATHA SureClick autoinjector should be able to answer your questions. For more information, call 1-844-REPATHA (1-844-737-2842) or visit www.EEPATHA.com Keep the REPATHA SureClick autoinjector out of the sight and reach of children.

Pinch skin firmly between your thumb and fingers, creating an area about 2 inches wide. It is important to keep skin stretched or pinched while injecting.

Step 3: Inject 3 A

Hold the stretch or pinch. With the orange cap off, place autoinjector on skin at 90 degrees. Do not touch the gray start button yet.

3 B

Firmly push down autoiqjector onto skin until it stops moving.

Step 1: Prepare 1 A

Remove one REPATHA SureClick autoinjector from the package.

Carefully lift the autoinjector straight up out of the box. Put the original package with any unused autoinjectors back in the refrigerator. Wait at least 30 minutes for the autoinjector to reach room temperature before injecting.

You can use:

• Thigh • Stomach (abdomen), except for a 2 inch area around your belly button If someone else is giving you the injection, they can also use the outer area of the upper arm.

This is important for administering the entire dose and helps minimize discomfort. REPATHA may take longer to inject if it has not reached room temperature. Do not heat the autoinjector. Let it warm up on its own.

Clean your injection site with an alcohol wipe. Let your skin dry. Do not touch this area again before injecting. Choose a different site each time you give yourself an injection. If you need to use the same injection site, just make sure it is not the same spot on that site you used last time. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.

'l

f

You must push all the way down but do not touch the gray start button until you are ready to inject.

Do not try to warm the autoinjector by using a heat

source such as hot water or microwave. Do not leave the autoinjector in direct sunlight.

Step 2: Get ready

Do not shake the autoinjector. Do not remove the orange cap from the autoinjector

yet.

1 B

2 A

Pull the orange cap straight off when you are ready to inject.

3 C

Inspect the REPATHA SureClick autoinjector.

Check the expiration date: do not use if this date has passed. Make sure the medicine in the window is clear and colorless to slightly yellow Do not use the autoinjector if the medicine is cloudy or discolored or contains particles.

It is normal to see a drop of liquid at the end of the needle or yellow safety guard Do not twist, bend, or wiggle the orange cap. Do not put the orange cap back onto the autoinjector. Do not put fingers into the yellow safety guard. Do not remove the orange cap from the autoinjector until you are ready to inject.

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When you are ready to inject, press the gray start button. You will hear a click.

Look for PDR drug information and services in your EHR 3 D

Keep pushing down on skin. Then lift your thumb. Your injection could take about 15 seconds. The time required for injection to give the entire dose may be longer than for other injectable medicines.

REPATHA • AMGEN/653 4 B

Check the injection site. instructions for use:

If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if needed. Do not rub the injection site.

REPATHA™ (ri-PAth-a) (evolocumabl * Single-Use Prefilled Syringe

Commonly Asked Questions

Guide to parts

What will happen if I press the gray start button before I am ready to do the injection on my skin?

Before use

You can lift your finger up off the gray start button and place the prefilled autoinjector back on your injection site. Then, you can push the gray start button again.

After use

Plunger rod

Used plunger

hear a 2m click. NOTE: After you remove the autoinjector from your skin, the needle will be automatically covered.

Can I move the autoinjector around on my skin while I am choosing an injection site?

Used syringe barrel

It is okay to move the autoinjector around on the injection site as long as you do not press the gray start button. However, if you press the gray start button and the yellow safety guard is pushed into the autoinjector, the injection will begin.

Medicine

Can I release the gray start button after I start my

Syringe barrel

injection?

You can release the gray start button, but continue to hold the autoinjector firmly against your skin during the injection.

Used Needle

Step 4: Finish 4 A

Throw away the used autoinjector and orange needle cap.

Gray needle cap on

Will the gray start button pop up after I release my thumb?

Do not reuse the autoinjector. Do not recap the autoinjector or put fingers into the

yellow safety guard.

Gray needle cap off

The gray start button may not pop up after you release your thumb if you held your thumb down during the injection. This is okay.

Needle is inside Needle is inside

What do I do if I did not hear a second click?

If you did not hear a second click, you can confirm a complete injection by checking that the window has turned yellow.

Important Before you use a Single-Use REPATHA Prefilled Syringe, read this important information:

• Put the used autoinjector and orange needle cap in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the autoinjector or orange cap in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, t> can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use. o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www fda.gov/ safesharpsdisposal Keep the autoinjector and the sharps disposal container out of the sight and reach of children.

Whom do I contact if I need help with the autoinjector or

• It is important that you do not try to give yourself or someone else the injection unless you have received training from your healthcare provider. • The gray needle cap on the REPATHA prefilled syringe contains dry natural rubber, which is made from latex. Tbll your healthcare provider if you are allergic to latex.

my injection?

Storage of REPATHA:

A healthcare provider familiar with REPATHA should be able to answer your questions. For more information, call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Amgen Inc. Thousand Oaks, CA 91320-1799 © 2015 Amgen Inc. All rights reserved. Issued: 08/2015 vl Welcome!

The REPATHA single-use prefilled SureClick autoinjector contains one 140 mg dose of REPATHA. Your healthcare provider has prescribed REPATHA as part of your treatment. Your healthcare provider will tell you how much REPATHA you need and how often it should be injected. Each REPATHA prefilled SureClick autoiqjector can only be used one time. Side 2 of this sheet contains information on how to give an injection of REPATHA. It is important that you do not try to give the injection unless you have received training from your healthcare provider. Please read all of the instructions on side 2 before using the REPATHA SureClick autoinjector.

• Keep the REPATHA prefilled syringe in the original carton to protect from light during storage. • Keep the REPATHA prefilled syringe in the refrigerator between 36°F to 46°F (2°C to 8°C). • If removed from the refrigerator, the REPATHA prefilled syringe should be kept at room temperature up to 77°F (25°C) in the original carton and must be used within 30 days. • Do not freeze the REPATHA prefilled syringe or use a REPATHA prefilled syringe that has been frozen. Do not:

• Do not use the REPATHA prefilled syringe if the packaging is open or damaged • Do not remove the gray needle cap from the REPATHA prefilled syringe until you are ready to inject. • Do not use the REPATHA prefilled syringe if it has been dropped onto a hard surface. Part of the REPATHA prefilled syringe may be broken even if you cannot see the break. Use a new REPATHA prefilled syringe, and call 1-844-REPATHA (1-844-737-2842). • Do not use the REPATHA prefilled syringe after the expiration date. A healthcare provider who knows how to use the REPATHA prefiUed syringe should be able to answer your questions. For more information, call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com. Keep the REPATHA prefilled syringe out of the sight and reach of children.

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654/AMGEN • REPATHA

1 D

Step 1: Prepare 1 A

It is normal to see a drop of medicine at the end of the needle.

Clean your injection site.

Remove the REPATHA prefilled syringe carton from the refrigerator and wait 30 minutes.

Place the cap in the sharps disposal container right away.

Do not twist or bend the gray needle cap. This can damage the needle.

Wait at least 30 minutes for the prefilled syringe ip the carton to reach room temperature before injecting.

Do not put the gray needle cap back onto the prefilled syringe. .

Do not try to remove any air bubbles in the syringe before the injection.

Clean your injection site with an alcohol wipe. Let your skin dry before injecting. Do not touch this area of skin again before injecting. 1 E

Remove prefilled syringe from tray. Turn tray over

This is important for administering the entire dose and helps minimize discomfort. REPATHA may take longer to inject if it has not reached room temperature. Do not heat the syringe. Let it warm up on its own.

2 B

Pinch your injection site to create a firm surface.

Gently Press

Check that the name REPATHA appears on the carton label. Do not try to warm the REPATHA prefilled syringe by using a heat source such as hot water or microwave. Do not leave the REPATHA prefilled syringe in direct sunlight. Do not shake the REPATHA prefilled syringe.

I 1 B

Gather all materials needed for your injection.

Wash your hands thoroughly with soap and water.

lb remove: • Peel paper off of tray. • Place the tray on your hand. • Turn the tray over and gently press the middle of the tray’s back to release the syringe into your palm. • If prefilled syringe does not release from tray, gently press on back of tray Do not pick up or pull the prefilled syringe by the plunger rod or gray needle cap. This could damage the syringe. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. Always hold the prefilled syringe by the syringe barrel.

Pinch skin firmly between your thumb and fingers, creating an area about 2 inches wide. It is important to keep the skin pinched while injecting.

On a clean, well-lit, flat work surface, place:

A >

• 1 REPATHA prefilled syringe in carton • Alcohol wipes • Cotton ball or gauze pad • Adhesive bandage • Sharps disposal container (see Step 4: Finish)

1 F

Check the medicine and syringe.

Plungor rod

Check the expiration date on the REPATHA prefilled syringe carton: do not use if this date has passed.

Syringe barrel

i'

mi

‘1

\ tar oG •

u

Syringe label with expiration date Gray needle cap on

i—i

Step 3: Inject 3 A

Medicine

Hold the pinch. Insert the needle into skin using a 45 to 90 degree angle.

Always hold the prefilled syringe by the syringe barrel. Check that:

1 C

• the name REPATHA appears on the prefilled syringe label. • the medicine in the prefilled syringe is clear and colorless to slightly yellow. • the expiration date on the prefilled syringe has not passed. If the expiration date has passed, do not use the prefilled syringe. Do not use the prefilled syringe if any part of the prefilled syringe appears cracked or broken. Do not use the prefilled syringe if the gray needle cap is missing or not securely attached. Do not use the prefilled syringe if the medicine is cloudy or discolored or contains particles. In any above cases, use a new prefilled syringe and call 1-844-REPATHA (1-844-737-2842) or visit www.REPATHA.com.

Choose your injection site.

Do not place your finger on the plunger rod while inserting the needle.

3 B

Using slow and constant pressure, push the plunger rod all the way down until the syringe is empty. You may have to push harder on the plunger than for other injectable medicines.

3 C

When done, release vour thumb, and gently lift the syringe off skin.

Step 2: Get ready

2 A

You can use:

• Thigh • Stomach (abdomen), except for a 2 inch area around your belly button

Carefully pull the gray needle cap straight out and away from your body.

If someone else is giving you the injection, they can also use the outer area of the upper arm.

Do not choose an area where the skin is tender, bruised, red. or hard Avoid injecting into areas with scars or stretch marks. Choose a different site each time you give yourself an injection. If you need to use the same injection site, just make sure it is not the same spot on that site vou used last time

1*

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Do not put the gray needle cap back onto the used syringe.

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NEXAVAR • BAYER/655

Bayer Healthcare LLC Step 4: Finish 4 A

1.3 Differentiated Thyroid Carcinoma

2

100 BAYER BOULEVARD WHIPPANY, NJ 07981

DOSAGE AND ADMINISTRATION 2.1 Recommended Dose for Hepatocellular Carci¬ noma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma 2.2 Dose Modifications for Suspected Adverse Drug Reactions

Place the used syringe in a sharps disposal container right away. Direct Inquiries to:

Phone: 1-888-84-BAYER (1-888-842-2937) http//www.bayerhealthcare.com

3 4 5

For Medical Information contact:

Vice President, Medical Communications 1-888-84-Bayer (1-888-842-2937)

DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Risk of Cardiac Ischemia and/or Infarction 5.2 Risk of Hemorrhage 5.3 Risk of Hypertension 5.4 Risk of Dermatologic Tbxicities 5.5 Risk of Gastrointestinal Perforation 5.6 Warfarin 5.7 Wound Healing Complications 5.8 Increased Mortality Observed with NEXAVAR Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer 5.9 Risk of QT Interval Prolongation 5.10 Drug-Induced Hepatitis 5.11 Embryofetal Risk 5.12 Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma

NEXAVAR® (sorafenib) tablets, oral HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NEXAVAR safely and effectively. See full prescribing information for NEXAVAR. NEXAVAR (sorafenib) tablets, oral

Do not reuse the used syringe.

Initial U.S. Approval: 2005

Do not use any medicine that is left in the used

syringe. • Put the used syringe in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the syringe in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/ safesharpsdisposal Keep the used syringe and sharps container out of the sight and reach of children.

Check the injection site. If there is blood, press a cotton ball or gauze pad on your injection site. Apply an adhesive bandage if needed. Do not rub the injection site.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

-INDICATIONS AND USAGENEXAVAR is a kinase inhibitor indicated for the treatment of • Unresectable hepatocellular carcinoma (1.1) • Advanced renal cell carcinoma (1.2) • Locally recurrent or metastatic, progressive, differenti¬ ated thyroid carcinoma refractory to radioactive iodine treatment (1.31

6

ADVERSE REACTIONS 6.1 6.2 6.3 6.4 6.5

-DOSAGE AND ADMINISTRATION• 400 mg (2 tablets) orally twice daily without food. (2.1) • Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug reactions. (2.2)

DRUG INTERACTIONS

7

7.1 Effect of Strong CYP3A4 Inducers on Sorafenib 7.2 Effect of Strong CYP3A4 Inhibitors on Sorafenib 7.3 Effect of Sorafenib on Other Drugs 7.4 Neomycin 7.5 Drugs that Increase Gastric pH

-DOSAGE FORMS AND STRENGTHS200 mg Tablets (3)

-CONTRAINDICATIONS• NEXAVAR is contraindicated in patients with known se¬ vere hypersensitivity to sorafenib or any other component of NEXAVAR. (4) • NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. (4)

8

USE IN SPECIFIC POPULATIONS 8.1 8.3 8.4 8.5 8.6 8.7

-WARNINGS AND PRECAUTIONS• Cardiac Ischemia and/or Infarction: Consider temporary or permanent discontinuation of NEXAVAR. (5.1) • Bleeding: Discontinue NEXAVAR if needed. (5.2) • Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. (5.3) • Dermatologic Toxicities: Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected. (5.4) • Gastrointestinal Perforation: Discontinue NEXAVAR. (5.5) • QT Prolongation: Monitor electrocardiograms and electro¬ lytes in patients at increased risk for ventricular arrhyth¬ mias. (5.9, 12.2) • Drug-Induced Hepatitis: Monitor liver function tests reg¬ ularly; discontinue for unexplained transaminase eleva¬ tions. (5.10) • Embryofetal Tbxicity: Advise women of potential risk to fe¬ tus and to avoid becoming pregnant. (5.11, 8.11 • Impairment of TSH suppression in DTC: Monitor TSH monthly and adjust thyroid replacement therapy in pa¬ tients with thyroid cancer. (5.12)

Adverse Reactions in HCC Study Adverse Reactions in RCC Study 1 Adverse Reactions in DTC Study Additional Data from Multiple Clinical Trials Postmarketing Experience

10 11 12

Pregnancy Nursing Mothers Pediatric Use Geriatric Use Patients with Hepatic Impairment Patients with Renal Impairment

OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 12.2 12.3

13

Mechanism of Action Pharmacodynamics Pharmacokinetics

NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14

CLINICAL STUDIES 14.1 14.2 14.3

16 17

Hepatocellular Carcinoma Renal Cell Carcinoma Differentiated Thyroid Carcinoma

HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the fulj prescribing information are not listed. FULL PRESCRIBING INFORMATION

Manufactured by: Amgen Inc. Thousand Oaks, CA 91320-1799 © 2015 Amgen Inc. All rights reserved. 20%) for NEXAVAR are diarrhea, fatigue, infection, alopecia, hand-foot skin re¬ action, rash, weight loss, decreased appetite, nausea, gas¬ trointestinal and abdominal pains, hypertension, and hem¬ orrhage. (6)

Welcome!

The REPATHA single-use prefilled syringe contains one 140 mg dose of REPATHA. Your healthcare provider has prescribed REPATHA as part of your treatment. Your healthcare provider will tell you how much REPATHA you need and how often it should be injected. Each REPATHA prefilled syringe can only be used one time. Side 2 of this sheet contains information on how to give an injection of REPATHA. It is important that you do not try to give the injection unless you have received training from your healthcare provider Please read all of the instructions on

To report SUSPECTED ADVERSE REACTIONS, contact Bayer Healthcare Pharmaceuticals Inc. at 1-888-842-2937, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

-DRUG INTERACTIONS• Avoid strong CYP3A4 inducers (7.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 7/2015

1

Shown in Product Identification Guide, page 305

INDICATIONS AND USAGE Hepatocellular Carcinoma

NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.2

Renal Cell Carcinoma

NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 1.3

Differentiated Thyroid Carcinoma

NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive io¬ dine treatment. 2

DOSAGE AND ADMINISTRATION

2.1 FULL PRESCRIBING INFORMATION: CONTENTS*

side 2 before using the REPATHA prefilled syringe

1 1.1

INDICATIONS AND USAGE 1.1 Hepatocellular Carcinoma 1.2 Renal Cell Carcinoma

Renal

Recommended Dose for Hepatocellular Carcinoma, Cell

Carcinoma,

and

Differentiated

Thyroid

Carcinoma

The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily withuut food (at least

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656/BAYER • NEXAVAR Table 1:

Suggested Dose Modifications for Dermatologic Toxicities in Patients with Hepatocellular or Renal Cell Carcinoma

Dermatologic Toxicity Grade

Occurrence

Suggested Dose Modification

Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities

Any occurrence

Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief

Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities

Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living

tients and 9.6% of placebo-treated patients; however the in¬ cidence of CTCAE Grade 3 bleeding was 1% in NEXAVARtreated patients and 1.4% in placebo-treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If any bleed¬ ing necessitates medical intervention, permanent discon¬ tinuation of NEXAVAR should be considered. Due to the po¬ tential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to ad¬ ministering NEXAVAR in patients with DTC. 5.3

l"1 occurrence

Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief If no improvement within 7 days, see below

No improvement within 7 days or 2nd or 3rd occurrence

Interrupt NEXAVAR treatment until toxicity resolves to Grade 0-1 When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)

4th occurrence

Discontinue NEXAVAR treatment

T* or 2nd occurrence

Interrupt NEXAVAR treatment until toxicity resolves to Grade 6-1 When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)

3rd occurrence

Discontinue NEXAVAR treatment

5.4 Table 2:

Recommended Doses for Patients with Differentiated Thyroid Carcinoma Requiring Dose Reduction

Dose Reduction

NEXAVAR Dose

First Dose Reduction

600 mg daily dose

400 mg and 200 mg 12 hours apart (2 tablets and 1 tablet 12 hours apart - either dose can come first)

Second Dose Reduction

400 mg daily dose

200 mg twice daily (1 tablet twice daily)

Third Dose Reduction

200 mg daily dose

200 mg once daily (1 tablet once daily)

I

I hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. 2.2 Dose Modifications for Suspected Adverse Drug Reactions

Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures [see Warn¬ ings and Precautions (5.7)1. Temporary interruption or permanent discontinuation of NEXAVAR may be required for the following: • Cardiac ischemia or infarction /see Warnings and Precau¬ tions (5.1)1 • Hemorrhage requiring medical intervention Isee (Warn¬ ings and Precautions (5.2)] • Severe or persistent hypertension despite adequate antihypertensive therapy Isee Warnings and Precautions (5.3)1 • Gastrointestinal perforation [see Warnings and Precau¬ tions (5.5)1 • QTc prolongation Isee Warnings and Precautions (5.9)1 • Severe drug-induced liver injury [see Warnings and Pre¬ cautions (5.10)J Dose modifications for Hepatocellular Carcinoma and Renal Cell Carcinoma When dose reduction is necessary, the NEXAVAR dose may be reduced to 400 mg once daily. If additional dose reduction is required, NEXAVAR may be reduced to a single 400 mg dose every other day Isee Warnings and Precautions (5)1. Suggested dose modifications for dermatologic toxicities are outlined in Table 1. [See table 1 above) Dose modifications for Differentiated Thyroid Carcinoma ISee table 2 above] When dose reduction is necessary for dermatologic toxici¬ ties, reduce the NEXAVAR dose as indicated in Table 3 below. (Set* table 3 at top of next pagel Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0-1 after at least 28 days of treatment on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased one dose level from the reduced dose. Approxi¬ mately 50‘S of patients requiring a dose reduction for der¬ matologic toxicity are expected to meet these criteria for re¬ sumption of the higher dose and roughly 50'S of patients resuming the previous dose are expected to tolerate the higher dots* ithat is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity)

3

DOSAGE FORMS AND STRENGTHS

Tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib. NEXAVAR tablets are round; biconvex, red film-coated tab¬ lets, debossed with the “Bayer cross” on one side and “200” on the other side. 4

CONTRAINDICATIONS

• NEXAVAR is contraindicated in patients with known se¬ vere hypersensitivity to sorafenib or any other component of NEXAVAR. • NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions (5.8)1 5 5.1

WARNINGS AND PRECAUTIONS Risk of Cardiac Ischemia and/or Infarction

Risk of Hypertension

Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hy¬ pertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institu¬ tion of antihypertensive therapy, consider temporary or per¬ manent discontinuation of NEXAVAR. Permanent discon¬ tinuation due to hypertension occurred in 1 of 297 NEXAVAR-treated patients in the HCC study, 1 of 451 NEXAVAR-treated patients in RCC Study 1, and 1 of 207 NEXAVAR-treated patients in the DTC study. Risk of Dermatologic Toxicities

Hand-foot skin reaction and rash represent the most com¬ mon adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with NEXAVAR. Management of dermatologic toxicities may include topical therapies for symptomatic relief, tem¬ porary treatment interruption and/or dose modification of NEXAVAR, or in severe or persistent cases, permanent dis¬ continuation of NEXAVAR /see Dosage and Administration (2.2)]. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 NEXAVAR-treated patients with HCC, 3 (0.7%) of 451 NEXAVAR-treated patients with RCC, and 11 (5.3%) of 207 NEXAVAR-treated patients with DTC. There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epi¬ dermal necrolysis (TEN). These cases may be lifethreatening. Discontinue NEXAVAR if SJS or TEN are suspected. 5.5

Risk of Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon adverse reac¬ tion and has been reported in less than 1% of patients tak¬ ing NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastroin¬ testinal perforation, discontinue NEXAVAR. 5.6

Warfarin

Infrequent bleeding or elevations in the International Nor¬ malized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients tak¬ ing concomitant warfarin regularly for changes in pro¬ thrombin time (PTt, INR or clinical bleeding episodes. 5.7

Wound Healing Complications

In the HCC study, the incidence of cardiac ischemia/ No formal studies of the effect of NEXAVAR on wound heal¬ infarction was 2.7% in NEXAVAR-treated patients com¬ ing have been conducted Temporary interruption of pared with 1.3% in the placebo-treated group, in RCC Study NEXAVAR is recommended in patients undergoing major 1, the incidence of cardiac ischemia/infarction was higher in surgical procedures. There is limited clinical experience re¬ the NEXAVAR-treated group 12.9%) compared with the garding the timing of reinitiation of NEXAVAR following placebo-treated group (0.4%), and in the DTC study, the in¬ major surgical intervention. Therefore, the derision to re¬ cidence of cardiac ischemia/infarction was 1.9% in the sume NEXAVAR following a major surgical intervention NEXAVAR-treated group compared with 0% in the placeboshould be based on clinical judgment of adequate wound treated group. Patients with unstable coronary artery dis¬ | healing. ease or recent myocardial infarction were excluded from 5.8 Increased Mortality Observed with NEXAVAR this study. Temporary or permanent discontinuation of Administered in Combination with Carboplatin/Paclitaxel NEXAVAR should be considered in patients who develop and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer cardiac ischemia and/or infarction. In a subset analysis of two randomized controlled trials in 5.2 Risk of Hemorrhage chemo-naive patients with Stage II1B-IV non-small cell An increased risk of bleeding may occur following lung cancer, patients with squamous cell carcinoma experi¬ NEXAVAR administration. In the HCC study, an excess of enced higher mortality with the addition of NEXAVAR com¬ bleeding regardless of causality was not apparent and the part'd to those treated with carboplatin/paclitaxel alone (HR rate of bleeding from esophageal varices was 2.4%' in 1.81. 95% Cl 1.19-2.74) and gemcitabine/cisplatin alone NEXAVAR-treated patients and 4% in placebo-treated pa¬ (HR 1.22, 95% Cl 0.82-1.801 The use of NEXAVAR in com¬ tients. Bleeding with a fatal outcome from any site was re¬ bination with carboplatin/paclitaxel is contraindicated in ; ported in 2.4% of NEXAVAR-treated patients and 4% in patients with squamous cell lung cancer. NEXAVAR in com¬ 1 placebo-treated patients. In RCC Study 1, bleeding regard¬ bination with gemcitabine/cisplatin is not recommended m less of causality was reported in 15.3% of patients in the patients with squamous cell lung cancer. The safety and ef¬ NEXAVAR-treated group and 8.2% of patients in the fectiveness of NEXAVAR has not been established in pa¬ placebo-treated group. The incidence of CTCAE Grade 3 tients with non-small cell lung cancer. and 4 bleeding was 2% and 0%, respectively, in NEXAVAR5.9 Risk of QT Interval Prolongation treated patients, and 1.3% and 0.2%, respectively, in NEXAVAR can prolong the QT/QTc interval. QT/QTc inter¬ placebo-treated patients. There was one fatal hemorrhage val prolongation increases the risk for ventricular arrhythin each treatment group in RCC Study 1. In the DTC study, mias.Avoid NEXAVAR in patients with congenital long QT bleeding was reported in 17.4% of NEXAVAR-treated pa¬ syndrome. Monitor electrolytes and electrocardiograms in

Sign up at PDR.net/reaistration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR patients with congestive heart failure, bradyarrhythmias. drugs known to prolong the QT interval, including Class la and 111 antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an in¬ crease from baseline of 60 milliseconds or greater [see Clin¬ ical Pharmacology (12.2)]. 5.10 Drug-Induced Hepatitis Sorafenib-induced hepatitis is characterized by a hepatocel¬ lular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur The incidence of severe drug-induced liver injury, defined as el¬ evated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clini¬ cal sequelae (for example, elevated INR, ascites, fata), or transplantation), was two of 3,357 patients (0.06*77) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue NEXAVAR. 5.11 Embryofetal Risk Based on its mechanism of action and findings in animals, NEXAVAR may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing poten¬ tial to avoid becoming pregnant while on NEXAVAR be¬ cause of the potential hazard to the fetus /sec Use in Specific Populations (8.1)]. 5.12 Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma NEXAVAR impairs exogenous thyroid suppression. In the DTC study, 99% of patients had a baseline thyroid stimulat¬ ing hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving NEXAVAR, the median maxi¬ mal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replace¬ ment medication as needed in patients with DTC.

6

ADVERSE REACTIONS

The following serious adverse reactions are discussed else¬ where in the labeling: • Cardiac ischemia, infarction /see Warnings and Precau¬ tions (5.1)] • Hemorrhage/see Warnings and Precautions (5.2)] • Hypertension /see Warnings and Precautions (5.3)] • Hand-foot skin reaction, rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis /see Warnings and Precau¬ tions (5.4)] • Gastrointestinal perforation /see Warnings and Precau¬ tions (5.5)] • QT Interval Prolongation /see Warnings and Precautions (5.9) and Clinical Pharmacology (12.2)] • Drug-Induced Hepatitis /see Warnings and Precautions (5.101] • Impairment of TSH suppression in DTC /see Warnings and Precautions (5.12)1 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in sections 6.1. 6.2 and 6.3 reflect ex¬ posure to NEXAVAR in 955 patients who participated in placebo controlled studies in hepatocellular carcinoma (N'=297l. advanced renal cell carcinoma (N=451), or differ¬ entiated thyroid carcinoma (N = 207). The most common adverse reactions (£20%), which were -, considered to be related to NEXAVAR, in patients with HCC, RCC or DTC are diarrhea, fatigue, infection, alope¬ cia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. 6.1 Adverse Reactions in HCC Study Table 4 shows the percentage of patients with HCC experi¬ encing adverse reactions that were reported in at least 10% of patients and at a higher rate1 in the NEXAVAR arm than the placebo arm. CTCAK Grade 3 adverse reactions were reported in 39% of patients receiving NEXAVAR compared to 24% of patients receiving placebo. CTCAE Grade 4 ad¬ verse reactions were reported in 6% of patients receiving NEXAVAR compared to 8% of patients receiving placebo. [See table 4 at top of next pagel Hypertension was reported in 9% of patients treated with NEXAVAR and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of NEXAVARtreated patients and 1% of placebo-treated patients. No pa¬ tients were reported with CTCAE Grade 4 reactions in ei¬ ther treatment group.

NEXAVAR • BAYER/657 Table 3: Recommended Dose Modifications for Dermatologic Toxicities for Patients with Differentiated Thyroid Carcinoma Dermatologic Toxicity Grade

Occurrence

NEXAVAR Dose Modification

Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities

Any occurrence

Continue treatment with NEXAVAR

Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities

1“' occurrence

Decrease NEXAVAR dose to 600 mg daily If no improvement within 7 days, see below

No improvement within 7 days at reduced dose or 2“doccurrence

Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose (see Table 2)

3"' occurrence

Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose (see Table 2)

4th occurrence

Discontinue NEXAVAR permanently

1" occurrence

Interrupt NEXAVAR until resolved or improved to grade 1 If NEXAVAR is resumed, decrease dose by one dose level (see Table 2)

2nd occurrence

Interrupt NEXAVAR until resolved or improved to grade 1 When NEXAVAR is resumed, decrease dose by 2 dose levels (see Table 2)

3rd occurrence

Discontinue NEXAVAR permanently

Grade 3: Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living

Hemorrhage/bleeding was reported in 18% of those receiv¬ ing NEXAVAR and 20% of placebo-treated patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo-treated group (CTCAE Grade 3 - 3% NEXAVAR and 5% placebo and CTCAE Grade 4 - 2% NEXAVAR and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in NEXAVAR-treated patients and 4% of placebotreated patients. Renal failure was reported in 10 g/dL. Before subsequent admin¬ istrations of Xofigo, the ANC should be > 1 x 109/L and the platelet count > 50 x 10fl/L. If there is no recovery to these values Within 6 to 8 weeks after the last administration'of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who ex¬ perience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody ex¬ ternal radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label; • Bone Marrow Suppression [see Warnings and Precautions (5.1)] 6.1

XOFIGO • BAYER/671 Table 3; Adverse Reactions in the Randomized Trial System/Organ Class

Xofigo (n=600)

Placebo (n=301)

Preferred Term Grades 1-4

Grades 3-4 %

Grades 1-4’

Grades 3-4

%

%

%

2

1

0

0

Nausea

36

2

35

2

Diarrhea

25

2

15

2

Vomiting

' 19

2

14

2

13

2

10

1. ■

3

1

Blood and lymphatic system disorders

Pancytopenia Gastrointestinal disorders

General disorders and administration site conditions

Peripheral edema Renal and urinary disorders

Renal failure and impairment

lH

Table 4: Hematologic Laboratory Abnormalities Hematologic Laboratory

Xofigo (n=600)

Placebo (n =301)

Abnormalities Grades 1-4

Grades 3-4

Grades 1-4

Grades 3-4

%

%

%

%

Anemia

93

6

88

6

Lymphocytopenia

72

20

53

7

Leukopenia

35

3

10

20 lesions or a superscan. Opiate pain medica¬ tions were used for cancer-related pain in 54% of patients, non-opiate pain medications in 44% of patients and no pain medications in 2% of patients. Patients were stratified by baseline ALP, bisphosphonate use, and prior docetaxel ex¬ posure. Prior bisphosphonates were used by 41% of patients and 58% had received prior docetaxel. During the treatment period, 83% of Xofigo patients and 82% of placebo patients received gonadotropin-releasing hormone agonists and 21% of Xofigo patients and 34% of placebo patients received con¬ comitant antiandrogens. Use of systemic steroids (41%) and bisphosphonates (40%) was balanced between the arms. The pre-specified interim analysis of overall survival re¬ vealed a statistically significant improvement in patients receiving XOFIGO plus best standard of care compared with patients receiving placebo plus best standard of care. An exploratory updated overall survival analysis performed before patient crossover with an additional 214 events re¬ sulted in findings consistent with the interim analysis (Ta¬ ble 5).

12.6

Subjects randomized Number of deaths Censored Median survival (months)* (95% Cl) p-value* Hazard ratio (95% CD*

Cardiac Electrophysiology

The effect of a single dose of 50 kBq/kg of radium-223 dichloride on the QTc interval was evaluated in a subgroup of 29 patients (21 received Xofigo and 8 received placebo) in the randomized clinical trial. No large changes in the mean QTc interval (i.e., greater than 20 ms) were detected up to 6 hours post-dose. The potential for delayed effects on the QT • interval after 6 hours was not evaluated.

13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis. Mutagenesis, Impairment of Fer¬

tility

Animal studies have not been conducted to evaluate the car¬ cinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clini¬ cally relevant doses 7 to 12 months after the start of treat¬ ment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also re¬ ported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the ef¬ fects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and repro¬ ductive function in humans based on its mechanism of ac¬ tion.

14

CLINICAL STUDIES

The efficacy and safety of Xofigo were evaluated in a double¬ blind, randomized, placebo-controlled phase 3 clinical trial of patients with castration-resistant prostate cancer with symptomatic bone metastases. Patients with visceral me¬ tastases and malignant lymphadenopathy exceeding 3 cm were excluded. The primary efficacy endpoint was overall survival. A key secondary efficacy endpoint was time to first symptomatic skeletal event (SSE) defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical in¬ tervention. There were no scheduled radiographic assess¬ ments performed on study. All patients were to continue an¬ drogen deprivation therapy. At the cut-off date of the pre¬ planned interim analysis, a total of 809 patients had been randomized 2:1 to receive Xofigo 50 kBq (1.35 microcur¬ ie )/kg intravenously every 4 weeks for 6 cycles (n = 541) plus best standard of care or matching placebo plus best stan¬ dard of care (n = 268). Best standard of care included local EBRT, corticosteroids, antiandrogens, estrogens, estramustine or ketoconazole. Therapy was continued until unaccept¬ able toxicity or initiation of cytotoxic chemotherapy, other systemic radioisotope, hemi-body EBRT or other investiga¬ tional drug. Patients with Crohn’s disease, ulcerative coli¬ tis, prior hemibody radiation or untreated imminent spinal cord compression were excluded from the study. In patients with bone fractures, orthopedic stabilization was performed before starting or resuming treatment with Xofigo. The following patient demographics and baseline disease characteristics were balanced between the arms. The me¬ dian age was 71 (range 44-94) with a racial distribution of 94% Caucasian, 4% Asian, 2% Black and 175 U/L)

8%

4%

Alkaline Phosphatase 0550 U/L)

1%

0%

AST (M: >180 U/L) (F: >170 U/L)

3%

3%

ALT (M: >215 U/L) (F: >170 U/L)

2%

3%

Hemoglobin (250 mg/dL)

2%

1%

Hematuria (>75 RBC/HPF)

3%

2%

Glycosuria (>3+)

4-4

300 mg qd x 14 days

600 mg qd x 14 days

11

40 kg, receiving the 600 mg dose of efa¬ virenz, Cmax was 6.57 pg/mL, Cmin was 2.82 pg/mL, and AUC(0_24| was 254.78 pM*hr. Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HTV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) C^, and AUC were 2.7 ± 0.9 pg/mL and 12.6 ± 5.4 pg*hr/mL. respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiv¬ ing a once daily dose of 200 mg. Tenofovir Disoproxil Fumarate: Steady-state pharmacoki¬ netics of tenofovir were evaluated in 8 HIV-1 infected pedi¬ atric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 pg/mL and 3.39 ± 1.22 pg*hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg. Geriatric Patients Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [See Use in Specific Populations (8.5)]. Patients with Impaired Renal Function Efavirenz: The pharmacokinetics of efavirenz have not been studied in subjects with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elim¬ ination should be minimal. Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are al¬ tered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min. and AUC0_of emtricitabine and tenofovir were increased /See Warnings and Precautions (5.7)]., Patients with Hepatic Impairment Efavirenz: A multiple-dose trial showed no significant ef¬ fect on efavirenz pharmacokinetics in subjects with mild he¬ patic impairment (Child-Pugh Class A) compared with con¬ trols. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics [See Warnings and Precautions (5.10) and Use in Specific Populations (8.6)]. Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected subjects with moderate to se¬ vere hepatic impairment. There were no substantial altera¬ tions in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions The drug interaction trials described were conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents, no drug interaction trials have been conducted us¬ ing ATRIPLA 'efavirenz/emtncitabine/U-nofovir disoproxil fumarate).

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Efavirenz: The steady-state pharmacokinetics of efavirenz and tenofovir were unaffected when efavirenz and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction trials have not been per¬ formed with efavirenz and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interac¬ tions would not be expected based on NRTIs elimination pathways. Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with K, values (8.5—17 pMl in the range of observed efavirenz plasma concentrations. In in vitro studies, efa¬ virenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K, values 82-160 pM) only at concentrations well above those achieved clinically. Coadministration of efa¬ virenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in al¬ tered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction trials were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between efa¬ virenz and zidovudine, lamivudine, azithromycin, flucon¬ azole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on efavirenz exposures. The ef¬ fects of coadministration of efavirenz on Cm„, AUC, and Cn„„ are summarized in Table 5 (effect of other drugs op efa¬ virenz) and Table 6 (effect of efavirenz on other drugs). For information regarding clinical recommendations see Drug Interactions (7). [See table 5 on previous page and abovel [See table 6 on pages 682 through 684] Emtricitabine and Tenofovir Disoproxil Fumarate: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF' were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated in¬ teractions involving emtricitabine and tenofovir with other medicinal products is low. Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to compe¬ tition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Drugs that decrease renal function may increase concentra¬ tions of emtricitabine and/or tenofovir. No clinically significant drug interactions have been ob¬ served between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF and zidovudine. Similarly, no clini¬ cally significant drug interactions have been observed be¬ tween tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir. indinavir, lamivudine, lopinavir/ritonavir, metha¬ done, nelfinavir, oral contraceptives, ribavirin, saquinavir/ ritonavir or tacrolimus in trials conducted in healthy volun¬ teers. Following multiple dosing to HIV-negative subjects receiv¬ ing either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF. The effects of coadministered drugs on the C^,, AUC, and ,Cmill of tenofovir are shown in Table 7. The effects of coad¬ ministration of tenofovir DF on Cm„, AUC, and Cmlu of co¬ administered drugs are shown in Table 8. [See table 7 at top of page 685] [See table 8 at top of page 685) Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir DF with didanosine enteric-coated capsules significantly in¬ creases the Cm(1( and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alpne under fasted conditions. The mechanism of this interaction is unknown [for didanosine dosing adjustment recommen¬ dations see Drug Interactions *

Coadministered Drug

Voriconazole

NA

NA

T 17* (T 6 to T 29)

NA

NA = not available * Increase = T; Decrease = 4; No Effect = «-» Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone.

y

§ Soft Gelatin Capsule H 90% Cl not available # Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).

reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases a, 0, y, and o are not inhibited by efa¬ virenz. Emtricitabine: Emtricitabine, a synthetic nucleoside ana¬ log of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5’-triphosphate. Emtricitabine 5’triphosphate inhibits the activity of the HIV-1 RT by com¬ peting with the natural substrate deoxycytidine 5’triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5’triphosphate is a weak inhibitor of mammalian DNA poly¬ merase a, (3, t, and mitochondrial DNA polymerase y. Tenofovir Disoproxil Fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine mono¬ phosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphory¬ lations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5’triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibi¬ tor of mammalian DNA polymerases a, (3, and mitochondrial DNA polymerase y. Antiviral Activity Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: In combination studies evaluating the antivi¬ ral activity in cell culture of emtricitabine and efavirenz to¬ gether, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral ef¬ fects were observed. Efavirenz: The concentration of efavirenz inhibiting repli¬ cation of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (ECg,, 9r,) ranged from 1-7-25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine. zalcitabine, and zidovudine), protease inhibitors (Pis) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and sa¬ quinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated anti¬ viral activity against clade B and most non-clade B isolates i subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2. Emtricitabine: The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGICCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (ECM) values for emtricitabine were in the range of 0.0013-0.64 pM (0.0003-0.158 pg/mEi

) I I I I

j |

In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovu¬ dine), NNRTIs (delavirdine, efavirenz, and nevirapine), and Pis (amprenavir, nelfinavir, ritonavir, and saquinavir), ad¬ ditive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007—0.075 pM) and showed strain specific activity against HIV-2 (ECso values ranged from 0.007-1.5 pM). Tenofovir Disoproxil Fumarate: The antiviral activity in cell culture of tenofovir against laboratory and clinical iso¬ lates of HIV-1 was assessed in lymphoblastoid cell lines, pri¬ mary monocyte/macrophage cells and peripheral blood lym¬ phocytes. The ECjo values for tenofovir were in the range of 0.04-8.5 pM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcit¬ abine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and Pis (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5-2.2 pM) and showed strain specific activity against HIV-2 (ECM values ranged from 1.6 pM5.5 pM). Resistance Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical trials. Genotypic anal¬ ysis of these isolates identified the M184V/1 and/or K65R amino acid substitutions in the viral RT. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir. In a clinical trial of treatment-naive subjects [Study 934, see Clinical Studies < 14)1 resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuations. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 analyzed subjects in the emtricitabine + tenofovir DF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combina¬ tion group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was ob¬ served in 2/19 analyzed subject isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substi¬ tution in their HIV-1 as analyzed through standard geno¬ typic analysis. In a clinical trial of treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects receiving tenofovir DF devel¬ oped the K65R substitution through 144 weeks of therapy; 7

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Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered L>.ug m the Presence ot Efavirenz

Mean % Ch ange ot Coac ministered Drug Pharrr acokinetic Px

AUC

^mln

400 mg qd with a light meal d 1-20

600 mg qd with a light meal d 7-20

27

4 59 (1 49 to 4 67)

4 74 (4 68 to 4 78)

4 93 (4 90 to 4 95)

400 mg qd d 1-6, then 300 mg qd d 7-20 with . ritonavir 100 mg qd and a light meal

600 mg qd 2 h after atazanavir and ritonavir d 7-20

13

T 14* (1 17 to T 58)

T39t (T 2 to T 88)

T 48* (T 24 to T 76)

300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz)

600 mg qd with a light snack d 11-24 (pm)

14

T 17 (T 8 to T 27)

-

4 42 (4 31 to 4 51)

1000 mg q8h x 10 days

600 mg qd x 10 days

20

After morning dose

4-F+

4 33* (4 26 to 4 39)

4 39* (4 24 to 4 51)

After afternoon dose

4-F?

4 37* (4 26 to 4 46)

4 52* (4 47 to 4 57)

After evening dose

4 29* (1 11 to 1 43)

4 46* (4 37 to 4 54)

4 57* (4 50 to 4 63)

4 19' 36 to T 3)

4 39' (4 3 to 4 62)

Lopinavir/ ritonavir

400/100 mg ql2h x 9 days

600 mg qd x 9 days

11, 75

Nelfinavir

750 mg q8h x 7 days

600 mg qd x 7 days

10

Metabolite AG-1402

Ritonavir

»

600 mg qd x 10 days

500 mg ql2h x 8 days

«-*i

(4

T 21 (T 10 to T 33) 4 40 (1 30 to 4 48)

T 20 (T 8 to T 34) 4 37 (4 25 to 4 48)

4 43 (4 21 to 4 59)

T 24 (T 12 to T 38)

T 18 (T 6 to T 33)

T 42 (T9 to T 86)*

11

After AM dose

T 24 (T 3 to T 50)"

After PM dose

Saquinavir SGC1'

1200 mg q8h x 10 days

600 mg qd x 10 days

12

1 50 (I 28 to 4 66)

4 62 (4 45 to 4 74)

4 56 (4 16 to 4 77)*

Maraviroc

100 mg bid

600 mg qd

12

4 51 (i 37 to 4 62)

4 45 (4 38 to 4 51)

4 45 (4 28 to 4 57)

400 mg single dose

600 mg qd

9

4- 36 (4 2 to 4 59)

4 36 (4 20 to 4 48)

4 21 (4 51 to

4 19 (4 11 to 4 25)

4 44 (4 26 to 4 58)

4 26 (416 to 4 35)

4 47 (4 35 to 4 56)

Raltegravir

T 28)

tion of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L1001/ V179D/Y181C in RT. Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical trials. Ge¬ notypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substi¬ tution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or iso¬ leucine (M184V/I). Tenofovir Disoproxil Fumarate: HIV-1 isolates with re¬ duced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to teno¬ fovir. Cross Resistance Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Cross-resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions se¬ lected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors ei¬ ther or both of these amino acid substitutions. Efavirenz: Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to base¬ line. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, LI001, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced suscep¬ tibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained sus¬ ceptibility to efavirenz. Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibil¬ ity in cell culture to didanosine, stavudine, tenofovir, zido¬ vudine, and NNRTIs (delavirdine, efavirenz, and nevira¬ pine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir. dem¬ onstrated reduced susceptibility to inhibition by emtricit¬ abine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. Tenofovir Disoproxil Fumarate: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, or didanosine. HIV-1 isolates with the K65R substitution also showed reduced suscepti¬ bility to emtricitabine and lamivudine. Therefore, cross¬ resistance among these drugs may occur in patients whose virus harbors the K65R substitution. The K70E substitu¬ tion selected clinically by tenofovir DF results in reduced susceptibility to abacavir. didanosine, emtricitabine. and la¬ mivudine. HIV-1 isolates from subjects (N=20l whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L. D67N, K70R. L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V sub¬ stitution without zidovudine resistance associated substitu¬ tions (N=8) had reduced response to V1READ. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2). or T69 inser¬ tion (N=4), all of whom had a reduced response. 13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis. Impairment of Fer¬ tility

Boceprevir

800 mg tid x 6 days

600 mg qd x 16 days

NA

4 8 (4 22 to T 81

Telaprevir

750 mg q8h x 10 days

600 mg qd x 20 days

21

49 (418 to T 2)

(Table continued on next page)

of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed greater than 1.4-fold i median 2.7) reduced susceptibility to tenofovir Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution. Efavirenz: Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most fre¬ quently observed amino acid substitution in clinical trials

with efavirenz is K103N (54%). One or more RT substitu¬ tions at amino acid positions 98, 100, 101, 103, 106, 108, 188,190, 225,227, and 230 were observed in subjects failing treatment with efavirenz in combination with other antiret¬ rovirals. Other resistance substitutions observed to emerge commonly included L1001 (7*S i, K101E/Q/R (14%), V108I (11%), Gi90S/T/A (7%), P225H (18%), and M2301/L (11%). HIV-1 isolates with reduced susceptibility to efavirenz (greater than 380-fbld increase in ECW value' emerged rap¬ idly under selection in cell culture. Genotypic characteriza¬

Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above back¬ ground in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic tox¬ icology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronu-

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR cleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known. Efavirenz did not impair mating or fertility of male or fe¬ male rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz Emtricitabine: In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/d'ay (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse mi¬ cronucleus assays. Emtricitabine did not affect fertility in male rats at approx¬ imately 140-fold or in male and female mice at approxi¬ mately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human expo¬ sures at the recommended 200 mg daily dose. Tenofovir Disoproxil Fumarate: Long-term oral carcinoge¬ nicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Tenofovir DF was mutagenic in the in vitro mouse lym¬ phoma assay and negative in an in vitro bacterial muta¬ genicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice. There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was ad¬ ministered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through Day seven of gestation. There was, how¬ ever, an alteration of the estrous cycle in female rats. 13.2

Animal Toxicology and/or Pharmacology

Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose. Tenofovir Disoproxil Fumarate: Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-foid those observed in humans caused bone tox¬ icity. In monkeys the bone toxicity was diagnosed as osteo¬ malacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofo¬ vir. In rats and dogs, the bone toxicity manifested as re¬ duced bone mineral density. The mechanism(s) underlying bone toxicity is unknown. Evidence of renal toxicity was noted in 4 animal species ad¬ ministered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were ob¬ served to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2- to 20-times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known. 14

CLINICAL STUDIES

Clinical Study 934 supports the use of ATRIPLA (efavirenz/ emtricitabine/tenofovir disoproxil fumarate i tablets in anti¬ retroviral treatment-naive HIV-1 infected patients. Addi¬ tional data in support of the use of ATRIPLA in treatmentnaive patients can be found in the prescribing information for VIREAD. Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to ATRIPLA. In antiretroviral treatment-experienced patients, the use of ATRIPLA tablets may be considered lor patients with HIV-1 strains that are expected to be susceptible to the compo¬ nents of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing /See Microbiology (12.4)1 Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled mul¬ ticenter trial comparing emtricitabine + tenofovir DF ad¬ ministered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive sub¬

ATRIPLA • BRISTOL-MYERS SQUIBB/683 Table 6 Icont.l Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Efavirenz

----— Mean % Change of Coadministered Drug Pharmacokinetic Parameters* (90% Cl) Coadministered Drug

Clarithromycin

Dose of Coadministered Drug (mg)

500 mg ql2h x 7 days

Efavirenz Dose (mg)

400 mg qd x 7 days

N

11

14-OH metabolite

Itraconazole

Rifabutin

Artemether/lumefantrine

4 46) T 34 (T 18 to T 53)

4 53 (4 42 to 4 63) T 26 (T 9 to T 45)

18

1 37 a 20 to 4 51) 4 35 a 12 to 4 52)

4 39 (4 21 to 4 53) 4 37 (4 14 to 4 55)

4 44 (4 27 to 4 58) 4 43 (4 18 to 4 60)

400 mg (oral suspension) bid x 10 and 20 days

400 mg qd x 10 and 20 days

11

4 45 (4 34 to 4 53)

4 50 (4 40 to 4 57)

NA

300 mg qd x 14 days

600 mg qd x 14 days

4 32 (4. 15 to 4 46)

4 38 (4 28 to 4 47)

4 45 (4 31 to 4 56)

4 2li 38

4 51 4 46 421

NA NA NA

4. 14 (4 1 to 4. 26) 4 15 2) b ^2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score. 1 For Ishak Fibrosis Score, improvement = >l-point decrease from baseline and worsening = >l-point increase from baseline.

Table 9:

Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Nucleoside-Inhibitor-Naive Subjects in Studies AI463022 and AI463027 Study AI463022

Study AI463027

(HBeAg-Positive)

(HBeAg-Negative)

Lamivudine 100 mg

BARACLUDE

Lamivudine

0.5 mg

100 mg

n=355

n=325

n=313

67%

36%

90%

72%

-6.86

-5.39

-5.04

-4.53

Lamivudine-refractory Subjects with Compensated Liver

68% 21%

60% 18%

78% NA

71% NA

Study AI463026 was a multinational, randomized, double¬ blind study of BARACLUDE in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B vi¬ rus infection and compensated liver disease. Subjects re¬ ceiving lamivudine at study entry either switched to BARACLUDE 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Cauca¬ sian, and 52% had previously received interferon-a. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance substitutions at base¬ line by an investigational line probe assay. At baseline, sub¬ jects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Am¬ plicor PCR assay was 9.36 log]0 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects. BARACLUDE was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibro¬ sis Score are shown in Table 10. Table 11 shows selected virologic, biochemical, and serologic endpoints.

BARACLUDE 0.5 mg n=354

HBV DNA” Proportion undetectable ( of subjects. In Studies AI463022 and AI463027, BARACLUDE was su¬ perior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater re¬ duction in Knodell Necroinflammatory Score with no wors¬ ening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 8. Selected viro¬ logic, biochemical, and serologic outcome measures are shown in Table 9. [See table 8 above! [See table 9 above] Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility

Carcinogenesis

Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in hu¬ mans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcino¬ genic findings. In mice, lung adenomas were increased in males and fe¬ males at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung ad¬ enomas and carcinomas were increased in male mice at ex¬ posures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not ob¬ served in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were in¬ creased in males and combined liver adenomas and carcino¬ mas were also increased at exposures 42 times those in hu¬ mans Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at expo¬ sures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 tunes those m humans Brain gliomas were induced in both

Mutagenesis

Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats. Impairment of Fertility

14 CLINICAL STUDIES 14.1 Outcomes in Adults At 48 Weeks

The safety and efficacy of BARACLUDE (entecavir) in adults were evaluated in three Phase 3 active-controlled tri¬ als. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evi¬ dence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Sub¬ jects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of BARACLUDE were also evaluated in a study of 191 HBV-infected subjects with decompensated liver dis¬ ease and in a study of 68 subjects co-infected with HBV and HIV. Nucleoside-inhibitor-naive Subjects with Compensated Liver Disease HBeAg-positioe: Study AI463022 was a multinational, ran¬ domized, double-blind study of BARACLUDE 0.5 mg once

Table 10:

Histologic Improvement and Change in Ishak

Fibrosis Score at Week 48, Lamivudine-Refractory Subjects in Study AI463026 BARACLUDE 1 mg n=124*

Lamivudine 100 mg n=116*

Histologic Improvement (Knodell Scores)

Improvement” No improvement

55% 34%

28% 57%

Improvement0 No change Worsening0

34% 44% 11%

16% 42% 26%

Missing Week 48 biopsy

11%

16%

Ishak Fibrosis Score

* Subjects with evaluable baseline histology 1 baseline Knodell Necroinflammatory Score £2'. b >2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score. 0 For Ishak Fibrosis Score, improvement = >l-point decrease from baseline and worsening = >l-point increase from baseline.

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR Table 11:

Selected Virologic, Biochemical, and Serologic

Endpoints at Week 48, Lamivudine-Refractory Subjects in

BARACLUDE • BRISTOL-MYERS SQUIBB/693 Product Strength and Dosage Form

Description

Quantity

NDC Number

0.5 mg film-coated tablet

White to off-white, triangular-shaped tablet, debossed with “BMS" on one side and “1611” on the other side.

30 tablets 90 tablets

, 0003-1611-12 0003-1611-13

1 mg film-coated tablet

Pink, triangular-shaped tablet, debossed with “BMS” on one side and “1612” on the other side.

30 tablets

0003-1612-12

0.05 mg/mL oral solution

Ready-to-use, orange-flavored, clear, colorless to pale yellow, aqueous solution in a 260 mL bottle.

210 mL

0003-1614-12

Study A1463026

HBV DNA" Proportion undetectable (104H observed with DAKLINZA (daclatasvir) n combination with sofosbuvir were headache and fatigue. (6.1)

those listed in a Medication Guide. Do not use COUMADIN (warfarin sodium) for a condition for which it was not pre¬

vider will decide if COUMADIN (warfarin sodium) is right

scribed. Do not give COUMADIN to other people, even if

for you. Talk to your healthcare provider about all of your health conditions.

they have the same symptoms that you have. It may harm them.

• you are pregnant unless you have a mechanical heart valve. COUMADIN may cause birth defects, miscarriage,

This Medication Guide summarizes the most important in¬

or death of your unborn baby.

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -DRUG INTERACTIONS-

formation about COUMADIN. If you would like more infor¬

• Drug Interactions: Coadministration of DAKLINZA can alter the concentration of other drugs and other drugs may alter the concentration of daclatasvir. Consult the full prescribing information before use for contraindicated drugs and other potential drug-drug interactions. (2.2, 4, 5.1, 7, 12.3)

mation, talk with your healthcare provider. You can ask

• you are allergic to warfarin or any of the other ingredients in COUMADIN. See the end of this leaflet for a complete list of ingredients in COUMADIN.

your healthcare provider or pharmacist for information

What should I tell my healthcare provider before taking COUMADIN?

If

about COUMADIN that is written for healthcare profes¬ sionals. you

would

like

more

information,

go

to

www.coumadin.com or call 1-800-321-1335.

See 17 for PATIENT COUNSELING INFORMATION

What are the ingredients in COUMADIN?

Before you take COUMADIN, tell your healthcare provider if you:

Active ingredient:

• have bleeding problems • fall often

Inactive ingredients: Lactose, starch, and magnesium stearate. The following tablets contain:

• have liver or kidney problems

1 mg:

D&C Red No. 6 Barium Lake

• have high blood pressure

2 mg:

FD&C Blue No. 2 Aluminum Lake and

2-1/2 mg:

FD&C Red No. 40 Aluminum Lake D&C Yellow No. 10 Aluminum Lake and

• have a heart problem called congestive heart failure • have diabetes • plan to have any surgery or a dental procedure

and FDA-approved patient labeling.

Warfarin Sodium

Revised: 7/2015 FULL PRESCRIBING INFORMATION: CONTENTS*

1 2

FD&C Blue No. 1 Aluminum Lake

• have any other medical conditions

3 mg:

Blue No. 2 Aluminum Lake, and FD&C Red No. 40 Aluminum Lake

should not take COUMADIN?" • are breast-feeding. You and your healthcare provider

4 mg:

FD&C Blue No. 1 Aluminum Lake

should decide if you will take COUMADIN and breast¬ feed.

5 mg:

FD&C Yellow No. 6 Aluminum Lake

6 mg:

FD&C Yellow No. 6 Aluminum Lake and

7-1/2 mg:

FD&C Blue No. 1 Aluminum Lake D&C Yellow No. 10 Aluminum Lake and

Tell all of your healthcare providers and dentists that you

may need to be stopped for a short time or you may need your dose adjusted.

Dosage Modification Due to Drug Interac¬ tions

3 4 5

2.3

Discontinuation of Therapy

DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1

Risk of Adverse Reactions or Loss of Virologic

5.2

Serious Symptomatic Bradycardia When Co-

Response Due to Drug Interactions administered Amiodarone

This Medication Guide has been approved by the U.S. Food and Drug Administration.

6

COUMADIN is distributed by:

Bristol-Myers Squibb Company

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medi¬

Princeton, New Jersey 08543 USA

cines, vitamins, and herbal supplements. Some of your

COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company.

other medicines may affect the way COUMADIN works.

Recommended Dosage

FD&C Yellow No. 6 Aluminum Lake

provider who prescribed COUMADIN for you before you have any surgery or dental procedure. Your COUMADIN

2.1 2.2

FD&C Yellow No. 6 Aluminum Lake, FD&C

• are pregnant or plan to become pregnant. See “Who

are taking COUMADIN. They should talk to the healthcare

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION

7

with

Sofosbuvir

and

ADVERSE REACTIONS 6.1

Clinical Trials Experience

6.2

Postmarketing Experience

DRUG INTERACTIONS 7.1

Potential for DAKLINZA

Other

Drugs

to

Affect

7.2

Potential for DAKLINZA to Affect Other Drugs

Certain medicines may increase your risk of bleeding. See

**The brands listed (other than COUMADIN®) are regis¬

“What is the most important information I should know about COUMADIN?”

tered trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

7.3

Established and Potentially Significant Drug Interactions

Know the medicines you take. Keep a list of them to show

1258498A3 / 1215385A4 / 1205734A4 / 1205736A4 Rev October 2011

7.4

Drugs without Clinically Significant Interac¬ tions with DAKLINZA

your healthcare provider and pharmacist when you get a new medicine.

How should I take COUMADIN? • Take COUMADIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to COUMADIN.

• You must have regular blood tests and visits with your healthcare provider to monitor your condition. • If you miss a dose of COUMADIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of COUMADIN the next day to make up for a missed dose. • Call your healthcare provider right away if you: • take too much COUMADIN • are sick with diarrhea, an infection, or have a fever

Shown in Product Identification Guide, page 305

DAKLINZA [dak lirt za]

8 ty

What are the possible side effects of COUMADIN? COUMADIN may cause serious side effects including: • See “What is the most important information I should know about COUMADIN?” • Death of skin tissue (skin necrosis or gangrene). This

Geriatric Use

8.7

Hepatic Impairment

8.8

Liver Transplant Patients

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAKLINZA safely and effectively. See full prescribing information for DAKLINZA. DAKLINZA™ (daclatasvir) tablets, for oral use Initial U.S. Approval: 2015

10 11 12

13

prevent death or loss (amputation) of your affected body part. • "Purple toes syndrome." Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color. Tfell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all of the side effects of COUMADIN. For more information, ask your healthcare provider or pharma¬ cist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

14 16

• Sustained virologic response (SVR) rates are reduced in patients with cirrhosis. (14)

-DOSAGE AND ADMINISTRATION17

• 60 mg taken orally once daily with or without food in com¬ bination with sofosbuvir. (2.1)

Pharmacokinetics

12.4

Microbiology

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis. Impairment of Fertility

CLINICAL STUDIES HOW SUPPLIED/STORAGE AND HANDLING 16.1

How Supplied

16.2

Storage

PATIENT COUNSELING INFORMATION

Reduce dosage to 30 mg once daily

FULL PRESCRIBING INFORMATION

90 mg once daily with moderate CYP3A inducers. (2.2)

1

INDICATIONS AND USAGE

DAKLINZA is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV)

-DOSAGE FORMS AND STRENGTHS60 mg and 30 mg (3)

genotype 3 infection isee Dosage and Administration 12) and

Clinical Studies 114)].

-CONTRAINDICATIONS-

Limitations of Use:

• Strong inducers of CYP3A, including phenytoin, carba-

• Sustained virologic response (SVR) rates are reduced in

mazepine, rifampin, and St. John's wort. (4)

HCV genotype 3-infected patients with cirrhosis receiving

-W ARNINGS AND PRECAUTIONS-

DAKLINZA in combination with sofosbuvir for 12 weeks Isee Clinical Studies 114)].

• Bradycardia When Coadministered with Sofosbuvir and Amiodarone:

2

Serious symptomatic bradycardia may oc¬

cur in patients taking amiodarone with sofosbuvir in com¬ bination with another HCV direct-acting agent, including

2.1

and/or advanced liver disease. Coadministration of amio¬

• Keep COUMADIN in a tightly closed container, and keep COUMADIN out of the light.

darone with DAKLINZA in combination with sofosbuvir is not recommended. In patients with no alternative treat¬

Keep COUMADIN and all medicines out of the reach of chil¬ dren.

ment options, cardiac monitoring is recommended. (5.2,

6.2, 7.3)

Recommended Dosage

orally, once daily in combination with sofosbuvir for 12 weeks. DAKLINZA may be taken with or without food.

blockers or those with underlying cardiac comorbidities

• Store COUMADIN at 59°F to 86*F (15*C to 30°C).

DOSAGE AND ADMINISTRATION

The recommended dosage of DAKLINZA is 60 mg, taken

DAKLINZA, particularly in patients also receiving beta

How should I store COUMADIN?

Pharmacodynamics

12.3

* Sections or subsections omitted from the full prescribing information are not listed.

12 weeks. (2.1)

with strong CYP3A inhibitors and increase dosage to

• Tablet:

Mechanism of Action

12.2

13.1

HCV genotype 3 infection. (1) Limitations of Use:

• Dose modification:

OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1

-INDICATIONS AND USAGE-

because blood clots form and block blood flow to an area

of your body. You may need medical care right away to

Pediatric Use Renal Impairment

• Recommended treatment duration:

1 you have pain, color, or temperature change to any area

8.4 8.6

can happen soon after starting COUMADIN. It happens of your body. Call your healthcare provider right away if

Lactation

tablets, for oral use

dicated for use with sofosbuvir for the treatment of chronic

• Do not do any activity or sport that may cause a serious ipjury.

Pregnancy

8.2 8.5

DAKLINZA is a hepatitis C virus (HCV) NS5A inhibitor in¬

What should I avoid while taking COUMADIN?

8.1

(daclatasvir)

• fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you

USE IN SPECIFIC POPULATIONS

The optimal duration of DAKLINZA and sofosbuvir for pa¬ tients with cirrhosis has not been established Isee Clinical

Studies (14)]. j !

For specific dosage recommendations for sofosbuvir, refer to the respective prescribing information.

Free mobile PDR app for fast drug references on Apple or Android devices

.Hu U:A

lYr* I'r'tnn,

'r‘-: :vr.-Ou—st'v rawiw-r

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

702/BRISTOL-MYERS SQUIBB • DAKLINZA

7

Table 1: Drugs that are Contraindicated with DAKLINZA

Strong induction of CYP3A by coadministered drug

Drugs that are Contraindicated with DAKLINZA”

Clinical Comment

Mechanism of Interaction

Anticonvulsants

May lead to loss of virologic

phenytoin, carbamazepine

response to DAKLINZA

DRUG INTERACTIONS

7.1

Antimycobacterial agents rifampin Herbal products St. John’s wort (Hypericum perforatum)

Potential for Other Drugs to Affect DAKLINZA (daclatasvir)

Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of daclatasvir [see Dosage and Ad¬ ministration (2.2), Contraindications (4), and Table 3). Strong inhibitors of CYP3A (eg, clarithromycin, itracona¬ zole, ketoconazole, ritonavir) may increase the plasma lev¬ els of daclatasvir (see Dosage and Administration (2.2) and

Table 3], 7.2 Potential for DAKLINZA to Affect Other Drugs

" This table is not a comprehensive list of all drugs that strongly induce CYP3A.

Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp>, organic anion transporting polypeptide (OATPi 1B1 and 1B3, and breast cancer resistance protein (BCRP). Ad¬

2.2

Dosage Modification Due to Drug Interactions

Coadministration

Refer to the drug interactions and contraindication sections

of

amiodarone

with

DAKLINZA

(daclatasvir) in combination with sofosbuvir is not recom¬

for other drugs before coadministration with DAKLINZA

[

ministration of DAKLINZA may increase systemic exposure to medicinal products that are substrates of P-gp, OATP

mended. For patients taking amiodarone who have no alter¬

1B1 or 1B3, or BCRP, which could increase or prolong their

(daclatasvir).

native treatment options and who will be coadministered

Strong inhibitors of cytochrome P450 enzyme 3A (CYP.'tA): Reduce the dosage of DAKLINZA to 30 mg once

therapeutic effect or adverse reactions (see Table 3).

DAKLINZA and sofosbuvir:

7.3

• Counsel patients about the risk of serious symptomatic

daily when coadministered with strong CYP3A inhibitors using the 30 mg tablet [see Drug Interactions (7)]. Moderate CYP3A inducers: Increase the dosage

Refer to the prescribing information for sofosbuvir for drug

bradycardia

of

DAKLINZA to 90 mg once daily using an appropriate com¬ bination of tablets (three 30 mg tablets or one 60 mg and one 30 mg tablet) when coadministered with moderate CYP3A inducers [see Drug Interactions (7)1. .

• Cardiac monitoring in an inpatient setting for the first 48

interaction information. The most conservative recommen¬

hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should oc¬

dation should be followed. Table 3 provides clinical recommendations for established

cur on a daily basis through at least the first 2 weeks of

or

treatment.

DAKLINZA and other drugs Isee Contraindications (4)].

Patients who are taking sofosbuvir in combination with

Strong CYP3A inducers: DAKLINZA is contraindicated in combination with strong CYP3A inducers [see Contraindica¬ tions (4) |.

other alternative treatment options should undergo similar

DAKLINZA who need to start amiodarone therapy due to no

Dosage reduction of DAKLINZA for adverse reactions is not

cardiac monitoring as outlined above.

recommended.

Due to amiodarone's long elimination half-life, patients dis¬

2.3

continuing amiodarone just prior to starting sofosbuvir in

Discontinuation of Therapy

If sofosbuvir is permanently discontinued in a patient re¬ ceiving DAKLINZA with sofosbuvir, then DAKLINZA

3

DOSAGE FORMS AND STRENGTHS

potentially

significant

drug

interactions

between

Clinically relevant increase in concentration is indicated as “t” and clinically relevant decrease as “A" [for drug interac¬ tion data, see Clinical Pharmacology (12-3)]. [See table 3 at top of next page]

7.4

combination with DAKLINZA should also undergo similar

should also be discontinued.

Established and Potentially Significant Drug Interac¬ tions

Drugs without Clinically Significant Interactions with DAKLINZA Based on the results of drug interaction trials Isee Clinical Pharmacology (12.3)], no clinically relevant changes in ex¬

cardiac monitoring as outlined above.

posure were observed for cyclosporine, escitalopram, ethinyl

Patients who develop signs or symptoms of bradycardia

estradiol/norgestimate, methadone, midazolam, tacrolimus,

should seek medical evaluation immediately. Symptoms

or tenofovir with concomitant use of daclatasvir. No clini¬

66 mg

may include near-fainting or fainting, dizziness or light¬

daclatasvir dihydrochloride), light green, biconvex, pen¬ tagonal, and debossed with “BMS” on one side and “215” on the other side.

headedness, malaise, weakness, excessive tiredness, short¬

cally relevant changes in daclatasvir exposure were ob¬ served with cyclosporine, escitalopram, famotidine, omepra¬

ness of breath, chest pain, confusion, or memory problems

zole, sofosbuvir, tacrolimus, or tenofovir. No clinically

[see Adverse Reactions (6.2) and Drug Interactions, Table 3

relevant interaction is anticipated for daclatasvir or the fol¬ lowing concomitant medications: peginterferon alfa. riba¬ virin, or antacids.

• Tablets:

• Tablets:

60 mg

30 mg

daclatasvir

daclatasvir

(equivalent

(equivalent

to

to

(7.3)].

33 mg

daclatasvir dihydrochloride), green, biconvex, pentagonal, and debossed with “BMS” on one side and “213” on the other side.

4

6 ADVERSE REACTIONS

CONTRAINDICATIONS

The following serious adverse reactions are described below

8

and elsewhere in the labeling: • Serious Symptomatic Bradycardia When Coadministered

8.1 Pregnancy

with Sofosbuvir and Amiodarone [see Warnings and Pre¬ cautions (5.2) [.

• DAKLINZA is contraindicated in combination with drugs that strongly induce CYP3A and, thus, may lead to lower

USE IN SPECIFIC POPULATIONS

Risk Summary No data with DAKLINZA in pregnant women are available to inform a drug-associated risk. In animal reproduction

exposure and loss of efficacy of DAKLINZA. Contraindi¬

6.1 Clinical Trials Experience

studies in rats and rabbits, no evidence of fetal harm was

cated drugs include, but are not limited to, those listed in Table 1 |see Drug Interactions (7) and Clinical Pharmacol¬

Because clinical trials are conducted under w idely varying

observed with oral administration of daclatasvir during or¬

conditions, adverse reaction rates observed in the clinical

ganogenesis at doses that produced exposures up to 6 and

ogy (12.3)].

trials of a drug cannot be directly compared to rates in the

22 times, respectively, the recommended human dose (RHD)

clinical trials of another drug and may not reflect the rates observed in practice.

of 60 mg. However, embryofetal toxicity was observed in

Approximately 1900 subjects with chronic HCV infection have been treated with the recommended dose of

posures of 33 and 98 times the human exposure, respec¬ tively, at the RHD of 60 mg [see Data]. Consider the benefits

DAKLINZA in combination with other anti-HCV drugs in clinical trials.

and risks of DAKLINZA when prescribing DAKLINZA to a

[See table 1 above!

5 5.1

WARNINGS AND PRECAUTIONS Risk of Adverse Reactions or Loss of Virologic Re¬ sponse Due to Drug Interactions

The concomitant use of DAKLINZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7)|:

In the ALLY-3 trial, 152 treatment-naive and treatment-

of concomitant

medications

treated with DAKLINZA 60 mg once daily in combination with sofosbuvir for 12 weeks. The most common adverse re¬

ognized pregnancies is 2% to 4% and 15% to 2091, respec¬ tively.

!

• possible clinically significant adverse reactions from greater exposures of concomitant drugs or DAKLINZA. See Table 1 for drugs contraindicated with DAKLINZA due

|

to loss of efficacy and passible development of resistance [see Contraindications (4)|. See Table 3 for steps to prevent or manage other possible and known significant drug interactions Isee Drug Interactions (7*). Consider the potential for

I

drug interactions before and during DAKLINZA therapy, review concomitant medications during DAKLINZA therapy,

|

actions (frequency of 1091 or greater) were headache and fa¬

Data

tigue. All adverse reactions were mild to moderate in sever¬

Animal Data

ity. One subject experienced a serious adverse event that

Daclatasvir was administered orally to pregnant rats at

was considered unrelated to DAKLINZA. and no subjects discontinued therapy for adverse events.

doses of 0,50,200, or 1000 mg/kg/day on gestation days 6 to

Adverse reactions considered at least possibly related to

15. Maternal tojcicity (mortality, adverse clinical signs, body-weight losses, and reduced fixid consumption' was

treatment and occurring at a frequency of 5ri• or greater are presented in Table 2.

noted at doses of 200 and 1000 mg/kg/day. In the offspring, malformations of the fetal brain, skull, eyes, ears, nose,

Table 2: Adverse Reactions Reported at >5% Frequency, DAKLINZA + Sofosbuvir for 12 Weeks Adverse Reaction

and monitor for the adverse reactions associated with the concomitant drugs.

Serious Symptomatic Bradycardia When Coadmin¬ istered with Sofosbuvir and Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically rec¬

or

5.2

pregnant woman.

\ experienced subjects with HCV genotype 3 infection were

• loss of therapeutic effect of DAKLINZA and possible devel¬ opment of resistance, • dosage adjustments DAKLINZA.

rats and rabbits at maternally toxic doses that produced ex¬

n(%) n=152

Headache Fatigue

21 (14%) 21 (14%)

lip, palate, or limbs were observed at doses of 200 and 1000 mg/kg. The dose of 1000 mg/kg was associated with profound embryolethality and lower fetal body weight. No malformations were noted at 50 mg/kg/day. Systemic expo¬ sure (AUC> at 50 mg/kg/day in pregnant females was 6-fold higher than exposures at the RHD. In rabbits, daclatasvir was initially administered at doses of 0, 40, 200, or 750 mg/kg/day during the gestation days 7 to

| 1

Nausea

12 (8%)

amiodarone is coadministered with sofosbuvir in combination with another HCV direct-acting antiviral, including

I

Diarrhea

7 (5%)

DAKLINZA. A fatal cardiac arrest was reported in a patient

'

Laboratory Abnormalities

vere reductions in body weight and food consumption. Mor¬

receiving a sofosbuvir-containing regimen (ledipasvir/ sofosbuvir!. Bradycardia has generally occurred within hours to davs, but cast's have been observed up to 2 weeks

Lipase Elevations:

Transient, asymptomatic lipase eleva¬

tality and euthanasia occurred in multiple dams at 750/

tions of greater than 3 times the upper limit of normal (ULN) were observed in 2't of subjects in ALLY-3.

370 mg/kg/day. At 200/99 mg/kg/day. fetal effects included

after initiating HCV treatment. Patients also taking beta

6.2 Postmarketing Experience Cardiac Disorders. Serious symptomatic bradycardia has

blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amio¬ darone Bradycardia generally resolved after disoontinuatmn of IK \ treatment. The mechanism for this bradycardia effect is unknow n

19. Daclatasvir dosing was modified due to vehicle toxicity during the study to doses of 20, 99, and 370 mg/kg/day, re¬ spectively. Maternal toxicity was noted at doses of 200/99 and 750/370 mg/kg/day with adverse clinical signs and se¬

been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral, including DAKLINZA [see

Warnings and Precautions (5.2) and Drug Interactions

(7.3)].

increased embryofetal lethality, reduced fetal body weights, and increased incidences of fetal malformations of the ribs as well as head and skull. No malformations were noted in rabbits at 40/20 mg/kg/day. Systemic exposures (AUC» at 40/20 mg/kg/day were 22-fold higher than exposures at the RHD. In a pre- and postnatal developmental study, daclatasvir was administered orally at 0, 25, 50, or 100 mg/kg/day from

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DAKLINZA • BRISTOL-MYERS SQUIBB/703

Table 3: Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name

Effect on Concentration9

Clinical Comment

general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Be¬ cause daclatasvir is highly protein bound (>99%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

Strong CYP3A inhibitors 11 Examples:

atazanavir/ritonavir,b

T Daclatasvir

Decrease DAKLINZA dose to 30 mg once daily when

clarithromycin, indinavir, itraconazole,

coadministered with strong inhibitors of CYP3A.

ketoconazole,b nefazodone, nelfinavir, posaconazole, saquinavir,

DESCRIPTION

DAKLINZA (daclatasvir) is an inhibitor of HCV nonslructural protein 5A (NS5A). The chemical name for drug sub¬ stance daclatasvir dihydrochloride is carbamic add, NJ4'[[l,l-biphenyI]-4,4'-diylbis|l//-imidazoIe-5,2-diyl-(2S>-2,l -pyrrolidinediylK lS)-l-( l-methylethyl)-2-oxo-2,l-ethanediylJllbis-, C,C’-dimethyl ester, hydrochloride (1:2). Its mo¬

telithromycin, voriconazole

Moderate CYP3A inhibitors

lecular formula is C40HWN806«2HC1, and its molecular

Examples:

weight is 738.88 (free base). Daclatasvir dihydrochloride has the following structural formula:

atazanavir, ciprofloxacin,

T Daclatasvir

Monitor for daclatasvir adverse events.

darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil

Moderate CYP3A inducers Examples:

bosentan,

i Daclatasvir

Increase DAKLINZA dose to 90 mg once daily when

dexamethasone, efavirenz,1' etravirine, modafinil. nafcillin, rifapentine

coadministered with moderate inducers of CYP3A. Daclatasvir dihydrochloride drug substance is white to yel¬ low. Daclatasvir is freely soluble in water (>700 mg/mLl.

Anticoagulants Dabigatran etexilate mesylate

DAKLINZA 60 mg tablets contain 60 mg daclatasvir (equiv¬ alent to 66 mg daclatasvir dihydrochloride) and the inactive

T Dabigatran

Use of DAKLINZA with dabigatran etexilate is not recommended in specific renal impairment groups, depending on the indication. Please see the dabigatran prescribing information for specific recommendations.

ingredients anhydrous lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magne¬ sium Stearate, and Opadrv green. DAKLINZA 30 mg tablets contain 30 mg daclatasvir (equivalent to 33 mg daclatasvir dihydrochloride) and the inactive ingredients anhydrous

Cardiovascular agents

lactose (58 mg), microcrystalline cellulose, croscarmellose Antiarrhythmic: Amiodarone

Amiodarone: effects unknown

Coadministration of amiodarone with DAKLINZA in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If coadministration

sodium, silicon dioxide, magnesium stearate, and Opadry green. Opadry green contains hypromellose, titanium diox¬ ide. polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide.

is required, cardiac monitoring is recommended. [See

12

Warnings and Precautions (5.2) and Adverse Reactions (6.2). ]

12.1

CLINICAL PHARMACOLOGY Mechanism of Action

Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus [see Microbiology (12.4)].

Antiarrhythmic: Digoxin

T Digoxin

Patients already receiving daclatasvir initiating

12.2

digoxin:

Cardiac Electrophysiology

Initiate treatment using the lowest annropriate

digoxin dosage. Monitor digoxin concentrations; adjust digoxin doses if necessary and continue monitoring. Patients already receiving digoxin prior to initiating daclatasvir:

Measure serum digoxin concentrations

Pharmacodynamics

At a dose 3 times the maximum recommended dose, daclatasvir does not prolong the QT interval to any clini¬ cally relevant extent.

12.3

Pharmacokinetics

before initiating daclatasvir. Reduce digoxin

The pharmacokinetic properties of daclatasvir were evalu¬

concentrations by decreasing digoxin dosage by

ated in healthy adult subjects and in subjects with chronic

approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.

subjects resulted in approximately dose-proportional in¬

HCV. Administration of daclatasvir tablets in HCV-infected creases in Cm„, AUC, and Cmi„ up to 60 mg once daily.

Lipid-lowering agents

Steady state is anticipated after approximately 4 days of once-daily

HMG-CoA reductase inhibitors: Atorvastatin Fluvastatin

T Atorvastatin T Fluvastatin

Pitavastatin

T Pitavastatin T Pravastatin

Pravastatin

T Rosuvastatin

Rosuvastatinb

Monitor for HMG-CoA reductase inhibitor associated adverse events such as myopathy.

T Simvastatin

Simvastatin The direction of the arrow (T = increase, 1 = decrease) indicates the direction of the change in pharmacokinetic parameters. b These interactions have been studied [see Clinical Pharmacology (12.3, Tables 5 and 6)\.

daclatasvir

administration.

8.5

ternal toxicity included mortality and dystocia; developmen¬

Safety was similar across older and younger subjects and there were no safety findings unique to subjects 65 years and older. Sustained virologic response (SVR) rates were comparable among older and younger subjects. No dosage adjustment of DAKLINZA (daclatasvir) is required for el¬ derly patients [see Clinical Pharmacology (12.3)].

tal toxicity included slight reductions in offspring viability in the perinatal and neonatal periods and reductions in birth weight that persisted into adulthood. There was nei¬ ther maternal nor developmental toxicity at doses up to 50 mg/kg/day. Systemic exposures (AUC) at this dose were

8.6

3.6-40 pM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Daclatasvir did not have a clinically rel¬ evant effect on the exposure of midazolam, a sensitive CYP3A substrate. Transporters Daclatasvir is a substrate of P-gp. However, cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. Daclatasvir, in vitro, did not inhibit organic cat¬ ion transporter (OCT) 2 and did not have a clinically rele¬ vant effect on the pharmacokinetics of tenofovir, an organic anion transporter (OAT) substrate. Daclatasvir demon¬ strated inhibitory effects on digoxin (a P-gp substrate) and rosuvastatin (an OATP 1B1, OATP 1B3, and BCRP sub¬ strate) in drug-drug interaction trials. Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs used as probes to evaluate potential drug-drug interactions. The ef¬ fects of daclatasvir on the C^,,, AUC, and Cm,„ of the coad¬ ministered drug are summarized in Table 5, and the effects of the coadministered drug on the C^,, AUC, and Cmln of daclatasvir are summarized in Table 6. For information re¬ garding clinical recommendations, see Contraindications (4) and Drug Interactions (7.3). Drug interaction studies were conducted in healthy adults unless otherwise noted. [See table 5 above] [See table 6 above] 1Z.4 Microbiology Mechanism of Action Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion as¬ sembly. Characterization of daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate

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DAKLINZA • BRISTOL-MYERS SQUIBB/706

Table 8: Treatment Outcomes in ALLY-3: DAKLINZA in Combination with Sofosbuvir in Subjects with HCV Genotype 3 Infection Treatment Outcomes

SVR

Treatment-Naive n=101

Treatment-Experienced n=51

Total n=152

90% (91/101)

86% (44/51)

89% (135/152)

98% (80/82) 58% (11/19)

92% (35/38) 69% (9/13)

96% (115/120) 63% (20/32)

1% (1/101) 9% (9/100)

0

14% (7/51)

0.7% (1/152) 11% (16/151)

All No cirrhosis” With cirrhosis Outcomes for subjects without SVR

On-treatment virologic failureb Relapse'

“ Includes 11 subjects with missing or inconclusive cirrhosis status. b One subject had quantifiable HCV RNA at end of treatment. ' Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at the end of treatment.

Daclatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity (Ames) as¬ says, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucieus study in rats. Impairment of Fertility > Daclatasvir had no effects on fertility in female rats at any dose tested. Daclatasvir exposures at these doses in females were approximately 24-fold the human systemic exposure at the therapeutic daily dose. In male rats, effects on repro¬ ductive endpoints at 200 mg/kg/day included reduced prostate/seminai vesicle weights, minimally increased dysmor¬ phic sperm, as well as increased mean pre-implantation loss in litters sired by treated males. Daclatasvir exposures at the 200 mg/kg/day dose in males were approximately 26fold the human systemic exposure at the therapeutic daily dose. Exposures at 50 mg/kg/day in males produced no no¬ table effects and was 4.7-fold the exposure in humans at the recommended daily dose. 14

Tablet Strength

Tablet Color/Shape

60 mg

Light green, biconvex, pentagonal

30 mg

Green, biconvex, pentagonal

Tablet Markings

Package Size

NDC Code

Debossed with “BMS” on one side and “215” on the other side

Bottles of 28

0003-0215-01

Debossed with “BMS” on one side and “213” on the other side

Bottles of 28

0003-0213-01

that daclatasvir interacts with the N-terminus within Do¬ main 1 of the protein, which may cause structural distor¬ tions that interfere with NS5A functions. Antiviral Activity Daclatasvir had a median EC50 value of 0.2 nM (range, 0.006-3.2 nM, n=17) against hybrid replicons containing ge¬ notype 3a subject-derived NS5A sequences without detect¬ able daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93. Daclatasvir ac¬ tivity was reduced against genotype 3a subject-derived rep¬ licons with resistance-associated polymorphisms at posi¬ tions 28, 30, 31, or 93, with a median ECjo value of 13.5 nM (range, 1.3-50 nM). Similarly, the EC50 values of daclatasvir against 3 genotype 3b and 1 genotype 3i subject-derived NS5A sequences with polymorphisms (relative to a geno¬ type 3a reference) at positions 30 or 31 were >3620 nM. The median EC^ values of daclatasvir for genotypes la, lb, 2, 4, and 5 subject-derived NS5A hybrid replicons were 0.008 nM (range, 0.002-2409 nM, n=40), 0.002 nM (range, 0.0007-10 nM, n=42), 16 nM (range, 0.005-60 nM, n=16), 0.025 nM (range, 0.001-158 nM, n=14), and 0.004 nM (range, 0.003-0.019 nM, n=3), respectively. The EC50 value against a single HCV genotype 6 derived replicon was 0.054 nM. Daclatasvir was not antagonistic with interferon alfa, HCV NS3/4A protease inhibitors, HCV NS5B nucleoside analog inhibitors, and HCV NS5B non-nucleoside inhibitors in cell culture combination antiviral activity studies using the cellbased HCV replicon system. Resistance In Cell Culture

HCV genotype 3a replicon variants with reduced suscepti¬ bility to daclatasvir were selected in cell culture, and the genotype and phenotype of daclatasvir-resistant variants were characterized. Phenotypic analysis of stable replicon cell lines showed that variant replicons containing A30K, A30T, L31F, S62L, and Y93H substitutions exhibited 56-, 1-, 603-, 1.75-, and 2737-fold reduced susceptibility to daclatasvir, respectively. In Clinical Studies

Of 152 HCV genotype 3-infected subjects treated in the ALLY-3 trial, 17 experienced virologic failure, of whom 12 had cirrhosis. Post-baseline NS5A and NS5B population nu¬ cleotide sequencing data were available for virus from 17/17 and 16/17 subjects, respectively. Virus from all 17 subjects at the time of virologic failure harbored one or more of the NS5A resistance-associated substitutions A30K/S, L31I, S62A/L/P/T, or Y93H. The most common substitution at fail¬ ure was Y93H (15/17 subjects), which was observed at base¬ line in 6 subjects and emerged in 9 subjects. For NS5B, 1 of 16 subjects had virus with the emergent NS5B resistanceassociated substitution S282T at failure. Persistence of Resistance-Associated Substitutions

Limited data from ALLY-3 on the persistence of daclatasvir resistance-associated substitutions in HCV genotype 3-infected subjects are available. In a separate long-term follow-up study of predominately HCV genotype 1-infected subjects treated with daclatasvir-containing regimens in phase 2/3 clinical trials, viral populations with treatmentemergent NS5A resistance-associated substitutions per¬ sisted at detectable levels for more than 1 year in most sub¬ jects.

Effect of Baseline HCV Polymorphisms on Treatment Re¬ sponse

In an analysis of 148 subjects with available baseline resis¬ tance data in ALLY-3, virus from 52% (77/148) of subjects had baseline NS5A polymorphisms at resistance-associated positions (defined as any change from reference at NS5A amino acid positions 28, 30, 31, 58, 62, 92, or 93) identified by population sequencing. The Y93H polymorphism was de¬ tected in 9% (13/148) of subjects receiving DAKLINZA (daclatasvir) and sofosbuvir and was associated with re¬ duced SVR12 rates (Table 7). Polymorphisms detected at other NS5A resistance-associated positions were not associ¬ ated with reduced SVR12 rates; these polymorphisms in¬ cluded M28V (n=l), A30K/S/T/V (n=14), P58R/S (n=3), and S62-any (n=66). Polymorphisms at positions associated with sofosbuvir resistance or exposure (defined as any change from reference at NS5B positions L159, S282, C316, L320, or V321) were not detected in the baseline NS5B sequence of any subject (n=150) in ALLY-3 by population-based se¬ quencing. Phylogenetic analysis of NS5A sequences indi¬ cated that all subjects with available data (n=148) were in¬ fected with HCV subtype 3a. Table 7: SVR12 Rates in Subjects with HCV Genotype 3 with/without the Baseline NS5A Y93H Polymorphism, by Cirrhosis Status Study Population

All subjects No cirrhosis” With cirrhosis

SVR 12 with Y93H

54% (7/13) 67% (6/9) 25% (1/4)

SVR 12 without Y93H

92% (124/135) 98% (105/107) 68% (19/28)

* Includes 11 subjects with missing or inconclusive cirrhosis status. Cross Resistance

Based on resistance patterns observed in cell culture repli¬ con studies and HCV genotype 3-infected subjects, cross¬ resistance between daclatasvir and other NS5A inhibitors is expected. Cross-resistance between daclatasvir and other classes of direct-acting antivirals is not expected. The im¬ pact of prior daclatasvir treatment experience on the effi¬ cacy of other NS5A inhibitors has not been studied. Con¬ versely, the efficacy of DAKLINZA in combination with sofosbuvir has not been studied in subjects who have previ¬ ously failed treatment with regimens that include an NS5A inhibitor. 13 13.1

NONCLLNICAL TOXICOLOGY Carcinogenesis, Mutagenesis. Impairment of Fer¬ tility

Carcinogenesis and Mutagenesis A 2-year carcinogenicity study in Sprague Dawley rats and a 6-month study in transgenic (Tg rasli2) mice were con¬ ducted with daclatasvir. In the 2-year study in rats, no drug-related increase in tumor incidence was observed at doses up to 50 mg/kg/day (both sexes). Daclatasvir expo¬ sures at these doses were approximately 6-fold (males and females) the human systemic exposure at the therapeutic daily dose. In transgenic mice no drug-related increase in tumor incidence was observed at doses of 300 mg/kg/day (both sexes).

CLINICAL STUDIES

The efficacy and safety of DAKLINZA (daclatasvir) in com¬ bination with sofosbuvir were evaluated in the phase 3 ALLY-3 (AI444-218) clinical trial. ALLY-3 was an open-label trial that included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment-naive (n= 101) or treatment-experienced (n=51). Most treatment-experienced subjects had failed prior treat¬ ment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational cvclophilin in¬ hibitor. Previous exposure to NS5A inhibitors was prohib¬ ited. Subjects received DAKLINZA 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. HCV RNA values were measured during the clinical trial using the COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the pri¬ mary endpoint and was defined as HCV RNA below the LLOQ at post-treatment week 12 1 SVR 12). The 152 treated subjecLs in ALLY-3 had a median age of 55 years (range, 24-73); 59% of the subjects were male; 90% were white, 5% were Asian, and 4% were black. Most sub¬ jects (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 21% of the subjects had compen¬ sated cirrhosis, and 40% had the IL28B rs 12979860 CC ge¬ notype. SVR and outcomes in subjects without SVR in ALLY-3 are shown by patient population in Table 8. For SVR outcomes related to the baseline NS5A Y93H polymorphism, see Mi¬ crobiology (12.4). SVR rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. (See table 8 above] 16 16.1

HOW SUPPLIEIVSTORAGE AND HANDLING How Supplied

DAKLINZA is packaged in bottles as described in the table. [See second table above! 16.2

Storage

Store DAKLINZA tablets at 25°C (77°F), with excursions permitted between 15°C and 30°C (59°F and 86'F) [see USP Controlled Room Temperature). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient label¬ ing (Patient Information). Drug Interactions Inform patients of the potential for drug interactions with DAKLINZA, and that some drugs should not he taken with DAKLINZA [see Contraindications (41, Drug Interactions (7), and Clinical Pharmacology (12.3)1.

Symptomatic Bradycardia When Used in Combination with Sofosbuvir and Amiodarone Advise patients to seek medical evaluation immediately for symptoms of bradycardia, such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems |see Warnings and Precautions (5.2), Ad¬ verse Reactions (6.2), and Drug Interactions (7.3)j. DAKLINZA Combination Therapy with Sofosbuvir Inform patients that DAKLINZA should not be used alone to treat genotype 3 chronic hepatitis C infection. DAKLINZA should be used in combination with sofosbuvir for the treatment of genotype 3 HCV infection [see Indica¬ tions and Usage (1)|. Missed Duses Instruct patients that if they miss a dose of DAKLINZA, the dose should be taken as soon as possible if remembered within the same day. However, if the missed dose is nut re¬ membered within the same day, the dose should be skipped and the next dose taken at the appropriate time. For in¬ structions for missed doses of other agents in the regimen, refer to the respective prescribing information.

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/06/BRISTOL-MYERS SQUIBB • DAKLINZA Hepatitis C Virus TYansmission Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that appropri¬ ate precautions to prevent transmission of the hepatitis C virus during treatment should be taken. Manufactured for: Bristol-Myers Squibb Company Princeton, NJ 08543 USA Product of Ireland 1344554A0 DAKLINZA (daclatasvir) is a trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.

• fainting or near-fainting "weakness “chest pain

» dizziness or » not feeling well lightheadedness ° shortness of "tiredness breath “confusion "memory problems The most common side effects of DAKLINZA (daclatasvir) when used in combination with sofosbuvir include: • headache • tiredness These are not all the possible side effects of DAKLINZA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DAKLINZA?

• Store DAKLINZA at room temperature between 68°F and 77°F (20°C and 25°C).

Patient Information DAKLINZA™ (dak tin za) (daclatasvir) tablets

Keep DAKLINZA and all medicines out of the reach of children. General information about the safe and effective use of DAKLINZA

Important information:

DAKLINZA is used in combination with the antiviral medicine sofosbuvir (SOVALDI). You should not take DAKLINZA alone to treat chronic hepatitis C infection.

You should also read the Patient Information for sofosbuvir (SOVALDI). What is DAKLINZA?

• DAKLINZA is a prescription medicine used with sofosbuvir to treat chronic (lasting a long time) hepatitis C genotype 3 infection in adults. • DAKLINZA should not be taken alone. It is not known if DAKLINZA is safe and effective in children under 18 years of age.

It is not known if treatment with DAKLINZA will prevent you from infecting another person with the hepatitis C virus during treatment. Talk with your healthcare provider about ways to prevent spreading the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DAKLINZA'for a condition for which it was not prescribed. Do not give DAKLINZA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DAKLINZA that is written for health professionals. What are the ingredients in DAKLINZA?

Before taking DAKLINZA, tell your healthcare provider about all of your medical conditions, including if you:

• • • •

have liver problems other than hepatitis C infection have had a liver transplant have heart problems are pregnant or plan to become pregnant. It is not known if DAKLINZA will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if DAKLINZA passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements. DAKLINZA and other medicines may affect each other. This can cause you to have too much or not enough DAKLINZA or other medicines in your body. This may affect the way DAKLINZA or your other medicines work or may cause side effects. Keep a list of your medicines to show your healthcare provider and pharmacist.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with DAKLINZA. • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell

you if it is safe to take DAKLINZA with other medicines.

Active ingredient: daclatasvir Inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmeliose sodium, silicon dioxide, magnesium stearate, and Opadry green. Opadry green contains hypromellose, titanium dioxide, polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide. Manufactured for: Bristol-Myers Squibb Company, Princeton, NJ 08543, USA Product of Ireland DAKLINZA is a trademark of Bristol-Myers Squibb Company. For more information, go to www.patientsupportconnect.com or call 1-844-442-6663. This Patient Information has been approved by the U,S. Food and Drug Administration. 1344554A0 Issued July 2015 Shown in Product Identification Guide, page 305 ■

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'

?

'

ELIQUIS® I ELL eh kwiss) (apixaban) tablets, for oral use

How should I take DAKLINZA?

• Take DAKLINZA exactly as your healthcare provider tells you to. • Do not change your dose unless your healthcare provider tells you to. • Do not stop taking DAKLINZA without first talking with your healthcare provider. • Take DAKLINZA 1 time each day with or without food. • If you miss a dose of DAKLINZA, take the missed dose as soon as you remember the same day. Take the next dose at your regular time. • If you miss a dose of DAKLINZA and remember the next day, skip the missed dose. Take the next dose at your regular time. • Do not take 2 doses of DAKLINZA at the same time to make up for the missed dose. • If you take too much DAKLINZA, call vour healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of DAKLINZA when used with sofosbuvir? DAKLINZA in combination with sofosbuvir and amiodarone may cause serious side effects, including: • Slow heart rate (bradycardia). DAKLINZA combination

treatment with sofosbuvir may result in slowing of the heart rate (pulse i along with other symptoms when taken with amiodarone. a medicine used to treat certain heart problems. Get medical help right away if you take amiodarone with sofosbuvir and DAKLINZA and get any of the following symptoms:

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ELIQUIS safely and effectively. See full prescribing information for ELIQUIS. ELIQUIS'8' (apixaban) tablets, for oral use Initial U.S. Approval: 2012

-RECENT MAJOR CHANGESDosage and Administration (2.4) 6/2015 -INDICATIONS AND USAGEELIQUIS (apixaban) is a factor Xa inhibitor indicated: • to reduce the risk of stroke and systemic embolism in pa¬ tients with nonvalvular atrial fibrillation. (1.1) • for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. (1.2) • for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PF, following initial therapy. (1.3, 1.4, 1.5) -DOSAGE AND ADMINISTRATION• Reduction of risk of stroke and systemic embolism in non¬ valvular atrial fibrillation: • The recommended dose is 6 mg orally twice daily. • In patients with at least 2 of the following characteris¬ tics: age >80 years, body weight 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. (2.1) • Prophylaxis of DVT following hip or knee replacement sur¬ gery: • The recommended dose is 2.5 mg orally twice daily. (2.1 > • Treatment of DVT and PE: • The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. (2.11 • Reduction in the risk of recurrent DVT and PE following initial therapy: • The recommended dose is 2.5 mg taken orally twice daily. (2.1) -DOSAGE FORMS AND STRENGTHS• Tablets: 2.5 mg and 5 mg (3) -CONTRAINDICATIONS• Active pathological bleeding (4) • Severe hypersensitivity to ELIQUIS (4) -WARNINGS AND PRECAUTIONS• ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss. (5.2' • Prosthetic heart valves: ELIQUIS use not recom¬ mended. (5.4) -ADVERSE REACTIONSMost common adverse reactions (>1%) are related to bleed¬ ing. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

-DRUG INTERACTIONS• Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban. Reduce ELIQUIS dose or avoid coadministration. (2.5, 7.1, 12.3) • Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces blood levels of apixaban: Avoid concomitant use. (7.2, 12.3) -USE IN SPECIFIC POPULATIONS• Pregnancy: Not recommended. (8.1) • Nursing Mothers: Discontinue drug or discontinue nurs¬ ing. (8.3) • Severe Hepatic Impairment: Not recommended. (8.7. 12.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 9/2015

WARNING:

(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (A) PREMATURE DISCONTINUATION OF ELIQUIS IN¬ CREASES THE RISK OF THROMBOTIC EVENTS: Pre¬ mature discontinuation of any oral anticoagulant, in¬ cluding ELIQUIS, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if ELIQUIS is discontinued for a reason other than pathological bleeding or comple¬ tion of a course of therapy. (2.4, 5.1, 14.1) (B) SPINAL/EPIDURAL HEMATOMA: Epidural or spi¬ nal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal pro¬ cedures. (5.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROM¬ BOTIC EVENTS (B) SPINAL/EPIDURAL HEMATOMA 1 INDICATIONS AND USAGE 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation 1.2 Prophylaxis of Deep Vein Thrombosis Follow¬ ing Hip or Knee Replacement Surgery 1.3 Treatment of Deep Vein Thrombosis 1.4 Treatment of Pulmonary Embolism 1.5 Reduction in the Risk of Recurrence of DVT and PE 2 DOSAGE AND ADMLNISTRATION 2.1 Recommended Dose 2.2 Missed Dose 2.3 Temporary Interruption for Surgery and Other Interventions 2.4 Converting from or to ELIQUIS 2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein

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Look for PDR drug information and services in your EHR 2.6 Administration Options DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation 5.2 Bleeding 5.3 Spinal/Epidural Anesthesia or Puncture 5.4 Patients with Prosthetic Heart Valves 5.5 Acute PE in Hemodynamically Unstable Pa¬ tients or Patients who Require Thrombolysis or Pulmonary Embolectomv 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Strong Dual Inhibitors of CYP3A4 and P-gp 7.2 Strong Dual Inducers of CYP3A4 and P-gp 7.3 Anticoagulants and Antiplatelet Agents 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCL1NICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation 14.2 Prophylaxis of Deep Vein Thrombosis Follow¬ ing Hip or Knee Replacement Surgery 14.3 Treatment of DVT and PE and Reduction'in the Risk of Recurrence of DVT and PE 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

ELIQUIS • BRISTOL-MYERS SQUIBB/707 Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE*

3 4 5

WARNING: (A) PREMATURE DISCONTINUA¬ TION OF ELIQUIS (apixaban) INCREASES THE RISK OF THROMBOTIC EVENTS (B) SPINAL/EPIDURAL HEMATOMA (A) PREMATURE DISCONTINUATION OF ELIQUIS IN¬ CREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontin¬ ued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [seeDosage and Admin¬ istration (2.41, Warnings and Precautions (5.1), and Clinical Studies (14.1)1 (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial an¬ esthesia or undergoing spinal puncture. These hema¬ tomas may result in long-term or permanent paraly¬ sis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemosta¬ sis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of ELIQUIS and neuraxial procedures is not known (see Warnings and Precautions (5.3)1 Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compro¬ mise is noted, urgent treatment is necessary (see Warnings and Precautions (5.3)1 Consider the benefits and risks before neuraxial inter¬ vention in patients anticoagulated or to be anticoagu¬ lated (see Warnings and Precautions (5.3)1

1

Warfarin N=9052 n (per 100 pt-year)

327 (2.13) 52 (0.33) 38 (0.24) 15 (0.10) 128 (0.83) 10 (0.06) 4 (0.03) 6 (0.04)

462 (3.09) 125 (0.82) 74 (0.49) 51 (0.34) 141 (0.93) 37 (0.24) 30 (0.20) 7 (0.05)

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

ELIQUIS* (apixabani is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Hazard Ratio (95% Cl*)

0.69 (0.60, 0.41 (0.30, 0.51 (0.34, 0.29 (0.16, 0.89 (0.70, 0.27 (0.13, 0.13 (0.05, 0.84 (0.28,

P-value

0.80) 0.57) 0.75) 0.51) 1.14) 0.53) 0.37) 2.15)

2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal outcome. Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed. 4 On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14. 1 GI bleed includes upper GI, lower GI, and rectal bleeding. ** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period. 1.2

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replace¬ ment surgery. 1.3

Treatment of Deep Vein Thrombosis

ELIQUIS is indicated for the treatment of DVT. 1.4

Treatment of Pulmonary Embolism

ELIQUIS is indicated for the treatment of PE. 1.5

Reduction in the Risk of Recurrence of DVT and PE

ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Pa¬ tients with Nonvalvular Atrial Fibrillation

FULL PRESCRIBING INFORMATION

1.1

Major' Intracranial* Hemorrhagic stroke8 Other ICH Gastrointestinal (GI)* Fatal** Intracranial Non-intracranial

ELIQUIS N=9088 n (per 100 pt-year)

The recommended dose of ELIQUIS (apixaban) for most pa¬ tients is 5 mg taken orally twice daily. The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the following characteristics: • age >80 years • body weight 1.5 mg/dL Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dosd should be taken 12 to 24 hours after surgery. • In patients undergoing hip replacement surgery, the rec¬ ommended duration of treatment is 35 days. • In patients undergoing knee replacement surgery, the rec¬ ommended duration of treatment is 12 days. Treatment of DVT and PE

The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE

The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE [see Clinical Studies (14.3)]. 2.2

Missed Dose

If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed doge. 2.3

Temporary Interruption for Surgery and Other Inter¬ ventions

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in lo¬ cation and easily controlled. Bridging anticoagulation dur¬ ing the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. 2.4 Converting from or to ELIQUIS Switching from warfarin to ELIQUIS: Warfarin should be

discontinued and ELIQUIS started when the international normalized ratio (INR) is below 2.0. Switching from ELIQUIS to warfarin: ELIQUIS affects INR. so that initial INR measurements during the transi¬

tion to warfarin may not be useful for determining the ap¬ propriate dose of warfarin. One approach is to discontinue ELIQUIS (apixaban) and begin both a parenteral anticoag¬ ulant and warfarin at the time the next dose of ELIQUIS would have been taken, discontinuing the parenteral anti¬ coagulant when INR reaches an acceptable range. Switching from ELIQUIS to anticoagulants other than war¬ farin (oral or parenteral): Discontinue ELIQUIS and begin

taking the new anticoagulant other than warfarin at the usual time of the next dose of ELIQUIS. Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: Discontinue the anticoagulant

other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than war¬ farin. 2.5

Strong Dual P-glycoprotein

Inhibitors

of

CYP3A4

and

For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 5091 when ELIQUIS is coad¬ ministered with drugs that are strong dual inhibitors of cy¬ tochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) Isee Clinical Pharmacology (12.3)].

In patients already taking 2.5 mg twice daily, avoid coad¬ ministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)]. 2.6

Administration Options

For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets may be crushed and sus¬ pended in 60 mL D5W and immediately delivered through a nasogastric tube (NGT) [see Clinical Pharmacology (12.3)]. Information regarding the administration of crushed and suspended ELIQUIS tablets swallowed by mouth is not available. 3 DOSAGE FORMS AND STRENGTHS • 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and “2V4" on the other side. • 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and “5” on the other side. 4 CONTRAINDICATIONS ELIQUIS is contraindicated in patients with the following conditions: • Active pathological bleeding [see Warnings and Precau¬ tions (5.2) and Adverse Reactions (6.1)]

• Severe hypersensitivity reaction to ELIQUIS (e g., ana¬ phylactic reactions) [see Adverse Reactions (6.1)] 5 5.1

WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Prema¬ ture Discontinuation

Premature discontinuation of any oral anticoagulant, in¬ cluding ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibril¬ lation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant /see Dosage and Administration (2.4) and Clinical Studies (14.1)]. 5.2 Bleeding ELIQUIS increases the risk of bleeding and can cause seri¬ ous. potentially fatal, bleeding [see Dosage and Administra¬ tion (2.1) and Adverse Reactions (6.1)].

Free mobile PDR app for fast drug references on Apple or Android devices

/08/BRISTOL-MYERS SQUIBB • ELIQUIS

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard Monitor patients frequently for signs and symptoms of neu¬ rological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compro¬ mise is noted, urgent diagnosis and treatment i9 necessary. Prior to neuraxial intervention the physician should con¬ sider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thrombopro¬ phylaxis.

Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics - ARISTOTLE Study n ot Events / N ot Patients (% per yr) Apixaban Hazard Ratio (95% Cl) Warfarin

Subgroup

462/9052 (3.1)

0.69 80 mL/min (41%)

-*

i-4«-

5.5

f-#-i H*H

i-•—4—i

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing informa¬ tion. • Increased risk of thrombotic events after premature dis¬ continuation /see Warnings and Precautions (5.1)1 • Bleeding /see Warnings and Precautions (5.2)1 • Spinal/epidural anesthesia or puncture /see Warnings and

i—I#—

! i—« —1 >•*

Precautions (5.3)] 6.1 Clinical Trials Experience

i—•-!—«

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

H#—I (-*-! |- -rH

Reduction of Risk of Stroke and Systemic Embolism in Pa¬ tients with Nonvaivuiar Atrial Fibrillation

i—•—k H#-h h-1’0— f

Geographic Region

Yes (31%) No (69%)

129 / 2846 (2.7) 198/6242(1.9)

164/2762(3.7) 298/6290 (2.8)

0.75(0.56,1.00) 0.68 (0.57, 0.80)

i—-!•—

0.75 (0.60, 0.95) 0.66 (0.55, 0.79)

1——f

0.125

FfH

0.25

0.5

2

Apixaban Better

Warfarin Better

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which vvere prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Table 2: Bleeding Events in Patients with Nonvaivuiar Atrial Fibrillation in AVERROES

Major Fatal Intracranial

ELIQUIS N=2798 n (%/year)

Aspirin N=2780 n (%/year)

Hazard Ratio (95% Cl)

P-value

45(1.41) 5(0.16) 11 10.34)

29(0.92) 5(0.161 11 (0.35)

1.54 (0.96, 2.45) 0.99 (0.23. 4.29) 0.99 (0.39, 2.51)

0.07 .. -

Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplate¬ let agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti¬ inflammatory drugs (NSAIDs) I see Drug Interactions 17.3)1. Advise patients of signs and symptoms of blood lass and to report them immediately or go to an emergency room. Dis¬ continue ELIQUIS i apixaban I in patients with active path¬ ological hemorrhage. There is no established way to reverse the anticoagulant ef¬ fect of apixaban. which can be expected to persist for at least 24 hours after the last dose, i.e.. for about two drug half-lives. A specific antidote for ELIQUIS is not available. Hemodialysis does not appear to have a substantial impact on apixaban exposure I see Clinical Pharmacology 112.3)1. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experi¬ ence with antifibrinolytic agents ftranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is nei¬ ther scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and apnitmini in indi¬ viduals receiving apixaban Use of procoagulant reversal I

Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy

Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of pa¬ tients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolec¬ tomy.

H#h h-*-H

0.68 (0.58, 0.80)

109/1693 (3.8)

Patients with Prosthetic Heart Valves

The safety and efficacy of ELIQUIS (apixaban) have not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these pa¬ tients.

i-*-f

0.64 (0.52, 0.79)

294 / 5879 (3.0)

5.4

4

*

0.73 (0.59, 0.91)

225 5868 (2 3) 102/3220(1.9)

Weight £60 kg (11%)

+
12 months for 9375 patients and >24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years). The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.771 and 2.571 of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.591 and 1.3% on ELIQUIS and aspirin, re¬ spectively. Bleeding in Patients w-ith Nonvaivuiar Atrial Fibrillation in ARISTOTLE and AVERROES Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleed¬ ing rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVER¬ ROES. [See table 1 at top of previous page] In ARISTOTLE, the results for major bleeding were gener¬ ally consistent across most major subgroups including age, weight, CHADS2 score (a scale firom 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use. geographic region, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year). [See figure 1 above] [See table 2 above) Other Adverse Reactions Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as aller¬ gic edema) and syncope were reported in 0.1% to Grade 2) occurring in less than 2% of subjects receiving atazanavir coadministered with cobicistat and emtricit¬ abine/tenofovir DF are listed below. These events have been included because of investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with atazanavir coadministered with cobicistat, and reported with greater frequency compared with the atazanavir coad¬ ministered with ritonavir group. Gastrointestinal Disorders: dominal pain

diarrhea, vomiting, upper ab¬

General Disorders and Administration Site Conditions: tigue Musculoskeletal and Connective Tissue Disorders: myolysis Nervous System Disorders: headache Psychiatric Disorders: somnia

fa¬

rhabdo-

depression, abnormal dreams, in¬

Renal and Urinary Disorders: drome Laboratory Abnormalities

nephropathy, Fanconi syn¬

The frequency of laboratory abnormalities (Grades 3-4) oc¬ curring in at least 2% of subjects in the atazanavir coadmin¬ istered with cobicistat group in Studies 105 and 114 is pre¬ sented in Table 3. Table 3:

Laboratory Abnormalities (Grades 3-4) Reported

Reported in >2% of HIV-1 Infected Treatment-Naive Adults

in >2% of HIV-1 Infected Treatment-Naive Adults in the

in the Atazanavir Coadministered with Cobicistat Group in Studies 105 and 114 (Week 48 pooled analysis)

Atazanavir Coadministered with Cobicistat Group in Studies 105 and 114 (Week 48 pooled analysis)

Atazanavir

Atazanavir

coadministered

coadministered

48 weeks Atazanavir

48 weeks Atazanavir

with cobicistat

with ritonavir

coadministered

coadministered

and

and

with cobicistat

emtricitabine/ tenofovir DF

emtricitabine/

and

with ritonavir and

tenofovir DF

emtricitabine/

(n=394)

(n=377)

tenofovir DF

emtricitabine/ tenofovir DF

Jaundice

5%

3%

|n=394)

(n=377)

Rash1’

5%

4%

Ocular icterus

3%

1%

65%

56%

Nausea

2%

2%

Creatine Kinase (>10.0 x ULN)

5%

6%

Serum Amylase* 2.0 x ULN)

4%

2%

ALT (>5.0 x ULN)

3%

2%

AST i>5.0 x ULN)

3%

2%

GGTO5.0 x ULN)

2%

1%

Urine Glucose (Glycosuria >1000 mg/dL)

3%

1%

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibi¬ tors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with prote¬ ase inhibitors was continued or reintroduced. A causal rela¬ tionship between protease inhibitor therapy and these events has not been established. 6

Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naive Adults Receiving

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), pe¬ ripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance" have been observed in patients re¬ ceiving antiretroviral therapy. The mechanism and long¬ term consequences of these events are currently unknown. A causal relationship has not been established. 5.13

Table 4:

Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir

Antiretrovirals that are Not Recommended

EVOTAZ is not recommended in combination with other an¬ tiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing recommendations for such com¬ binations have not been established and coadministration may result in decreased plasma concentrations of the anti¬ retroviral agents, leading to loss of therapeutic effect and development of resistance. EVOTAZ is not recommended in combination with products containing the individual components of EVOTAZ (atazanavir or cobicistat). EVOTAZ is not recommended in combination with ritonavir or products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. See Drug Interactions (7) for additional recommendations on use with other anti¬ retroviral agents. 5.9

EVOTAZ • BRISTOL-MYERS SQUIBB/717

‘ Frequencies of adverse reactions are based on Grades 2-4 adverse events attributed to study drugs. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria. Nephrolithiasis: Nephrolithiasis has previously been iden¬ tified in patients receiving atazanavir Isee Warnings and Precautions 15.5)/. In the pooled analysis of Studies 105 and

Laboratory Parameter Abnormality

Ibtal Bilirubin (>2.5 x ULN)

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Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

718/BRISTOL-MYERS SQUIBB • EVOTAZ Table 5:

Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies* or Predicted Interactions

Urine RBC (Hematuria) (>75 RBC/HPF)

3%

2%

Concomitant Drug Class: Clinical Comment

Effect on Concentration

Specific Drugs

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs)

HIV Antiretroviral Agents: didanosine buffered formulations entcric-coated (EC) capsules

i atazanavir l didanosine

tenofovir disoproxil fumarate

l atazanavir T tenofovir

HIV Antiretroviral Agents:

Coadministration of atazanavir with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure (presumably due to the increase in gastric pH caused by buffers in the didanosine tablets). It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times. Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions [see Warnings and Precautions (5.4)].

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

efa viren z

1 atazanavir i cobicistat times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carci¬ nomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thy¬ roid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose. Mutagenesis Atazanavir: Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Cobicistat: CobiciBtat was not genotoxic in the reverse mu¬ tation bacterial test (Ames testi, mouse lymphoma or rat micronucleus assays.

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR Impairment of Fertility Atazanavir: At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir coadminis¬ tered with 100 mg/day ritonavir) significant effects on mat¬ ing, fertility, or early embryonic development were not ob¬ served. Cobicistat: Cobicistat did not affect fertility in male or fe¬ male rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats ex¬ posed daily from before birth (in utero) through sexual ma¬ turity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

14

CLINICAL STUDIES

The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naive subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg coadministered with cobicistat 150 mg once daily or atazanavir 300 mg coadministered with ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as a single tablet. Randomization was stratified by screening HIV-1 RNA level (5100,000 copies/mL or >100,000 copies/mL). The mean age of subjects was 37 years (range: 19-70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range: 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm3 (range: 1-1455) and 17% had CD4+ cell counts 100,000 copies/mL. Virologic outcomes in Study 114 through Week 48 are pre¬ sented in Table 8. In Study 114, the mean increase from baseline in CD4+ cell count at Week 48 was 213 cells/mm3 in patients receiving atazanavir coadministered with cobicistat and 219 cells/mm3 in patients receiving atazanavir coadministered with ritonavir. [See table 8 above]

16

HOW SUPPLIED/STORAGE AND HANDLING

EVOTAZ™ (atazanavir/cobicistat) tablets, 300 mg atazanavir and 150 mg cobicistat, are oval, biconvex, pink, film:coated, debossed with “3641” on one side and plain on the other side. Each bottle contains 30 tablets (NDC-00033641-11), a silica gel desiccant and is closed with a childresistant closure. Store EVOTAZ tablets at 25°C (77'F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Con¬ trolled Room Temperature]. Keep container tightly closed.

17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient Information). A statement to patients and healthcare providers is in¬ cluded on the product’s label: ALERT: Find out about medicines that should NOT be taken with EVOTAZ. Inform patients that EVOTAZ is not a cure for HIV infection and they may continue to experience illnesses associated with HIV infection, including opportunistic infections. In¬ form patients that sustained decreases in plasma HIV RNA are associated with a reduced risk of progression to AIDS and death. Advise patients they should remain under the care of a healthcare provider when using EVOTAZ. Advise patients to avoid doing things that can spread HIV’ infection to others. • Do not share or reuse needles or other injection equip¬ ment. • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. • Do not breastfeed. It is not known if EVOTAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk. Dosing Instructions Advise patients to take EVOTAZ with food every day and take other concomitant antiretroviral therapy as prescribed. Inform patients that EVOTAZ must always be used in com¬ bination with other antiretroviral drugs. Tell patients not to discontinue therapy without consulting with their health¬ care provider. Advise patients not to miss a dose of EVOTAZ, but if they do miss a dose they should follow the guidelines below. • If a dose of EVOTAZ is missed by 12 hours or less, take the missed dose of EVOTAZ right away. Take the next dose of EVOTAZ at the usual time.

EVOTA2 • BRISTOL-MYERS SQUIBB/723 Table 8:

Virologic Outcomes of Randomized Treatment of Study 114 in HIV-1 Infected Treatment-Naive Adults at Week 48* Atazanavir 300 mg coadministered with cobicistat 150 mg (once daily)

Atazanavir 300 mg coadministered with ritonavir 100 mg

emtricitabine/tenofovir disoproxil fumarate (n=344)

emtricitabine/tenofovir disoproxil fumarate (n=348)

HIV-1 RNA 50 copies/mLb No Virologic Data at Week 48 Window Discontinued Study Drug Due to AE or Death' Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA of patients treated with the cyclosporine control regimen CAN was not evalu¬ ated after the first year following transplantation. The clin¬ ical significance of this finding is unknown 16

HOW SUPPLIED/STORAGE AND HANDLING

NLl.OJIX* (belatacept! Ivophihzed powder for intravenous infusion is supplied as a single use vial with a silicone-free

disposable syringe in the following packaging configuration:

Tfell patients to immediately report any signs and symptoms of infection during therapy with NULOJIX [see Warnings

and Precautions ) in patients with mel¬ anoma was rash. (6.1) Most common adverse reactions (a^OriF) in patients with ad¬ vanced squamous non-small cell lung cancer were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.Fde.gov/medwtBfi.

Dose Modifications

|

nudism or hyperthyroidism

i

Withhold OPDIVO for any of the following • Grade 2 pneumonitis /see Hbrnings and Precaution • Grade 2 or 3 colitis /are Warning* and Precaution* '5 2'/

• Aspartate aminotransferase (AST) or alanine aminotrans¬ ferase (ALT' greater than 3 and up to 5 limes upper limit of normal (ULN) or total bilirubin greater than 15 and up to 3 times ULN /see Warnings and Precaution* Grade 2 increased creatinine, requirement for corticoster¬ (2/268) of patients at 3.5 and 6 months after OPDIVO initi¬ ation. respectively. OPDIVO was permanently discontinued in both patients: both received high-dose corticosteroids lat

Storage of Infusion

followed by corticosteroid taper. Permanently discontinue

The product does not contain a preservative.

OPDIVO for severe (Grade 3) or life-threatening (Grade 4)

least 40 mg prednisone equivalents). Immune-mediated ne¬ phritis resolved and did not recur with continuation of cor¬

After preparation, store the OPDIVO infusion either: • at room temperature for no more than 4 hours from the

pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Adminis¬

ticosteroids in one patient. Renal dysfunction was ongoing in one patient.

tration (2.2)1. 5.2 Immune-Mediated Colitis

In Trial 3, the incidence of elevated creatinine was 22%.

time of preparation. This includes room temperature stor¬ age of the infusion in the IV container and time for admin¬ istration of the infusion or

Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of

• under refrigeration at 2°C to 8°C (36°F-46°F) for no more

patients receiving OPDIVO and 18% (18/102) of patients re¬

was 0.8 months. The patient received high-dose corticoster¬

than 24 hours from the time of infusion preparation. Do not freeze.

ceiving chemotherapy. Immune-mediated colitis, defined as

oids. OPDIVO was withheld, and the patient discontinued due to disease progression prior to receiving additional

Administration

requiring use of corticosteroids with no clear alternate eti¬ ology, occurred in 2.2% (6/268) of patients receiving

Administer the infusion over 60 minutes through an intra¬

OPDIVO: five patients with Grade 3 and one patient with

OPDIVO. Immune-mediated renal dvsfunction was ongo¬ ing.

venous line containing a sterile, non-pyrogenic, low protein

Grade 2 colitis. The median time to onset of immune-

Monitor patients for elevated serum creatinine prior to and

binding in-line filter (pore size of 0.2 micrometer to 1.2 mi¬ crometer).

mediated colitis from initiation of OPDIVO was 2.5 months

periodically during treatment. Administer corticosteroids at

(range: 1 to 6 months). In three patients, colitis was diag¬ nosed after discontinuation of OPDIVO for other reasons,

a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum

and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients.

creatinine elevation and permanently discontinue OPDIVO.

Do not coadminister other drugs through the same intravenous line. Flush the intravenous line at end of infusion. 3

DOSAGE FORMS AND STRENGTHS

Injection: 40 mg/4 mL (10 mg/mL) and (10 mg/mL) solution in a single-use vial.

100 mg/10 mL

|

Five of these six patients received high-dose corticosteroids

For severe (Grade 3) or moderate (Grade 2) serum creati¬ nine elevation, withhold OPDIVO and administer cortico¬

(at least 40 mg prednisone equivalents) for a median dura¬ tion of 1.4 months (range: 3 days to 2.4 months) preceding

steroids at a dose of 0.5 to 1 mg/kg/day prednisone equiva¬ lents followed by corticosteroid taper; if worsening or no

corticosteroid taper. The sixth patient continued on low-

improvement occurs, increase dose of corticoeteroids to 1 to

dose corticosteroids started for another immune-mediated

2 mg/kg/dav prednisone equivalents and permanently dis¬

None.

adverse reaction. Immune-mediated colitis improved to

5

Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolu¬

continue OPDIVO /see Dosage and Administration (2-2) and Adverse Reactions (6.1)1. 5.5 Immune-Mediated Hypothyroidism and Hyperthy¬ roidism

4

5.1

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis

tion (defined as improved to Grade 0 with completion of cor-

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the

ucosteroidsi without additional events of colitis. Grade 2 co¬ litis was ongoing in one patient.

In Trial 1, where patients were evaluated at baseline and !

during the trial for thyroid function. Grade 1 or 2 hypothy-

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OPDiVO • BRISTOL-MYERS SQUIBB/735

roidism occurred in 8% (21/268) of patients receiving

Table 2: Selected Laboratory Abnormalities Worsening from Baseline Occurring in £10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of >5% (All Grades! or >2% (Grades 3-41) (Trial 1)

OPDIVO (nivolumab) and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days to 11.7 months). Seventeen of the 21 pa¬ tients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while

Percentage of Patients with Worsening Laboratory Test frdm Baseline*

continuing to receive levothyroxine.

OPDIVO

Chemotherapy

Grade 1 or 2 hyperthyroidism occurred in 37? (8/268) of pa¬ tients receiving OPDIVO and 17? (1/102) of patients receiv¬

Test

All Grades

Grades 3-4 2.4

12

1.0

2.4

13

All Grades

Grades 3-4

ing chemotherapy. The median time to onset in OPDIVOtreated patients was 1.6 months (range: 0 to 3.3 months).

Increased AST

Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had docu¬

Increased alkaline phosphatase

28 22

Hyponatremia

25

5

mented resolution of hyperthyroidism; all three patients re¬

Increased ALT

16

1.6

18 5

1.1 1.1 0

ceived medical management for Grade 2 hyperthyroidism.

Hyperkalemia

15

2.0

6

0

In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and every 6 weeks. Hypo¬

“ Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range 252 to 256 patients) and chemotherapy group (range 94 to 96 patientsi.

thyroidism occurred in 4.3% (5/117) of patients. The median time to onset for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with hypothyroidism re¬ ceived levothyroxine. Complete resolution of hypothyroid¬

randomized trial in patients with unresectable or meta¬

ism occurred in one patient allowing discontinuation of le¬

static melanoma and in Trial 3, a single-arm trial in pa¬

hyperthyroidism. There are no recommended dose adjust¬ ments of OPDIVO for hypothyroidism or hyperthyroidism.

able or metastatic melanoma received OPDIVO 3 mg/kg ev¬

metastatic squamous NSCLC and progression on both a prior platinum-based therapy and at least one additional systemic therapy [see Clinical Studies 65 years of age and 14% >75 years of age. The majority of patients were male (73%) and white (85%). All patients received two or more prior systemic

ery

of

treatments. Baseline disease characteristics of the popula¬

5.6

Other Immune-Mediated Adverse Reactions

chemotherapy (n=102), either dacarbazine 1000 mg/m" ev¬

tion were recurrent Stage Illb (6%), Stage IV (94%), and

Other clinically significant immune-mediated adverse reac¬

ery 3 weeks or the combination of carboplatin AUC 6 every

brain metastases (1.7% ). Baseline ECOG performance sta¬

tions can occur. Immune-mediated adverse reactions may

3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clin¬

tus was 0 (22%) or 1 (78%).

occur after discontinuation of OPDIVO therapy.

ical Studies (14.1)]. The median duration of exposure was

OPDIVO was discontinued due to adverse reactions in 27%

The following clinically significant, immune-mediated ad¬

5.3 months (range: 1 day to 13.8+ months) with a median of

verse reactions occurred in less than 27? of OPDIVO-treated

eight doses (range: 1 to 31) in OPDIVO-treated patients and

of patients. Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious

patients in Trials 1 and 3 (n=385): adrenal insufficiency,

was 2 months (range: 1 day to 9.6+ months) in chemother¬

adverse reactions occurred in 59%, of patients receiving

uveitis, pancreatitis, facial and abducens nerve paresis, de-

apy treated patients. In this ongoing trial, 24% of patients

OPDIVO. The most frequent serious adverse reactions re¬

myelination, autoimmune neuropathy, motor dysfunction,

received OPDIVO for greater than 6 months and 3% of pa¬

and vasculitis. Across clinical trials of OPDIVO administered at doses of

tients received OPDIVO for greater than 1 year.

ported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneu¬

In Trial 1, patients had documented disease progression fol¬

monitis, hypercalcemia, pleural effusion, hemoptysis, and

3 mg/kg and 10 mg/kg the following additional clinically sig¬

lowing treatment with ipilimumab and, if BRAF V600 mu¬

nificant, immune-mediated adverse reactions were identi¬ fied: hvpophysitis, diabetic ketoacidosis, hypopituitarism,

tation positive, a BRAF inhibitor. The trial excluded pa¬

pain. Table 3 summarizes adverse reactions that occurred in at

vothyroxine. Interruption of OPDIVO did not occur in these

tients with metastatic squamous non-small cell lung cancer

five patients.

(NSCLC).

Hyperthyroidism occurred in 1.7% (2/117) of patients. One

Clinically significant adverse reactions were evaluated in a

patient experienced Grade 2 hyperthyroidism 5.2 months

total of 691 patients enrolled in Trials 1, 3, or an additional

after the first dose of OPDIVO, requiring treatment with

dose

high-dose corticosteroids and methimazole. Thyroid labora¬

(nivolumab) at doses of 0.1 to 10 mg/kg every 2 weeks [see

tory tests returned to normal 4.7 months later.

Warnings and Precautions (5:1, 5.6)]. Unresectable or Metastatic Melanoma

Monitor thyroid function prior to and periodically during

finding

study

(n=306)

administering

OPDIVO

The safety of OPDIVO was evaluated in Trial 1, a random¬

treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of

ized, open-label trial in which 370 patients with unresect¬ 2

weeks

(n=268)

or

investigator’s

choice

tients with autoimmune disease, prior ipilimumab-related

least 10% of patients. The most common adverse reactions

Guillain-Barre syndrome, and myasthenic syndrome. For any suspected immune-mediated adverse reactions, ex¬

Grade 4 adverse reactions (except for endocrinopathies) or

(reported in at least 20% of patients) were fatigue, dyspnea,

Grade 3 ipilimumab-related adverse reactions that had not

musculoskeletal pain, decreased appetite, cough, nausea,

clude other causes. Based on the severity of the adverse re¬

resolved or were inadequately controlled within 12 weeks of

and constipation.

action, withhold OPDIVO, administer high-dose corticoster¬

the initiating event, patients with a condition requiring

oids, and if appropriate, initiate hormone-replacement

chronic systemic treatment with corticosteroids (>10 mg

therapy. Upon improvement to Grade 1 or less, initiate cor¬

daily prednisone equivalent) or other immunosuppressive

ticosteroid taper and continue to taper over at least 1

medications, a positive test for hepatitis B or C, and a his¬

month. Consider restarting OPDIVO after completion of

tory of HIV.

corticosteroid taper based on the severity of the event [see

The study population characteristics in the OPDIVO group

Dosage and Administration 10% of Patients for All NCI CTCAE* Grades or >5% for Grades 3-4 (Trial 3) OPDIVO (n=117) Adverse Reaction

All Grades

to a pregnant woman. In animal reproduction studies, ad¬

melanoma, 73% received two or more prior therapies for ad¬

ministration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in in¬

vanced or metastatic disease, and 18% had brain metasta¬ sis. There were more patients in the OPDIVO group with

creased abortion and premature infant death. Advise preg¬

elevated LDH at baseline (51% vs. 38%).

nant women of the potential risk to a fetus. Advise females

OPDIVO was discontinued for adverse reactions in 97? of

of reproductive potential to use effective contraception dur¬

patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse

Fatigue

50

Asthenia

19

the last dose of OPDIVO /see Use in Specific Populations

reactions occurred in 41% of patients receiving OPDIVO.

Edema"

, and 3.0% of efavirenz-treated patients (n=329). In Study AJ424045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/ 116) of lopinavir/ritonavir-treated patients who had on-

study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or secondor third-degree AV block). ECG monitoring should be con¬ sidered in these patients. [See Clinical Pharmacology

(12.2).] 5.2

Rash

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ (atazanavir). The median time to onset of rash in clinical studies was 7.3 weeks and the me¬ dian duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or se¬ vere rash (occurring at a rate of £2%) are presented for the individual clinical studies [see Adverse Reactions (6. III. Dos¬ ing with REYATAZ was often continued without interrup¬ tion in patients who developed rash. The discontinuation rate for rash in clinical trials was bilirubin related to in¬ hibition of UDP-glucuronosyl transferase (UGT). This hy¬ perbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative eti¬ ologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal lULN). Alternative antiret¬ roviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations pre¬ sents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established. [See Adverse Reac¬ tions (6.1, 6.2/.] 5.4

Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylke¬ tonuria (PKU). REYATAZ oral powder contains phenylala-

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REYATA2 • BRISTOL-MYERS SQUIBB/749

Table 8: Selected Treatment-Emergent Adverse Reactions* of Moderate or Severe Intensity Reported in >2% of Adult Treatment-Naive Patients,6 Studies AI424-034, AI424-007, and AI424-008 Study AI424-034

Studies AI424-007, -008

64 weeks0

120 weekscd

73 weekso d netfinavir 750 mg TID

64 weeks0

REYATAZ 400 mg

or 1250 mg BID +

efavirenz 600 mg once

once daily + stavudine

stavudine +

lamivudine +

daily + lamivudine +

+ lamivudine or

lamivudine or

zidovudine* (n=404)

zidovudine* (n=401)

didanosine (n=279)

didanosine (n=191)

6%

6%

1%

2%

The most common adverse reactions were nausea, jaundice/ scleral icterus, and rash.

14%

12%

6%

4%

7%

*

7%

♦

4% 4% 1%

7% 4% 2%

3% 3%

3% 2% 16%

Selected clinical adverse reactions of moderate or severe in¬ tensity reported in >2% of treatment-naive patients receiv¬ ing combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

3% 2%

3% 7%

5.1 x ULN 25.1 x ULN >2.6 x ULN >2.1 x ULN >5.1 x ULN >240 mg/dL Low 5.1 x ULN >2.6 x ULN >2.1 x ULN 22.1 x ULN 25.1 x ULN 2240 mg/dL 2751 mg/dL Low 5 times ULN devel¬ oped in 9% of the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavirtreated patients. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted be¬ tween seropositive and seronegative patients. /See Warn¬ ings and Precautions (5.3).] 6.4

* " b c d

None reported in this treatment arm. Based on regiments) containing REYATAZ. Median time on therapy. Includes long-term follow-up. ULN = upper limit of normal. As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

dyslipidemia was less with REYATAZ (atazanavir i/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. [See table 15 at top of page 752]

b Based on the regimen containing REYATAZ. ' Median time on therapy. d As a fixed-dose combination.

6.2 Clinical Trial Experience in Pediatric Patients Laboratory Abnormalities in Treatment-Naive Patients

Adverse Reactions in Pediatric Patients: REYATAZ Capsules

The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ (atazanavir) 400 mg (with¬ out ritonavir) with Grade 3-4 laboratory abnormalities are presented in Tables 10 and 11, respectively. [See table 10 above) [See table 11 above)

For Study A1424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total choles¬ terol. and triglycerides are shown in Tables 13 and 14, re¬ spectively. [See table 13 at top of next page] ISee table 14 at top of next page]

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric pa¬ tients at least 6 years of age from the open-label, multi¬ center clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2-4 adverse events (£5%, regardless of causality) reported in pediatric patients were cough (21%), fever (18%), jaundice/scleral ic¬ terus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in ], pruritus, angioedema 7

DRUG INTERACTIONS

See also Contraindications (4) and Clinical Pharmacology (12.3). 7.1

Potential for REYATAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coad¬ ministration of REY’ATAZ and drugs primarily metabolized by CYP3Aor UGT1A1 may result in increased plasma con¬ centrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow ther¬ apeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not ex¬ pected. I See Clinical Pharmacology. Table 22 (12.3).] The magnitude of CYP3A-mediated drug interactions on co¬ administered drug may change when REYATAZ is coadmin-

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REYATAZ • BRISTOL-MYERS SQUIBB/751

istered with ritonavir. See the complete prescribing infor¬ mation for ritonavir for information on drug interactions with ritonavir. 7.2 Potential (atazanavir)

for

Other

Drugs

to

Affect

Established and Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted in¬ teractions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. [See table 16 on pages 753 through 757]] 7.4

Drugs with No Observed or Predicted Interactions with REYATAZ

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically signifi¬ cant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for infor¬ mation on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Ad¬ ditionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with metha¬ done, fluconazole, acetaminophen, or atenolol. /See Clinical Pharmacology, Tables 21 and 22 (12.3).] 8 8.1

Study AI424-045*

REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that in¬ duce CYP3A4 may decrease atazanavir plasma concentra¬ tions and reduce REYATAZ’s therapeutic effect. Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if protonpump inhibitors, antacids, buffered medications, or H2receptor antagonists are administered with REYATAZ [see Dosage and Administration 2% of Adult Treatment-Experienced Patients,

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B

Antiretroviral Pregnancy Registry: To monitor maternalfetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the back¬ ground rate. However, because the studies in humans can¬ not rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed. Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an in¬ creased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ. including pregnant women. All infants, includ¬ ing neonates exposed to REYATAZ in utero, should be mon¬ itored for the development of severe hyperbilirubinemia during the first few days of life. Clinical Considerations

Dosing During Pregnancy and the Postpartum Period: • REYATAZ should not be administered without ritonavir. • REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir. • For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions: • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadminis¬ tered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antag¬ onist and tenofovir in treatment-experienced pregnant women. • No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher dur¬ ing the first 2 months after delivery. /See Dosage and Ad¬ ministration (2.5) and Clinical Pharmacology (12.3).] Human Data

Clinical Trials: In clinical trial A1424-182, REYATAZ/ ritonavir (300/100 mg or 400/100 mgi in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA

Change* (n=335*l

mg/dL (n=291'|

Change* (n=291*|

92 37

105 46

+14% +29%

105 44

+ 14% +21%

93 36

111 48

+19% +37%

110 46

+ 17% +29%

149 126

169 145

+13% +15%

169 140

+13% + 13%

150 129

187 194

+25% +52%

186 184

+25% +50%

“ REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and I'll in the REYATAZ/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ/ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10'? in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ/ritonavir arm. c Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir, 200 mg emtricitabine once daily. fl The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of patients with LDL-cholesteroI measured. f Fasting.

Table 14: Lipid Values, Mean Change from Baseline, Study AI424-034

LDL-Cholesterol1 HDL-Cholesterol Tbtal Cholesterol Triglycerides1

Baseline

REYATAZ** Week 48

Week 48

Baseline

Week 48

Week 48

mg/dL

mg/dL

Change*

mg/dL

Change*

(n=383*|

(n=283*|

(n=272*l

mg/dL ln=378*l

(n=264*l

(n=253'l

98 39 164 138

98 43 168 124

+1% +13% +2% -9%

98 38 162 129

114 46 195 168

+ 18% +24% +21% +23%

efavirenz*-'

" REYATAZ 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily l> Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and 200 mg/day) should be used cautiously with REYATAZ/ritonavir.

The use of voriconazole in patients receiving REYATAZ/ ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ/ritonavir Coadministration of voriconazole with REYATAZ i without ritonavir) may affect atazanavir concentrations; however, no data are available.

The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever IFMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. (Table continued on next page)

j HTV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also ob-

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REYATAZ • BRISTOL-MYERS SQUIBB/755

Table 16 (cont.f. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies” or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

Concomitant Drug Class: Specific Drugs

Effect on Concentration of Atazanavir or Concomitant Drug

Antipsychotics: quetiapine

T quetiapine

Benzodiazepines: parenterally administered midazo!amb

T midazolam

Calcium channel blockers: diltiazem

felodipine, nifedipine, nicardipine, and verapamil Endothelin receptor antagonists: bosentan

HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin

Hr Receptor antagonists

T diltiazem and desacetyl-diltiazem

T calcium channel blocker i. atazanavir T bosentan

T atorvastatin T rosuvastatin

-l atazanavir

served at the protease cleavage sites following drug selec¬ tion. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other Pis (amprenavir, indinavir, lopinavir, nelfinavir, rito¬

Clinical Comment Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. Coadministration of bosentan in patients on REYATAZ/ ritonavir: For patients who have been receiving REYATAZ/ ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomvolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant women is not recommended. (Tbble continued on next page)

navir, and saquinavir). The 150L and 150V substitutions yielded selective resistance to ATV and amprenavir, respec¬ tively, and did not appear to be cross-resistant. Clinical Studies of Treatment-Nawe Patients: Comparison of Ritonavir-Boosted REYATAZ (atazanavir) vs. Unboosted

REYATAZ (atazanavir): Study A1424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs. REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologie failure isolates with ATV resis¬ tance in each arm is shown in Table 23. [See table 23 at top of page 7641 Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who expe¬ rienced virologie failure I HIV-1 RNA >400 copies/mL) or d iseontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9% I through 96 weeks of treat¬ ment. In the ATV/RTV arm, one of the virologie failure iso¬ lates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, 1851/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure iso¬ lates had baseline phenotypic ATV resistance and IASdefined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold de¬ crease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substi¬ tutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtric¬ itabine resistance with the emergence of either the M184I (n=l) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologie failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on ther¬ apy with the development of PI substitutions L10V, VIII, I54V, G73S, and V82A in addition to baseline PI substitu¬ tions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologie failure isolates developed the M184V substitution and phenotypic emtricitabine resis¬ tance and two developed phenotypic tenofovir disoproxil re¬ sistance. Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clini¬ cal isolates from treatment-naive patients who experienced virologie failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an av¬ erage of 50 weeks of ATV' therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F. G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatmentnaive patients, viral isolates that developed the I50L sub¬ stitution, without other mqjor PI substitutions, showed phe¬ notypic resistance to ATV but retained in cell culture susceptibility to other Pis (amprenavir, indinavir, lopinavir. nelfinavir. ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the 150L substitution on the efficacv of subsequentlv administered Pis. Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologie failure developed substitutions that were associated with resistance to multiple Pis and dis¬ played decreased susceptibility to multiple Pis. The most common protease substitutions to develop in the viral iso¬ lates of patients who failed treatment with jYTV 300 mg once daily and RTV 100 mg once daily (together with teno¬ fovir and an NRTI) included V32I. L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82AZT/L, I85V, and L89V/Q/M/T. Other substitutions that develop!si on ATV/RTV' treatment including E34K/A/Q. G48V. I84V. N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other Pis and could include the develop¬ ment of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experienc¬ ing virologie failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resis¬ tance. Clinical Studies of Pediatric Subjects in AI424-397 /PRINCE 1) and AI424-451 lPRINCE III: No treatmentemergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other Pis arose in the viruses from one subject each (L19I/R. M36M/I, H69K/R. and 172I/V I. None of these viruses acquired phenotypic re¬ sistance to ATV', ATV/RTV', or any NNRT1 or NRTI. In

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756/BRISTOL-MYERS SQUIBB • REYATAZ

Table 16 (cont.h Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies* or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

Concomitant Drug Class: Specific Drugs

Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone

Effect on Concentration of Atazanavir or Concomitant Drug

4- ethinyl estradiol T norgestimatec T ethinyl estradiol T norethindrone'1

• Vt

Immunosuppressants: cyclosporine, sirolimus, tacrolimus

T immunosuppressants

Inhaled beta agonist: salmeterol

T salmeterol

Inhaled /nasal steroid: fluticasone

REYATAZ T fluticasone

REYATAZ/ritonavir T fluticasone

Macrolide antibiotics: clarithromycin

T clarithromycin I 14-OH clarithromycin T atazanavir

AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/1, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance u> ATV tATV phenotypic fold change: 1.74. using a commer¬ cial investigational assay with an ATV' cutoff of 2.2 fold change i. Secondary PI substitutions also arose in the vi¬ ruses of one subject each, including V11V/1, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and

Clinical Comment In treatment-experienced patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir or an H2RA for pregnant women during the second and third trimester. REYATAZ is not recommended for pregnant women during the second and third trimester taking REYATAZ with both tenofovir and an H2RA. Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 meg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 meg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 meg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Concomitant use of fluticasone propionate and REYATAZ/ ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1 J], Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced: consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied. (Table continued on next page)

Q61/E/G emerged in the viruses of two subjects who failed treatment with ATY/RTV, Viruses from three subjects devel¬ oped M184V in the reverse transcriptase, and all three ex¬ hibited phenotypic resistance to emtricitabine and lamivudine. Cross-Resistance Cross-resistance among Pis has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of Pl-experienced patients showed that

isolates cross-resistant to multiple Pis were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73SA7C, A71WT, I54V, M461/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other Pis with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritona¬ vir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients. Pi-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other Pis. Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic re¬ sponse at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced patients re¬ ceiving ATV/RTV once daily or lopinavir (LPVVRTV twice daily in Study AI424-045 is shown in Table 24. Overall, both the number and type of baseline PI substitu¬ tions affected response rates in treatment-experienced pa¬ tients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1-2 PI substitutions, including one of these substitutions. Table 24: HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis Virologic Response = HIV RNA ■> IT-

i*

•

f»l-

“ Data provided are under fed conditions unless otherwise noted. b All drugs were given under fasted conditions. c 400 mg ddl EC and REYATAZ were administered together with food on Days 8 and 19. d Upon further dose normalization of ethinyl estradiol 25 meg with atazanavir relative to ethinyl estradiol 35 meg without atazanavir, the ratio of geometric means (90% confidence intervals) for Cmnx, AUC, and Cmin were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. e Upon further dose normalization of ethinyl estradiol 35 meg with atazanavir/ritonavir relative to ethinyl estradiol 25 meg without atazanavir/ritonavir, the ratio of geometric means (90% confidence intervals) for C,mlx, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. f All subjects were on a 28 day lead-in period; one full cycle of Ortho Tri-Cyclen®. Ortho Tri-Cyclen® contains 35 meg of ethinyl estradiol. Ortho Tri-Cyclen® LO contains 25 meg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 meg. * 17-deacetyl norgestimate is the active component of norgestimate. h (R>-methadone is the active isomer of methadone. 1 Study was conducted in HIV-infected individuals. 1 Subjects were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20. 1 Not the recommended therapeutic dose of atazanavir. m When compared to rifabutin 150 mg QD alone dl-10 (n=14). Total of Rifabutin + 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). “ Rosiglitazone used as a probe substrate for CYP2C8. ° Mean ratio (with/without coadministered drug). T indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the.Cm„„ is about 2905 higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir and REYATAZ was separated by 12 hours. r Administration of tenofovir and REYATAZ was temporally separated by 12 hours. NA = not available.

• REYATAZ (atazanavir) oral powder that is mixed in infant formula or liquid should not be given using a baby bottle. When preparing REYATAZ oral powder with either food or liquid, choose a clean, flat work surface. Place a clean paper towel on the work surface. Place the supplies you w ill need on the paper towel. Wash and dry your hands before and after preparing REYATAZ oral powder. Preparing a dose of REYATAZ oral powder mixed with food:

Before you prepare a dose of REYATAZ oral powder mixed with food, gather the following supplies:

.

1

• paper towel • tablespoon • small clean container

(such as a small cup or bowl) • a food such as applesauce or yogurt • the correct number of packets of REYATAZ oral powder needed for the prescribed dose

1

Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure B).

i

Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure C).

Step 4. Empty the contents of the packet into the small container onto the food (see Figure D).

Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose.

Step 5. Use a tablespoon to

gently mix the powder and the food together (see Figure E).

Steps 6 through 8 must be completed within 1 hour of mixing the medicine. Step 6. Use the tablespoon or a small spoon to feed the REYATAZ oral powder and food mixture to your child. Look in your child’s mouth to make sure that all of the mixture is swallowed. Step 7. Add 1 tablespoon

•hot

more of food to the empty container and gently stir to mix with any contents that may still be in the container.

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764/BRISTOL-MYERS SQUIBB • REYATAZ

Table 23: Summary of Virologic Failures* at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs. Unboosted REYATAZ: Randomized Patients

Step 8. Use the tablespoon or a small spoon to feed your child the mixture, making sure your child has swallowed all of the mixture.

REYATAZ 300 mg

REYATAZ 400 mg

+

Step 9. Give your child ritonavir as prescribed right after taking REYATAZ oral powder. Step 10. Wash the container and tablespoon. Allow the container and spoon to dry. Throw away the paper towel and clean the work surface. Preparing a dose of REYATAZ oral powder mixed with liquid in a small drinking cup: Before you prepare a dose of REYATAZ oral powder mixed with liquid in a small drinking cup, gather the following supplies: • paper towel • spoon • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F. • small drinking cup • liquid such as milk or water • the correct number of packets of REYATAZ oral powder needed for the prescribed dose

Virologic Virologic Virologic Virologic Virologic

15 (16%) 5 0/5 (0%>b 0/5 (0%)b 2/5 (40%)b

34 (32%) 17 4/17 (24%)b 2/17 (12% l*1 11/17 (65% )b

“ Virologic failure includes patients who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response. b Percentage of Virologic Failure Isolates with genotypic and phenotypic data. c Mixture of I50I/L emerged in 2 other ATV 400 mg-treated patients. Neither isolate was phenotypically resistant to ATV.

Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138)

Responderb'c,d Virologic failure6 Rebound Never suppressed through Week 96 Death Discontinued due to adverse event Discontinued for other reasonsf

Figure G

(n=105)

Failure (>50 copies/mL) at Week 96 Failure with Genotypes and Phenotypes Data Failure Isolates with ATV-resistance at Week 96 Failure Isolates with I50L Emergence at Week 96c Failure Isolates with Lamivudine Resistance at Week 96

Outcome

Step 1. Using the 30 mL medicine cup, pour at least 30 mL of liquid into the small drinking cup (see Figure G).

ritonavir 100 mg (n=95)

REYATAZ 300 mg + ritonavir 100 mg (once daily) with tenofovir/emtricitabine (once daily)* (n=441)

lopinavir 400 mg + ritonavir 100 mg (twice daily) with tenofovir/emtricitabine (once daily)* (n=437)

96 Weeks

96 Weeks

75% 17% 8% 9% '• 1% 3% 4%

68% 19% 10% 9% 1% 5% 7%

' Asa fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily. b Patients achieved HIV RNA 2% of SUSTIVA-treated patients in two clinical trials are presented in Table 4. [See table 4 above] Patients Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVAcontaining regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (sur¬ face antigen positive) and/or C (hepatitis C antibody posi¬ tive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the SUSTIVA arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with SUSTIVA-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.8)1. Lipids

other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all er¬ ythema multiforme). Five pediatric patients (2.7%) discon¬ tinued from the study because of rash [see Warnings and Precautions (5.7)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of SUSTIVA (efavirenz). Because these re¬ actions are reported voluntarily from a population of un¬ known size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: allergic reactions, asthenia, redistribu¬ tion/accumulation of body fat [see Warnings and Precautions r5.12)1 Central and Peripheral Nervous System: abnormal coordi¬ nation, ataxia, cerebellar coordination and balance distur¬ bances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: hepatic enzyme increase, he¬ patic failure, hepatitis. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre¬ existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death. Metabolic and Nutritional: hypercholesterolemia, hyper¬ triglyceridemia Musculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide Respiratory: dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Special Senses: abnormal vision, tinnitus 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3Aor CYP2B6 may have decreased plasma concentrations when coadministered with SUSTIVA. Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be ex¬ pected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administra¬ tion (2.1)]. Drug interactions with SUSTIVA are summa¬ rized in Table 5 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 7 and 8)1. This table includes potentially significant interactions, but is not all inclusive. [See table 5 on pages 777 through 7791 Other Drugs Based on the results of drug interaction studies [see Clinical Pharmacology (12.3, Tables 7 and 8/), no dosage adjustment is recommended when SUSTIVA is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, raltegravir, tenofovir disoproxil fumarate, and zidovudine. Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine and zido¬ vudine. Clinically significant interactions would not be ex¬ pected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. 7.2 Cannabinoid Test Interaction Efavirenz does not bind to cannabinoid receptors. False¬ positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases from baseline in nonfasting total cho¬ lesterol and HDL of approximately 20% and 25%, respec¬ tively, were observed. In patients treated with SUSTIVA + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels £240 mg/dL and £300 mg/dL were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + zidovudine + lamivu¬ dine; 54% and 20%, respectively, of patients treated with 8 USE IN SPECIFIC POPULATIONS SUSTIVA + indinavir; and 28% and 4%, respectively, of pa¬ 8.1 Pregnancy tients treated with indinavir + zidovudine + lamivudine. Pregnancy Exposure Registry The effects of SUSTIVA on triglycerides and LDL in this There is a pregnancy exposure registry that monitors preg¬ study were not well characterized since samples were taken nancy outcomes in women exposed to SUSTIVA during from nonfasting patients. The. clinical significance of these pregnancy. Physicians are encouraged to register patients findings is unknown [see Warnings and Precautions d (28-44%)

T 36%d (28-44%)

1 21% (10-33%) 1 40% (30-48%)

T 20% (8-34%) 1 37% (25-48%)

T 32%d (21-44%)

1 43% (21-59%)

11

T 24% (12-38%) 4-+

After PM dose

Saquinavir SGCf

1200 mg q8h x 10 days

600 mg qd x 10 days

12

l 50% (28-66%)

Lamivudine

150 mg ql2h x 14 days

600 mg qd x 14 days

9

4-*-

Ttenofovir*

300 mg qd

600 mg qd x 14 days

29

«-►

Zidovudine

300 mg ql2h x 14 days

600 mg qd x 14 days

9

Maraviroc

100 mg bid

600 mg qd . . »**-

12

Raltegravir

400 mg single dose

600 mg qd

Boceprevir

800 mg tid x 6 days

Simeprevir

Azithromycin

T 18% (6-33%) 4—*

1 62% (45-74%)

T 42%

. (9-86%r T 24% (3-50%)' 1 56% (16-77%f T 265% (37-873%)

-

.

4->

4-P

T 225% (43-640%)

i 51% (37-62%)

1 45% (38-51%)

1 45% (28-57%)

9

1 36% (2-59%)

1 36% (20-48%)

1 21% (1 51-T 28%)

600 mg qd x 16 days

NA

i 8% (1 22-T 8%)

1 19% (11-25%)

1 44% (26-58%)

150 mg qd x 14 days

600 mg qd x 14 days

23

l 51% (1 46-1 56%)

1 71% (1 67-1 74%)

1 91% (1 88-1 92%)

600 mg single dose

400 mg qd x 7 days

14

T 22% (4-42%)

NA

(Table continued on next page)

13.2 Animal Toxicology Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9) 1.

ql2h) + lamivudine (150 mg ql2h). Twelve hundred sixtysix patients (mean age 36.5 years Irange 18-811, 60% Caucasian, 8305 male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and Pl-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3

14 CLINICAL STUDIES 14.1 Adults Study 006. a randomized, open-label trial, compared SUSTIVA (efavirenz) (600 mg once daily) + zidovudine (ZDV, 300 mg ql2hl + lamivudine iLAM, 150 mg ql2h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h> + zidovudine (300 mg

and the median baseline HIV’-1 RNA level was 4.8 log,0 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive ULN). YERVOY has not been studied in patients with moderate (TB >1.5 x to 3.0 x ULN and any AST) or severe (TB >3 x ULN and any AST) hepatic impairment. [See Clinical Pharmacology (12.3).] 10

OVERDOSAGE

There is no information on overdosage with YERVOY. 11

DESCRIPTION

YERVOY (ipilimumab) is a recombinant, human monoclo¬ nal antibody that binds to the cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4). Ipilimumab is an IgGl kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-vellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white. amorphous ipilimumab particulates. It is supplied in single-use vials of 50 mgHO mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triam¬

13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility Carcinogenesis The carcinogenic potential of ipilimumab has not been eval¬ uated in long-term animal studies. Mutagenesis The genotoxic potential of ipilimumab has not been evalu¬ ated. Impairment of Fertility Fertility studies have not been performed with ipilimumab. 13.2 Animal Toxicology and/or Pharmacology In addition to the severe findings of abortion, stillbirths, and postnatal deaths observed in pregnant cynomolgus monkeys that received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through partu¬ rition [see Use in Specific Populations 65 years of age, the median age was 57 years, 71% had Mlc stage, 12%’ had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received al¬ desleukin, and 38% had elevated LDH level. Sixty-one per¬ cent of patients randomized to either YERVOY-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months. The OS results are shown in Table 3 and Figure L [See table 3 above] [See figure 1 above] The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% Cl: 3.7%, 8.4%) in the YERVOY+gplOO arm. 10.9% (95% Cl: 6.3%, 17.4%) in the YERVOY arm, and 1.5% (95% Cl: 0.2%, 5.2%) in the gplOO arm. The median duration of response was 11.5 months in the YERVOY+gplOO arm and has not been reached in the YERVOY or gplOO arm. 16

HOW SUPPLIED/STORAGE AND HANDLING

YERVOY is available as follows:

Carton Contents

NDC

One 50 mg vial (5 mg/mL), single-use vial

NDC 0003-2327-11

One 200 mg vial (5 mg/mL), single-use vial

NDC 0003-2328-22

Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials from light. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Medication Guide). • Inform patients of the potential risk of immune-mediated adverse reactions. • Advise patients to read the YERVOY Medication Guide before each YERVOY infusion. • Advise women that YERV’OY may cause fetal harm. • Advise nursing mothers not to breastfeed while taking YERVOY. Manufactured by: Bristol-Myers Squibb Company Princeton. NJ 08543 USA U.S. License No. 1713 1321675A2 Rev August 2015

YERVOY • BRISTOL-MYERS SQUIBB/789 Table 3: Overall Survival Results

Hazard Ratio (vs. gplOO) (95% Cl) p-value Hazard Ratio (vs. YERVOY) 29? in the treatment group and greater than the rate on placebo > during the treatment period are listed in Table 4 ISee table 4 at top of next page] Commonly observed adverse reactions (incidence of 529? in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.

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KAPVAY • CONCORDIA/799

Look for PDR drug information and services in your EHR Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial-Treatment Period (Study 2) Percentage of Patients Reporting Event

Percentage of Patients Reporting Event KAPVAY+STM (N=102)

PBO+STM (N=96)

Nasal Congestion

4%

2%

Headache

3%

1%

Irritability

3%

2%

Throat Pain

3%

1%

Gastroenteritis Viral

2%

0%

Rash

2%

0%

Preferred Term

* Taper Period: weeks 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving KAPVAY dis¬ continued from the pediatric monotherapy study due to ad¬ verse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from som¬ nolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a con¬ trolled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebosubtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -6.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day. 6.2 Postmarketing Experience The following adverse reactions have been identified during past-approval use of KAPVAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events exclude those already mentioned in 6.1: Psychiatric: hallucinations Cardiovascular: Q-T prolongation 7

DRUG INTERACTIONS

The following have been reported with other oral immediate release formulations of clonidine: (See table 6 above! 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: Risk Summary There are no adequate or well-controlled studies with KAPVAY in pregnant women. In animal embryofetal stud¬ ies, increased resorptions were seen in rats and mice admin¬ istered oral clonidine hydrochloride from implantation through organogenesis at 10 and 5 times, respectively, the maximum recommended human dose (MRHD). No embryotoxic or teratogenic effects were seen in rabbits adminis¬ tered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD. KAPVAY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose jMRHDj of 0.4 mg/day on a mg/m" basis) produced no evidence of tera¬ togenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in

KAPVAY+STM (N=102)

PBO+STM fN=96)

PSYCHIATRIC DISORDERS Somnolence* Aggression Affect Lability Emotional Disorder

19% 2% 2% 2%

7% 1% 1% 0%

GENERAL DISORDERS Fatiguet Irritability

14% 2%

4% 7%

NERVOUS SYSTEM DISORDERS Headache Insomnia

7% 4%

12% 3%

GASTROINTESTINAL DISORDERS Upper Abdominal Pain

7%

4%

RESPIRATORY DISORDERS Nasal Congestion

2%

2%

METABOLISM AND NUTRITION DISORDERS Decreased Appetite

6%

3%

CARDIAC DISORDERS Dizziness

5%

1%

Preferred Term

* Somnolence includes the terms: “somnolence” and “sedation”. f Fatigue includes the terms “fatigue” and “lethargy”.

Table 6 Clinically Important Drug Interactions Concomitant Drug Name or Drug Class

Clinical Rationale

Clinical Recommendation

Tricyclic antidepressants

Increase blood pressure and may counteract clonidine’s hypotensive effects

Monitor blood pressure and adjust as needed

Antihypertensive drugs

Potentiate clonidine’s hypotensive effects

Monitor blood pressure and adjust as needed

CNS depressants

Potentiate sedating effects

Avoid use

Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)

Potentiate bradycardia and risk of AV block

Avoid use

a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the low¬ est dose employed in this study. 8.3 Nursing Mothers Clonidine hydrochloride is present in human milk. The de¬ velopmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KAPVAY and any potential adverse effects on the breastfed child from KAPVAY or from the underlying maternal condi¬ tion. Exercise caution when KAPVAY is administered to a nursing woman. 8.4 Pediatric Use The safety and efficacy of KAPVAY in the treatment of ADHD have been established in |x>diatric patients 6 to 17 years of age. Use of KAPVAY in pediatric patients 6 to 17 years of age is supported by three adequate and wellcontrolled studies; a short-term, placebo-controlled mono¬ therapy trial, a short-term adjunctive therapy trial and a longer-term randomized monotherapy trial /see Clinical Studies (14)1. Safety and efficacy in pediatric patients below the age of 6 years has not been established. Juvenile Animal Data A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approx¬ imately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation (delayed sexual maturation) was seen in males treated with the highest dose (with a no¬

effect dose of 100 mcg/kg/day, whiclr is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or ncurobehavioral develop¬ ment. 8.6 Renal Impairment The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dos¬ age of KAPVAY should be based on degree of impairment Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialy¬ sis, there is no need to give supplemental KAPVAY following dialysis. • 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance KAPVAY is not a controlled substance and has no known potential for abuse or dependence. 10

OVERDOSAGE

Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 min¬ utes to two hours after exposure. Treatment Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. 11

DESCRIPTION

KAPVAY (clonidine hydrochloride I extended-release is a centrally acting alpha2-adrenergic agonist available as

Free mobile?DR app for fast drug references on Apple or Android devices

800/CONCORDIA • KAPVAY

Help patients save on Rx drugs: PDRriet/PharmacyDiscountCard 14 CLINICAL STUDIES

Table 7 Pharmacokinetic Parameters of Clonidine in Healthy Adult Volunteers CATAPRES-Fasted n=15 Parameter

KAPVAY-Fed n=15

KAPVAY-Fasted n=14

Mean

SD

Mean

SD

MEAN

SD

Cm„x (pg/mL)

443

59.6

235

34.7

258

33.3

AUCinf (hr* pg/mL)

7313

1812

6505

1728

6729

1650

hTm„ (hr)

2.07

0.5

6.80

3.61

6.50

1.23

T ^ (hr)

12.57

3.11

12.67

3.76

12.65

3.56

0.1 mg or 0.2 mg extended-release tablets for oral adminis¬ tration. Each 0.1 mg and 0.2 mg tablet is equivalent to 0.087 mg and 0.174 mg, respectively, of the free base. The inactive ingredients are sodium lauryl sulfate, lactose monohydrate, hypromellose type 2208, partially pregelati¬ nized starch, colloidal silicon dioxide, and magnesium stea¬ rate. The formulation is designed to delay the absorption of active drug in order to decrease peak to trough plasma con¬ centration differences. Clonidine hydrochloride is an imid¬ azoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2imidazoline hydrochloride. The following is the structural formula:

Cl

Figure 1 Mean Clonidine Concentration-Time Profiles after Single Dose Administration

Clonidine hydrochloride is an odorless, bitter, white, crys¬ talline substance soluble in water and alcohol.

Multiple-dose Pharmacokinetics in Children and Adoles¬ cents Plasma clonidine concentrations in children and adoles¬ cents (0.1 mg bid and 0.2 mg bid) with ADHD are greater than those of adults with hypertension with children and adolescents receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in children and adoles¬ cents was higher than CL/F observed in adults with hyper¬ tension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of “sedation-like” AEs (somnolence and fa¬ tigue) appeared to be independent of clonidine dose or con¬ centration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clonidine stimulates alpha2-adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known. 12.2 Pharmacodynamics Clonidine is a known antihypertensive agent. By stimulat¬ ing alpha2-adrenergic receptors in the brain stem, clonidine reduces sympathetic outflow from the central nervous sys¬ tem and decreases peripheral resistance, renal vascular re¬ sistance, heart rate, and blood pressure. 12.3 Pharmacokinetics Single-dose Pharmacokinetics in Adults 13 NONCLINICAL TOXICOLOGY Immediate-release clopidine hydrochloride and KAPVAY 13.1 Carcinogenesis, Mutagenesis and Impairment of have different pharmacokinetic characteristics; dose substi¬ Fertility tution on a milligram for milligram basis will result in dif¬ Clonidine HC1 was not carcinogenic when administered in ferences in exposure. A comparison across studies suggests the diet of rats (for up to 132 weeks) or mice (for up to 78 that the Cmax is 50% lower for KAPVAY compared to weeks) at doses of up to 1620 (male rats), 2040 (female rats), immediate-release clonidine hydrochloride. or 2500 (mice) mcg/kg/day. These doses are approximately Following oral administration of an immediate release for¬ 20, 25, and 15 times, respectively, the maximum recom¬ mulation, plasma clonidine concentration peaks in approxi¬ mended human dose (MRHD) of 0.4 mg/day on a mg/m2 ba¬ mately 3 to 5 hours and the plasma half-life ranges from 12 sis. to 16 hours. The half-life increases up to 41 hours in pa¬ There was no evidence of genotoxicity in the Ames test for tients with severe impairment of renal function. Following mutagenicity or mouse micronucleus test for clastogenicity. oral administration about 40-60% of the absorbed dose is Fertility of male or female rats was unaffected by clonidine recovered in the urine as unchanged drug in 24 hours. HC1 doses as high as 150 mcg/kg/day (approximately 3 About 50% of the absorbed dose is metabolized in the liver. times the MRHD on a mg/m2 basis). In a separate experi¬ Although studies of the effect of renal impairment and stud¬ ment, fertility of female rats appeared to be adversely af¬ ies of clonidine excretion have not been performed with fected at dose levels of 500 and 2000 mcg/kg/day (10 and 40 KAPVAY, results are likely to be similar to those of the im¬ times the MRHD on a mg/m2 basis). mediate release formulation. 13.2 Animal Toxicology and/or Pharmacology The pharmacokinetic profile of KAPVAY administration was In several studies with oral clonidine hydrochloride, a doseevaluated in an open-label, three-period, randomized, cross¬ dependent increase in the incidence and severity of sponta¬ over study of 15 healthy adult subjects who received three neous retinal degeneration was seen in albino rats treated single-dose regimens of clonidine: 0.1 mg of KAPVAY under for six months or longer. Tissue distribution studies in dogs fasted conditions, 0.1 mg of KAPVAY following a high fat and monkeys showed a concentration of clonidine in the meal, and 0.1 mg of clonidine immediate-release j choroid. In combination with amitriptyline, clonidine (Catapres*) under fasted conditions. Treatments were sep¬ hydrochloride administration led to the development of cor¬ arated by one-week washout periods. neal lesions in rats within 5 days. Mean concentration-time data from the 3 treatments are In view of the retinal degeneration seen in rats, eye exami¬ shown in Table 7 and Figure 1. After administration of nations were performed during clinical trials in 908 adult KAPVAY, maximum clonidine concentrations were approxi¬ patients before, and periodically after, the start of clonidine mately 50% of the Catapres maximum concentrations and | therapy for hypertension. In 353 of these 908 patients, the occurred approximately 5 hours later relative to Catapres, eye examinations were carried out over periods of 24 Similar elimination half-lives were observed and total sys¬ months or longer. Except for some dryness of the eyes, no temic bioavailability following KAPVAY was approximately drug-related abnormal ophthalmologies! findings were re¬ 89% of that following Catapres. corded and, according to specialized tests such as electroretFood had no effect on plasma concentrations, bioavailability, ! inography and macular dazzle, retinal function was un¬ or elimination half-life. changed.

Efficacy of KAPVAY in the treatment of ADHD was estab¬ lished in children and adolescents (6 to 17 years) in: • One short-term, placebo-controlled monotherapy trial (Study 1) • One short-term adjunctive therapy to psychostimulants trial (Study 2) • One randomized withdrawal trial as monotherapy (Study 3) Short-term Monotherapy and Adjunctive Therapy to Psy¬ chostimulant Studies for ADHD The efficacy of KAPVAY in the treatment of ADHD was es¬ tablished in 2 (one monotherapy and one adjunctive ther¬ apy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or com¬ bined hyperactive/inattentive subtypes. Signs and symp¬ toms of ADHD were evaluated using the investigator ad¬ ministered and scored ADHD Rating Scale-FV-Parent Version (ADHDRS-IV) total score including hyperactive/ impulsivity and inattentive subscales. Study 1 (CLON-301), was an 8-week randomized, double¬ blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary ef¬ ficacy endpoint. Patients were randomly assigned to one of the following three treatment groups: KAPVAY (CLON) 0.2 mg/day (N=78), KAPVAY 0.4 mg/day (N=80), or placebo (N=78). Dosing for the KAPVAY groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses). Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment. At both doses, improvements in ADHD symp¬ toms were statistically significantly superior in KAPVAYtreated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8). Study 2 (CLON-302) was an 8-week randomized, double¬ blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary ef¬ ficacy end point. Patients had been treated with a psycho¬ stimulant (methylphenidate or amphetamine) for four weeks with inadequate response. Patients were randomly assigned to one of two treatment groups: KAPVAY adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The KAPVAY dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response. The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment. ADHD symptoms were statistically significantly improved in KAPVAY plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the'ADHDRS-IV total score (Table 8). [See table 8 at top of next page I Maintenance Monotherapy for ADHD Study 3 (SHN-KAP-401), was a double-blind, placebocontrolled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR di¬ agnosis of ADHD. The study consisted of a 10-week, openlabel phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase. All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized opti¬ mal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses). Eli¬ gible patients had to demonstrate treatment response as de¬ fined by > 30% reduction in ADHD-RS-TV total score and a Clinical Global Impression-Improvement score of 1 or 2 dur¬ ing the open label phase. Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups. KAPVAY (N=68) and Placebo (N=67), to evaluate the long¬ term efficacy of maintenance dose of KAPVAY in the double¬ blind phase. The primary efficacy endpoint was the percent¬ age of patients with treatment failure defined as a £ 30% increase (worsening) in ADHD-RS-IV total score and > 2 points increase (worsening) in Clinical Global Impression Severity Scale in 2 consecutive visits or early termination for any reason. A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the KAPVAY group and 42 patients (62.7%-) in the placebo group, with a statistically significant difference in the pri¬ mary endpoint favoring KAPVAY (Table 9). The cumulative proportion of patients with treatment failure over time dur¬ ing the double-blind phase is displayed in Figure 2. Table 9 Treatment Failure: Double-Blind Full Analysis Set (Study 3) Double-Blind Full Analysis Set Study 3

Number of subjects Number of treatment failures

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Kapvay®

Placebo

68

67

31 (45.6%)

42(62.7%)

LANOXIN • CONCORDIA/801

Look for PDR drug information and services in your EHR Table 8 Short-Term Trials

Basis of Treatment Failure Study Number

11 (16.2%)

9(13.4%)

Lack of efficacy1

1 (1.5%)

3 (4.5%)

Withdrawal of informed assent/ consent

4 (5.9%)

20(29.9%)

Clinical criteria"11

ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4U> edition; CGI-S = Clinical Global Impression-Severity * At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S. b Two subjects (1 placebo and 1 KAPVAY) withdrew consent, but met the clinical criteria for treatment failure c Three subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.

1.0

- Kapvay

®

I 09

a.

|

08

I 0 7’ •C

I 06

I 1 0.5 £ ? 0.4

0

20

40

60

80

100

120

140

160

180

200

220

Days from Randomization to Treatment Failure

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)

16

HOW SUPPLIED/STORAGE AND HANDLING

KAPVAY extended-release tablets are white, non-scored, standard convex with debossing (“651" for 0.1 mg and “652" for 0.2 mg) on one side. NDC 59212-658-60 - 0.1 mg round tablets supplied in bottles containing 60 tablets. NDC 59212-659-60 - 0.2 mg oval tablets supplied in bottles containing 60 tablets. Store at 20°-25°C (68°-77°F) |see USP Controlled Room Temperature]. Dispense in a tight container. 17

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Difference* (95% Cl)

Study 1

KAPVAY (0.2 mg/day) KAPVAY (0.4 mg/day) Placebo

43.8(7.47) 44.6 (7.73) 45.0 (8.53)

-15.0 (1.38) -15.6(1.33) -6.5(1.35)

-8.5 (-12.2, - 4.8) -9.1 (-12.8, - 5.5)

Study 2

KAPVAY (0.4 mg/day) + Psychostimulant Psychostimulant alone

38.9 (6.95) 39.0 (7.68)

-15.8 0.18) -11.3 (1.24)

-4.5 (-7.8, -1.1)

10(14.9%)

15 (22.1%)

Other early terminations

Primary Efficacy Measure: ADHDRS-IV Total Score

Treatment Group

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved Patient Label¬ ing (Patient Information) Dosage and Administration Advise patients that KAPVAY must be swallowed whole, never crushed, cut, or chewed, and may be taken with or without food. When initiating treatment, provide dosage es¬ calation instructions (see Dosage and Administration (2. V). Missed Dose If patients miss a dose of KAPVAY, advise them to skip the dose and take the next dose as scheduled and not to take more than the prescribed total daily amount of KAPVAY in any 24-hour period /see Dosage and Administration (2.4)1. Hypotension/Bradycardia Advise patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypo¬ tension. orthostatic hypotension, bradycardia, or dehydra¬ tion, to avoid becoming dehydrated or overheated /see Warn¬ ings and Precautions (5.1)1. Sedation and Somnolence Instruct patients to use caution when driving a car or oper¬ ating hazardous machinery until they know how they will respond to treatment with KAPVAY. Also advise patients to avoid the use of KAPVAY with other centrally active depres¬ sants and with alcohol /see Warnings and Precautions (5.2)1. Rebound Hypertension Advise patients not to discontinue KAPVAY abruptly /see Warnings and Precautions (5.3)1. Allergic Reactions Advise patients to discontinue KAPVAY and seek immedi¬ ate medical attention if any signs or symptoms of a hyper¬ sensitivity reaction occur, such as generalized rash, urti¬ caria, or angioedema /see Warnings and Precautions (5.4)1.

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; Cl: unadjusted confidence interval. “Difference (drug minus placebo) in least-squares mean change from baseline.

Patient Information KAPVAY® (KAP-vay) (clonidine hydrochloride) Extended-Release Tablets Read the Patient Information that comes with KAPVAY be¬ fore you start taking it and each time you get a refill. There may be new information. This Patient Information leaflet does not take the place of talking to your doctor about your medical condition or treatment. What is KAPVAY? KAPVAY is a prescription medicine used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Your doctor may prescribe KAPVAY alone or together with cer¬ tain other ADHD medicines. • KAPVAY is not a central nervous system (CNS) stimulant. • KAPVAY should be used as part of a total treatment pro¬ gram for ADHD that may include counseling or other ther¬ apies. Who should not take KAPVAY? • Do not take KAPVAY if you are allergic to clonidine in KAPVAY. See the end of this leaflet for a complete list of ingredients in KAPVAY. What should I tell my doctor before taking KAPVAY? Before you take KAPVAY, tell your doctor if you: • have kidney problems • have low or high blood pressure • have a history of passing out (syncope) • have heart problems, including history of heart attack • have had a stroke or have stroke symptoms • had a skin reaction (such as a rash) after taking clonidine in a transdermal form (skin patch) • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if KAPVAY will harm your unborn baby. Talk to your doc¬ tor if you are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. KAPVAY can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take KAPVAY. Tell your doctor about all of the medicines that you take, including prescription and non-prescription medicines, vita¬ mins, and herbal supplements. KAPVAY and certain other medicines may affect each other causing serious side effects. Sometimes the doses of other medicines may need to be changed while taking KAPVAY. Especially tell your doctor if you take: • anti-depression medicines • heart or blood pressure medicine • other medicines that contain clonidine • a medicine that makes you sleepy (sedation) Ask your doctor or pharmacist for a list of these medicines, if you are not sure if your medicine is listed above. Know the medicines that you take. Keep a list of your medi¬ cines with you to show your doctor and pharmacist when you get a new medicine. How should I take KAPVAY? • Take KAPVAY exactly as your doctor tells you to take it. • Your doctor will tell you how many KAPVAY tablets to take and when to take them. Your doctor may change your dose of KAPVAY. Do not change your dose of KAPVAY without talking to your doctor, • Do not stop taking KAPVAY without talking to your doc¬ tor • KAPVAY can be taken with or without food. • KAPVAY should be taken 2 times a day (in the morning and at bedtime). • If you miss a dose of KAPVAY, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time. • Take KAPVAY tablets whole. Do not chew, crush or break KAPVAY tablets. Tbll your doctor if you cannot swallow KAPVAY tablets whole. You may need a different medi¬ cine. • If you take too much KAPVAY, call your Poison Control Center or go to the nearest hospital emergency room right away. What should I avoid while taking KAPVAY? • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking KAPVAY until you talk

with your doctor. KAPVAY taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepi¬ ness or dizziness worse. • Do not drive, operate heavy machinery or do other danger¬ ous activities until you know how KAPVAY will affect you. • Avoid becoming dehydrated or overheated. What are possible side effects of KAPVAY? KAPVAY may cause serious side effects, including: • Low blood pressure and low heart rate. Your doctor should check your heart rate and blood pressure before starting treatment and regularly during treatment with KAPVAY. • Sleepiness. • Withdrawal symptoms. Suddenly stopping KAPVAY may cause withdrawal symptoms including: increased blood pressure, headache, increased heart rate, lightheaded¬ ness, tightness in your chest and nervousness. The most common side effects of KAPVAY include: • sleepiness • tiredness • irritability • trouble sleeping (insomnia) • nightmare • constipation • dry mouth • decreased appetite • dizziness Tell your doctor if you have any side effects that bother you or that does not go away. These are not all of the possible side effects of KAPVAY. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store KAPVAY? • Store KAPVAY between 68'>-770F (20*-25"C). • Keep KAPVAY in a tightly closed container. Keep KAPVAY and all medicines out of the reach of chil¬ dren. General information about the safe and effective use of KAPVAY Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use KAPVAY for a condition for which it was not prescribed. Do not give KAPVAY to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most im¬ portant information about KAPVAY. If you would like more information, talk with your doctor. You can also ask your doctor or pharmacist for information about KAPVAY that is written for healthcare professionals. For more information about KAPVAY, go to www.KAPVAY.com or call 1-877-370-1142. What are the ingredients in KAPVAY? • Active Ingredient: clonidine hydrochloride * • Inactive Ingredients: sodium lauryl sulfate, lactose monohydrate, hypromellose type 2208, partially pregelati¬ nized starch, colloidal silicon dioxide, and magnesium stearate Revised: 1/2015 Manufactured for: Concordia Pharmaceuticals Inc. St. Michael, Barbados BB11005 Kapvay® is a registered trademark of Concordia Pharma¬ ceuticals Inc. Shown in Product Identification Guide, page 306

LANOXIN*

B

(digoxin) tablets, for oral use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LANOXIN safely and effectively See full prescribing information for LANOXIN. LANOXIN* (digoxin) tablets, for oral use Initial U S. Approval: 1954

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802/CONCORDIA • LANOXIN

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-INDICATIONS AND USAGELANOXIN is a cardiac glycoside indicated for: • Treatment of mild to moderate heart failure in adults, (l.li • Increasing myocardial contractility in pediatric patients with heart failure. 5% and more fre¬ quently in the subjects treated with ADVAIR DISKUS were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumo¬ nia, candidiasis, and dvsphonia. Overall, 55 (7%) of the sub¬ jects treated with ADVAIR DISKUS and 25 (3%) of the sub¬ jects treated with salmeterol developed pneumonia. The incidence of pneumonia was higher in subjects older than 65 years, 9% in the subjects treated with ADVAIR DISKUS compared with 4% in the subjects treated with ADVAIR DISKUS younger than 65 years. In the subjects treated with salmeterol. the incidence of pneumonia was the same (3%) in both age-groups. ISee Warnings and Pre¬ cautions (5.5), Use in Specific Populations (8.5).I

Obstructive Pulmonary Disease Associated With Chronic Bronchitis

Adverse Event

Ear, nose, and throat Candidiasis mouth/throat Throat irritation Hoarseness/dysphonia Sinusitis Lower respiratory Viral respiratory infections Neurology Headaches Dizziness

Salmeterol

ADVAIR DISKUS

Fluticasone Propionate

250/50

250 meg

50 meg

Placebo

(n = 178)

(n = 183)

In = 177)

(n = 185)

%

%

%

%

10

6

8 5 3

5 3 8

3 4

7

18 years were also performed. Pediatric subjects accounted for ap¬ proximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,6531) and the placebo group (0.12% [2/1,622); relative risk: 1.0 )95%- Cl: 0.1. 7.21). All-cause hospitalization, how¬ ever, was increased in the salmeterol group (2% 135/1,6531 > versus the placebo group (less than 1% 116/1,622); relative risk: 2.1 195% Cl: 1.1, 3.71). The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in ADVAIR HFA, or other long-term asthma control therapy mitigates the risk of asthma-related death. [See table 1 above I

Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment All Subjects

28

56

84

112

140

188

196

Duabon of Traabmert (days)

No at nsfc at sian ofnterva) —&*neterd — Placebo

18176 13.179

13.066 13,060

12.764 12,706

12.480 12,416

18211 18136

11313 11866

11336 11.525

| Caucasar 0.4% 0.3% 02% 0.1%

08% 0

28

56

84

112

140

168

196

Ourabon of Trea»nant (days)

Noafoskai start of interval —S^rtterd --Placebo

9281 9861

9202 9266

9020 9.063

8850 8884

8690 8722

8803 8646

8271 8330

Afrcan Amencan

i

ij

04% •

If

02%

II

00% -1---FT*-»---1---0 2B 56 84 112 140 168 196

03%

__r

0.1%

Ouafen 3% Incidence in Adult and Adolescent Subjects with Asthma

ADVAIR HFA Inhalation Aerosol

Fluticasone Propionate CFC Inhalation Aerosol

Salmeterol CFC Inhalation Aerosol

Placebo HFA Inhalation Aerosol

In = 176) %

45/21 (n = 187) %

115/21 (n = 94) %

44 meg (n = 186) %

110 meg (n s 91) %

21 meg (n = 274) %

Ear, nose, and throat Upper respiratory tract infection Throat irritation Upper respiratory inflammation Hoarseness/dvsphon ia

16 9 4 3

24 7 4 1

13 12 3 2

15 13 7 0

17 9 5 1

13 7 3 0

Lower respiratory Viral respiratory infection

3

5

4

5

3

4

Neurology Headache Dizziness

21 4

15 1

24 1

16 0

20 0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.14 19541 Cl; 0.85, 1.441 compared with placebo). Trial 2: Clinical Trial with ADVAIR HFA 45/21 Inhalation Aerosol: This active-controlled. 12-wuck, US trial com¬ pared ADVAIR HFA 45/21 with fluticasone propionate CFC inhalation aerosol 44 meg and salmeterol CFC inhalation aerosol 21 meg, each given as 2 inhalations twice daily, in 283 subjects using as-needed albuterol alone. The primary efficacy endpoint was predose FEV,. Baseline FEV, mea¬ surements were similar across treatments: ADVAIR HFA 45/21, 2.37 L: fluticasone propionate 44 meg, 2.31 L; and salmeterol, 2.34 L. Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving ADVAIR HFA 45/21 had sig¬ nificantly greater improvements in FEV, (0.69 L, 3341) com¬ pared with fluticasone propionate 44 meg (0.51 L, 2541) and salmeterol (0.47 L, 22%). Trial 3: Clinical Trial with ADVAIRJIFA 115/21 Inhala¬ tion Aerosol: This placebo-controlled. 12-week, IIS trial compared ADVAIR HFA 115/21 with fluticasone propionate CFC inhalation aerosol 110 meg or salmeterol CFC inhala¬ tion aerosol 21 meg, each given as 2 inhalations twice daily, in 365 subjects using inhaled corticosteroids (daily doses of beclomethasone dipropionate 378 to 840 meg; budesonide 800 to 1,200 meg; flunisolide 1,260 to 2,000 meg; fluticasone propionate inhalation aerosol 440 to 660 meg; fluticasone propionate inhalation powder 400 to 600 meg; or triamcino¬ lone acetonide 900 to 1,600 meg). The primary efficacy end¬ points were predose FEV, and withdrawals due to worsen¬ ing asthma. Baseline FEV, measurements were similar across treatments: ADVAIR HFA 115/21,2.23 L; fluticasone propionate 110 meg, 2.18 L; salmeterol, 2.22 L; and placebo, 2.17 L. Efficacy results in this trial were similar to those observed in Trials 1 and 2. Subjects receiving ADVAIR HFA 115/21 had significantly greater improvements in FEV, (0 41 L, 20% i compared with fluticasone propionate 110 meg 10.19 L, 9% i, salmeterol (0.15 L, 8% i, and placebo (-0.12 L, -®%). Sig-

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838/GLAXOSMITHKLINE • ADVAIR HFA nificantly fewer subjects receiving ADVAIR HFA 115/21 were withdrawn from this trial for worsening asthma (7%) compared with salmeterol (24%) and placebo (54%). Fewer subjects receiving ADVAIR HFA 115/21 were withdrawn due to worsening asthma (7%) compared with fluticasone propionate 110 meg (11%); however, the difference was not statistically significant. Trial 4: Clinical Trial with ADVAIR HFA 230/21 Inhala¬ tion Aerosol: This active-controlled 12-week non-US trial compared ADVAIR HFA 230/21 with fluticasone propionate CFC inhalation aerosol 220 meg, each given as 2 inhala¬ tions twice daily, and with ADVAIR DISKUS 500/50 given as 1 inhalation twice daily in 509 subjects using inhaled cor¬ ticosteroids (daily doses of beclomethasone dipropionate CFC inhalation aerosol 1,500 to 2,000 meg; budesonide 1,500 to 2,000 meg; flunisolide 1,500 to 2,000 meg; fluticasone propionate inhalation aerosol 660 to 880 meg; or fluticasone propionate inhalation powder 750 to 1,000 meg). The primary efficacy endpoint was morning PEF. Baseline morning PEF measurements were similar across treatments: ADVAIR HFA 230/21, 327 L/min; ADVAIR DISKUS 500/50, 341 L/min; and fluticasone propionate 220 meg, 345 L/min. As shown in Figure 3, morning PEF improved significantly with ADVAIR HFA 230/21 compared with fluticasone propionate 220 meg over the 12-week treat¬ ment period. Improvements in morning PEF observed with ADVAIR HFA 230/21 were similar to improvements ob¬ served with ADVAIR DISKUS 500/50.

Figure 4. Percent Change in Serial 12-Hour FEVi in Subjects Previously Using either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) First Treatment Day

The purple actuator supplied with ADVAIR HFA should not be used with any other product canisters, and actuators from other products should not be used with an ADVAIR HFA canister. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to oper¬ ate. The inhaler should be discarded when the counter reads 000. Keep out of reach of children. Avoid spraying in eyes. Contents under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator. Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature). Store the inhaler with the mouthpiece down. For best results, the in¬ haler should be at room temperature before use. SHAKE WELL FOR 5 SECONDS BEFORE EACH SPRAY. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Medication Guide and Instructions for Use). Asthma-Related Death: Inform patients that salmeterol, one of the active ingredients in ADVAIR HFA, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Also inform them that currently available data are

Figure 3. Mean Percent Change from Baseline in Morning Peak Expiratory Flow in Subjects Previously Treated with Inhaled Corticosteroids (Trial 4)

inadequate to determine whether concurrent use of in¬ Baseline

Figure 5. Percent Change in Serial 12-Hour FEVi in Subjects Previously Using either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) Last Treatment Day (Week 12) A ADVAIR HFA45/21 2 inhalations twice daily (n = 85)

ADVAIR DISKUS 500/50 161

147

119

Fluticasone propionate inhalation aerosol 220 meg 172

155

133

14.2

One-Year Safety Trial

Clinical Trial with ADVAIR HFA 45/21, 115/21, and 230/21 Inhalation Aerosol: This 1-year, open-label, non-US trial evaluated the safety of ADVAIR HFA 45/21, 115/21, and 230/21 given as 2 inhalations twice daily in 325 subjects. This trial was stratified into 3 groups according to baseline asthma therapy: subjects using short-acting beta2-agonists alone (n = 42), salmeterol (n = 91), or inhaled corticosteroids (n = 277). Subjects treated with short-acting beta2-agonists alone, salmeterol, or low doses of inhaled corticosteroids w'ith or without concurrent salmeterol received ADVAIR HFA 45/21. Subjects treated with moderate doses of inhaled corticosteroids with or without concurrent salmeterol re¬ ceived ADVAIR HFA 115/21. Subjects treated with high doses of inhaled corticosteroids with or without concurrent salmeterol received ADVAIR HFA 230/21. Baseline FEV, measurements ranged from 2.3 to 2.6 L. Improvements in FEV, (0.17 to 0.35 L at 4 weeks) were seen across all 3 treatments and were sustained throughout the 52-week treatment period. Few subjects (3%) were with¬ drawn due to worsening asthma over 1 year. 14.3 Onset of Action and Progression of Improvement in Control

The onset of action and progression of improvement in asthma control were evaluated in 2 placebo-controlled US trials and 1 active-controlled US trial. Following the first dose, the median time to onset of clinically significant bronchodilatation (215% improvement in FEV,l in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV, occurred within 4 hours, and clinically significant improvement was maintained for 12 hours (see Figure 4). Following the initial dose, predose FEV, relative to Day 1 baseline improved markedly over the first week of treat¬ ment and continued to improve over the 12 weeks of treat¬ ment in all 3 trials. No diminution in the 12-hour bronchodilator effect was ob¬ served with either ADVAIR HFA 45/21 (Figures 4 and 5) or ADVAIR HFA 230/21 as assessed by FEV, following 12 weeks of therapy.

Week 12 Baseline

Reduction in asthma symptoms and use of rescue VENTOLIN Inhalation Aerosol and improvement in morn¬ ing and evening PEF also occurred within the first day of treatment with ADVAIR HFA, and continued to improve over the 12 weeks of therapy in all 3 trials. 16

HOW SUPPLIED/STORAGE AND HANDLING

ADVAIR HFA 45/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered ac¬ tuations in boxes of 1 (NDC 0173-0715-20) and 8-g pressur¬ ized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0715-22). ADVAIR HFA 115/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered ac¬ tuations in boxes of 1 (NDC 0173-0716-20) and 8-g pressur¬ ized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0716-22). ADVAIR HFA 230/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered ac¬ tuations in boxes of 1 i NDC 0173-0717-20) and 8-g pressur¬ ized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0717-22). Each canister is fitted with a counter and supplied with a purple actuator with a light purple strapeap. Each inhaler is sealed in a plastic-coated, moisture-protective foil pouch with a desiccant that should be discarded when the pouch is opened. Each inhaler is packaged with a Medication Guide leaflet.

haled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Not for Acute Symptoms: Inform patients that ADVAIR HFA is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise pa¬ tients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide pa¬ tients with such medication and instruct them in how it should be used. Instruct patients to seek medical attention immediately if they experience any of the following: • Decreasing effectiveness of inhaled, short-acting beta2agonists • Need for more inhalations than usual of inhaled, shortacting beta2-agonists • Significant decrease in lung function as outlined by the physician , Tell patients they should not stop therapy with ADVAIR HFA without physician/provider guidance since symptoms may recur after discontinuation. Do Not Use Additional Long-Acting Beta -Agonists: In¬ struct patients not to use other LABA for asthma. Local Effects: Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) anti¬ fungal therapy while still continuing therapy with ADVAIR HFA, but at times therapy with ADVAIR HFA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swal¬ lowing after inhalation to help reduce the risk of thrush. Pneumonia: Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare pro¬ viders if they develop symptoms of pneumonia. Immunosuppression: Warn patients who are on immuno¬ suppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their phy¬ sicians without delay. Inform patients of potential worsen¬ ing of existing tuberculosis; fungal, bacterial, viral, or par¬ asitic infections; or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Advise patients that ADVAIR HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, in¬ form patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic cortico¬ steroids. Patients should taper slowly from systemic corti¬ costeroids if transferring to ADVAIR HFA. Immediate Hypersensitivity Reactions: Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, brunchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR HFA. Patients should discontinue ADVAIR HFA if such re¬ actions occur. Reduction in Bone Mineral Density: Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity: Inform patients that orally in¬ haled corticosteroids, including fluticasone propionate, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by I any route.

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ADVAIR HFA • GLAXOSMITHKLINE/839

Look for PDR drug information and services in your EHR Ocular Effects: Inform patients that long-term use of in¬ haled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye ex¬ aminations. Risks Associated with Beta-Agonist Therapy: Inform pa¬ tients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. ADVAIR, ADVAIR DISKUS, DISKUS, FLONASE, FLOVENT, ROTADISK, SEREVENT, and VENTOLIN are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. ADH:10PI MEDICATION GUIDE ADVAIR® lad' vair] HFA 45/21 (fluticasone propionate 45 meg and salmeterol 21 meg) Inhalation Aerosol ADVAIR® HFA 115/21 (fluticasone propionate 115 meg and salmeterol 21 meg) Inhalation Aerosol ADVAIR® HFA 230/21 (fluticasone propionate 230 meg and salmeterol 21 meg) Inhalation Aerosol Read the Medication Guide that comes with ADVAIR HFA Inhalation Aerosol before you start using it and each time you get a refill. There may be new information. This Medi¬ cation Guide does not take the place of talking to your healthcare provider about your medical condition or treat¬ ment. What is the most important information I should know about ADVAIR HFA? ADVAIR HFA can cause serious side effects, including: • People with asthma who take long-acting beta2adrenergic agonist (LABA) medicines, such as salmeterol (one of the medicines in ADVAIR HFA), have an increased risk of death from asthma problems. It is not known whether fluticasone propionate, the other medicine in ADVAIR HFA, reduces the risk of death from asthma problems seen with salmeterol. • Call your healthcare provider if breathing problems worsen over time while using ADVAIR HFA. You may need different treatment. • Get emergency medical care if: • your breathing problems worsen quickly. • you use your rescue inhaler, but it does not relieve your breathing problems. • ADVAIR HFA should be used only if your healthcare pro¬ vider decides that your asthma is not well controlled with a long-term asthma control medicine, such as an inhaled corticosteroid. • When your asthma is well controlled, your healthcare pro¬ vider may tell you to stop taking ADVAIR HFA. Your healthcare provider will decide if you can stop ADVAIR HFA without loss of asthma control. Your healthcare pro¬ vider may prescribe a different asthma control medicine for you, such as an inhaled corticosteroid. • Children and adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems. What is ADVAIR HFA? • ADVAIR HFA combines the inhaled corticosteroid (ICS) medicine fluticasone propionate and the LABA medicine salmeterol. • ICS medicines such as fluticasone propionate help to de¬ crease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. • LABA medicines such as salmeterol help the muscles around the airways in your lungs stay relaxed to prevent ' symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. • ADVAIR HFA is not used to relieve sudden breathing problems. • It is not known if ADVAIR HFA is safe and effective in children younger than 12 years of age. • ADVAIR HFA is used for asthma as follows: • ADVAIR HFA is a prescription medicine used to control symptoms of asthma and to prevent symptoms such as wheezing in adults and adolescents aged 12 years and older. • ADVAIR HFA contains salmeterol, the same medicine found in SEREVENT* DISKUS® (salmeterol xinafoate inhalation powder). I ABA medicines such as salmeterol increase the risk of death from asthma problems. • ADVAIR HFA is not for adults and adolescents with asthma who are well controlled with an asthma control medicine, such as a low to medium dose of an inhaled corticosteroid medicine.

Free

• pneumonia. ADVAIR HFA contains the same medicine Who should not use ADVAIR HFA? Do not use ADVAIR HFA found in ADVAIR DISKUS® (fluticasone propionate and • if you are allergic to fluticasone propionate, salmeterol, or salmeterol inhalation powder). ADVAIR DISKUS is used any of the ingredients in ADVAIR HFA. See “What are the to treat people with asthma and people with chronic ob¬ ingredients in ADVAIR HFA?” below for a complete list of structive pulmonary disease (COPp). People with CQPD ingredients. have a higher chance of getting pneumonia. ADVAIR What should I tell my healthcare provider before using DISKUS may increase the chance of you getting pneumo¬ ADVAIR HFA? nia. It is not known if ADVAIR HFA is safe and effective in Tell your healthcare provider about all of your health con¬ ditions, including if you: people with COPD. Call your healthcare provider right • have heart problems. away if you have any of the following symptoms: • have high blood pressure. • increase in mucuB (sputum) production • have seizures. • change in mucus color • have thyroid problems. • fever • have diabetes. • chills • have liver problems. • increased cough • have weak bones (osteoporosis). • increased breathing problems • have an immune system problem. • have eye problems such as glaucoma or cataracts. • weakened immune system and increased chance of get¬ • are allergic to any of the ingredients in ADVAIR HFA or ting infections (immunosuppression). any other medicines. See “What are the ingredients in • reduced adrenal function (adrenal insufficiency). Adrenal ADVAIR HFA?” below for a complete list of ingredients. insufficiency is a condition where the adrenal glands do • have any type of viral, bacterial, or fungal infection. not make enough steroid hormones. This can happen • are exposed to chickenpox or measles. when you stop taking oral corticosteroid medicines (such • have any other medical conditions. as prednisone) and start taking a medicine containing an • are pregnant or planning to become pregnant. It is not inhaled steroid (such as ADVAIR HFA). When your body is known if ADVAIR HFA may harm your unborn baby. under stress such as from fever, trauma (such as a car ac¬ • are breastfeeding. It is not known if the medicines in cident), infection, surgery, or worse COPD symptoms, ADVAIR HFA pass into your milk and if they can harm adrenal insufficiency can get worse and may cause death. your baby. Symptoms of adrenal insufficiency include: Tell your healthcare provider about all the medicines you • sudden breathing problems immediately after inhaling take, including prescription and over-the-counter medi¬ your medicine. cines, vitamins, and herbal supplements. ADVAIR HFA and • serious allergic reactions. Call your healthcare provider or certain other medicines may interact with each other. This get emergency medical care if you get any of the following may cause serious side effects. Especially, tell your health¬ symptoms of a serious allergic reaction: care provider if you take antifungal or anti-HIV medicines. • rash Know the medicines you take. Keep a list of them to show • hives your healthcare provider and pharmacist when you get a • swelling of your face, mouth, and tongue new medicine. • breathing problems How should I use ADVAIR HFA? • effects on heart. Read the step-by-step instructions for using ADVAIR HFA • increased blood pressure at the end of this Medication Guide. • a fast or irregular heartbeat • Do not use ADVAIR HFA unless your healthcare provider • chest pain has taught you how to use the inhaler and you understand • effects on nervous system. how to use it correctly • tremor • ADVAIR HFA comes in 3 different strengths. Your health¬ • nervousness care provider prescribed the strength that is best for you. • bone thinning or weakness (osteoporosis). • Use ADVAIR HFA exactly as your healthcare provider • slowed growth in children. A child's growth should be tells you to use it. Do not use ADVAIR HFA more often checked often. than prescribed. • eye problems including glaucoma and cataracts. You • Use 2 inhalations of ADVAIR HFA 2 times each day. Use should have regular eye exams while using ADVAIR HFA. ADVAIR HFA at the same time each day, about 12 hours • changes in laboratory blood levels (sugar, potassium, cer¬ apart. tain types of white blood cells). • If you miss a dose of ADVAIR HFA, just skip that dose. Common side effects of ADVAIR HFA include: Take your next dose at your usual time. Do not take • upper respiratory tract infection 2 doses at 1 time. • throat irritation • If you take too much ADVAIR HFA, call your healthcare • hoarseness and voice changes provider or go to the nearest hospital emergency room • headache right away if you have any unusual symptoms, such as • dizziness worsening shortness of breath, chest pain, increased heart • nausea and vomiting rate, or shakiness. Tell your healthcare provider about any side effect that • Do not use other medicines that contain a LABA for any bothers you or that does not go away. reason. Ask your healthcare provider or pharmacist if any These are not all the side effects with ADVAIR HFA. Ask of your other medicines are LABA medicines. your healthcare provider or pharmacist for more informa¬ • Do not stop using ADVAIR HFA, even if you are feeling tion. better, unless your healthcare provider tells you to. Call your doctor for medical advice about side effects. You • Talk to your healthcare provider right away if you stop us¬ may report side effects to FDA at 1-800-FDA-1088. ing ADVAIR HFA. How should I store ADVAIR HFA? • ADVAIR HFA does not relieve sudden symptoms. Always • Store ADVAIR HFA at room temperature between 68'F have a rescue inhaler with you to treat sudden symptoms. and 77°F (20“C and 25*0 with the mouthpiece down. If you do not have a rescue inhaler, call your healthcare • The contents of your ADVAIR HFA are under pressure: provider to have one prescribed for you. Do not puncture Do not use or store near heat or open • Call your healthcare provider or get medical care right flame. Temperatures above 120°F may cause the canister away if: to burst. • your breathing problems get worse. • Do not throw into fire or an incinerator. • you need to use your rescue inhaler more often than • Safely throw away ADVAIR HFA in the trash when the usual. counter reads 000 • your rescue inhaler does not work as well to relieve your • Keep ADVAIR HFA and all medicines out of the reach of symptoms. children. • you need to use 4 or more inhalations of your rescue in¬ General information about the safe and effective use of haler in 24 hours for 2 or more days in a row. ADVAIR HFA. • you use 1 whole canister of your rescue inhaler in Medicines are sometimes prescribed for purposes not men¬ 8 weeks. tioned in a Medication Guide. Do not use ADVAIR HFA for a • your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you. ! condition for which it was not prescribed. Do not give your ADVAIR HFA to other people, even if they have the same • you have asthma and your symptoms do not improve af¬ condition that you have. It may harm them. ter using ADVAIR HFA regularly for 1 week. This Medication Guide summarizes the most important in¬ What are the possible side effects with ADVAIR HFA? formation about ADVAIR HFA. If you would like more in¬ ADVAIR HFA can cause serious side effects, including: formation, talk with your healthcare provider or pharma¬ • See "What is the most important information I should cist. You can ask your healthcare provider or pharmacist for know about ADVAIR HFA?" information about ADVAIR HFA that was written for • fungal infection in your mouth or throat (thrush). Rinse healthcare professionals. your mouth with water without swallowing after using For more information about ADVAIR HFA, call 1-888-825ADVAIR HFA to help decrease your chance of getting 5249 or visit our website at www advair com. thrush.

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840/GLAXOSMITHKLINE • ADVAIR HFA What are the ingredients in ADVAIR HFA? Active ingredients: fluticasone propionate, salmeterol xin afoate Inactive ingredient: propellant HFA-134a Instructions for Use For Oral Inhalation Only Your ADVAIR HFA inhaler • The metal canister holds the medicine. See Figure A.

mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 1 more time to finish prim¬ ing it. How to use your ADVAIR HFA inhaler Follow these steps every time you use ADVAIR HFA. Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the window in the actu¬ ator. Shake the inhaler well for 5 seconds before each spray. Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, and take out any you see. Step 2. Hold the inhaler with the mouthpiece down. See Figure E.

• The canister has a counter to show how many sprays of medicine you have left. The number shows through a win¬ dow in the back of the actuator. See Figure B.

Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your bps around it. See Figure F.

• The counter starts at either 124 or 064, depending on which size inhaler you have. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000. • Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister. • The purple plastic actuator sprays the medicine from the canister. The actuator has a protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the canister is not in use. The strap keeps the cap attached to the actuator. • Do not use the actuator with a canister of medicine from any other inhaler. • Do not use an ADVAIR HFA canister with an actuator from any other inhaler. Before using your ADVAIR HFA inhaler • Take ADVAIR HFA out of the foil pouch just before you use it for the first time. Safely throw away the pouch and the drying packet that comes inside the pouch. • The inhaler should be at room temperature before you use it. Priming your ADVAIR HFA inhaler • Before you use ADVAIR HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. • Tb prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the in¬ haler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes.

Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. See Figure F. Step 5. After the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth. Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can. Wait about 30 seconds and shake the inhaler well for 5 sec¬ onds. Repeat steps 2 through 6. Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure G.

Step 10. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine. See Figure I.

Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight. Step 12. Put the cap back on the mouthpiece after the ac¬ tuator has dried. Replacing your ADVAIR HFA inhaler • When the counter reads 020. you should refill your pre¬ scription or ask your healthcare provider if you need an¬ other prescription for ADVAIR HFA. • When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of med¬ icine. • Do not use the inhaler after the expiration date, which is on the packaging it comes in. For correct use of your ADVAIR HFA inhaler, remember: • The canister should always fit firmly in the actuator. • Breathe in deeply and slowly to make sure you get all the medicine. • Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully. • After each dose, rinse your mouth with water and spit it out. Do not swallow the water. • Do not take the inhaler apart. • Always keep the protective cap on the mouthpiece when your inhaler is not in use. • Always store your inhaler with the mouthpiece pointing down. • Clean your inhaler at least 1 time each week. If you have questions about ADVAIR HFA or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit www.advair.com. _ This Medication Guide and Instructions for Use have been approved by the U.S. Food and Drug Administration. ADVAIR, ADVAIR DISKUS, FLOVENT. and SEREVENT are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. December 2014 ADIL10MG

AMERGE

H

[a-merj'] (naratriptan hydrochloride) Tablets, for oral use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AMERGE safely and effectively. See full prescribing information for AMERGE. AMERGE (naratriptan hydrochloride) Tablets, for oral use Initial U.S. Approval: 1998 -INDICATIONS AND USAGE-

• Shake and spray the inhaler like this 3 more times to fin¬ ish priming it. The counter should now read 120 or 060. depending on which size inhaler you have. See Figure D.

Step 8. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it snaps firmly into place. Cleaning your ADVAIR HFA inhaler Clean your inhaler at least 1 time each week after your eve¬ ning dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H.

AMERGE is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults. (1) Limitations of Use: • Use only if a clear diagnosis of migraine has been estab¬ lished. (1) • Not indicated for the prophylactic therapy of migraine attacks. (1) • Not indicated for the treatment of cluster headache < 1 > -DOSAGE AND ADMINISTRATION• Recommended dose: 1 mg or 2.5 mg. (2.1) • May repeat dose after 4 hours if needed; not to exceed 5 mg in any 24-hour period. (2.1) • Mild or moderate renal or hepatic impairment: recom¬ mended starting dose is 1 mg not to exceed 2.5 mg in any 24-hour period. (2.2, 2.3) -DOSAGE FORMS AND STRENGTHSTablets:

• You must prime your inhaler again if you have not used it ) in more than 4 weeks or if you drop it. Take the cap off the 1

Step 9. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the can¬ ister out of the plastic actuator.

1 mg and 2.5 mg. (3, 16)

-CONTRAINDICATIONS• History of coronary artery disease or coronary artery vas¬ ospasm (4)

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AMERGE • GLAXOSMITHKLINE/841

Look for PDR drug information and services in your EHR • Wolff-Parkinson-White syndrome or other cardiac acces¬ sory conduction pathway disorders (4) • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4) • Peripheral vascular disease (4) • Ischemic bowel disease (4) • Uncontrolled hypertension (4) • Recent (within 24 hours) use of another 5-HT, agonist (e.g., another triptan) or an ergotamine-containing medi¬ cation (4) • Hypersensitivity to AMERGE (angioedema and anaphy¬ laxis seen) (4) • Severe renal or hepatic impairment (4) -WARNINGS AND PRECAUTIONS• Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1) • Arrhythmias: Discontinue AMERGE if occurs. (5.2) • Chest/throat/neck/jaw pain, tightness, pressure, or heavi¬ ness: Generally not associated with myocardial ische¬ mia; evaluate for CAD in patients at high risk. (5.3) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue AMERGE if occurs. (5.4) • Gastrointestinal ischemic reactions and peripheral vaso¬ spastic reactions: Discontinue AMERGE if occurs. (5.5) • Medication overuse headache: Detoxification may be necessary. (5.6) • Serotonin syndrome: Discontinue AMERGE if occurs. (5.7) -ADVERSE REACTIONSMost common adverse reactions (>2 % and > placebo) were paresthesias, nausea, dizziness, drowsiness, malaise/fa¬ tigue, and throat/neck symptoms. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -USE IN SPECIFIC POPULATIONS• Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Dosage Adjustment in Patients With Renal Impairment 2.3 Dosage Adjustment in Patients With Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions 5.6 Medication Overuse Headache 5.7 Serotonin Syndrome 5.8 Increase in Blood Pressure 5.9 Anaphylactic/Anaphylactoid Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs 7.2 Other 5-HT, Agonists 7.3 Selective Serotonin Reuptake Inhibitors/Se¬ rotonin Norepinephrine Reuptake Inhibitors and Se¬ rotonin Syndrome 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.8 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/HTORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing I information are not listed.

FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

AMERGE?" is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: • Use only if a clear diagnosis of migraine has been estab¬ lished. If a patient has no response to the first migraine attack treated with AMERGE, reconsider the diagnosis of migraine before AMERGE is administered to treat any subsequent attacks. • AMERGE is not indicated for the prevention of migraine attacks. • Safety and effectiveness of AMERGE have not been estab¬ lished for cluster headache. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of AMERGE is 1 mg or 2.5 mg. If the migraine returns or if the patient has only partial re¬ sponse, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period. The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established. 2.2 Dosage Adjustment in Patients With Renal Impair¬ ment AMERGE is contraindicated in patients with severe renal impairment (creatinine clearance: 5% in any Treatment Group) Reported by Patients in Short-term* Double-blind Clinical Trials With AVANDIA as Monotherapy AVANDIA Monotherapy N = 2,526 %

Placebo N= 601 %

Metformin N = 225 %>

Sulfonylureasb N = 626 %

Upper respiratory tract infection

9.9

8.7

8.9

7.3

Injury

7.6

4.3

7.6

6.1

Headache

5.9

5.0

8.9

5.4

Back pain

4.0

3.8

4.0

5.0

Hyperglycemia

3.9

5.7

4.4

8.1

Fatigue

3.6

5.0

4.0

19

Sinusitis

3.2

4.5

5.3

3.0

Diarrhea

2.3

3.3

15.6

3.0

Hypoglycemia

0.6

0.2

1.3

5.9

Preferred Term

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA [see Adverse Reactions (6.2)]. The observed changes may be related to the increased plasma volume ob¬ served with treatment with AVANDIA.

’ Short-term trials ranged from 8 weeks to 1 year. b Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21).

5.9

Lower pre-treatment hemoglobin/hematocrit levels in pa¬ tients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these trials /see Adverse Reactions (6.2)1. In clinical trials, edema was reported in 4.8% of patients receiving AVANDIA as monotherapy compared with 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. The reporting rate of edema was higher for AVANDIA 8 mg in sulfonylurea combinations (12.4%) compared with other combinations, with the exception of insulin. Edema was re¬ ported in 14.7% of patients receiving AVANDIA in the insu¬ lin combination trials compared with 5.4% on insulin alone. Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with AVANDIA [see Boxed Warning, Warnings and Precautions

Diabetes and Blood Glucose Control

Patients receiving AVANDIA in combination with other hy¬ poglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be nec¬ essary. Periodic fasting blood glucose and IlbAlc measurements should be performed to monitor therapeutic response. _ 5.10

Ovulation

Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking AVANDIA /see Use in Spe¬ cific Populations (8.1)]. Thus, adequate contraception in pre¬ menopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials: therefore, the frequency of this occurrence is not known. Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology (13.1)], the clinical sig¬ nificance of this finding is not known. If unexpected men¬ strual dysfunction occurs, the benefits of continued therapy with AVANDIA should be reviewed. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail elsewhere in the labeling: • Cardiac Failure [see Warnings and Precautions (5.1)1 • Major Adverse Cardiovascular Events [see Warnings and Precautions (5.2)]

• Edema [see Warnings and Precautions (5.3)] • Weight Gain [see Warnings and Precautions (5.4)] • Hepatic Effects [see Warnings and Precautions (5.5)] • Macular Edema [see Warnings and Precautions (5.6)1 • Fractures [see Warnings and Pn-cautions (5.7)] • Hematologic Effects /see Warnings and Precautions (5.8)] • Ovulation [see Warnings and Precautions (5.10)] 6.1

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult: In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with AVANDIA. Short-term TYials of AVANDIA as Monotherapy and in Com¬ bination With Other Hypoglycemic Agents: The incidence

and types of adverse events reported in short-term clinical trials of AVANDIA as monotherapy are shown in Table 3. ISee table 3 above] Overall, the types of adverse reactions without regard to causality reported when AVANDIA was used in combination with a sulfonylurea or metformin were similar to those dur¬ ing monotherapy with AVANDIA. Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to mod¬ erate in severity and usually did not require discontinua¬ tion of treatment with AVANDIA. In double-blind trials, anemia was reported in 1.9% of pa¬ tients receiving AVANDIA as monotherapy compared with 0.79 on placebo, 0.6% on sulfonylureas, and 2.2% on met¬ formin. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared with monotherapy with AVANDIA or in combination with a sulfonylurea (2.3%).

(5.1)].

In controlled combination therapy trials with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were with¬ drawn for hypoglycemia ( versus 11%), -nasopharyngitis t3% versus 12%), and diarrhea (1% versus 13% ). In this trial, one case of di¬ abetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the rosiglitazone group who had FPG of approximately 300 mg/dL, 2+ ketonuria, and an elevated anion gap. 6.2 Laboratory Abnormalities Hematologic: Decreases in mean hemoglobin and hemato¬

crit occurred in a dose-related fashion in adult patients

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862/GLAXOSMITHKLINE • AVANDIA Table 5. Cardiovascular (CV) Outcomes for the RECORD Trial

Primary Endpoint

AVANDIA N = 2.220

Active Control N = 2,227

Hazard Ratio

95% Cl

inhibitor or an inducer of CYP2C8 is started or stopped dur¬ ing treatment with rosiglitazone, changes in diabetes treat¬ ment may be needed based upon clinical response. [See Clinical Pharmacology (12.4).1

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Secondary Endpoint All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. 0.68-1.08 0.86 157 136 All-cause death This background risk is increased in pregnancies compli¬ cated by hyperglycemia and may be decreased with good 0.59-1.18 0.84 71 60 CV death metabolic control. It is essential for patients with diabetes 0.80-1.63 1.14 56 or history of gestational diabetes to maintain good meta¬ 64 Myocardial infarction bolic control before conception and throughout pregnancy. 0.49-1.06 0.72 63 46 Careful monitoring of glucose control is essential in such pa¬ Stroke tients. Most experts recommend that insulin monotherapy 0.74-1.15 0.93 165 154 CV death, myocardial infarction, or stroke be used during pregnancy to maintain blood glucose levels as close to normal as possible. 1.35-3.27 2.10 29 61 Heart failure Human Data: Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clin¬ ical significance of these findings is unknown. There are no adequate and well-controlled trials in pregnant women. Table 6 Week 24 FPG and HbAlc Change From Baseline Last-observation—carried Forward in Children With Baseline AVANDIA should be used during pregnancy only if the po¬ HbAlc >6.5% tential benefit justifies the potential risk to the fetus. Previously-treated Patients Animal Studies: There was no effect on implantation or Naive Patients the embryo with rosiglitazone treatment during early preg¬ Rosiglitazone Metformin Rosiglitazone Metformin nancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both N = 32 N = 43 N = 45 N = 40 Parameter rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approxi¬ FPG (mg/dL) mately 20 and 75 times human AUC at the maximum rec¬ ommended human daily dose, respectively). Rosiglitazone 205 221 165 170 Baseline (mean) caused placental pathology in rats (3 mg/kg/day). Treatment -5 -33 -11 -21 Change from baseline (mean) of rats during gestation through lactation reduced litter 21 8 Adjusted treatment difference3 size, neonatal viability, and postnatal growth, with growth (-9, 51) (-15, 30) (rosiglitazone-metformin)b (95% Cl) 28% retardation reversible after puberty. For effects on the pla¬ 44% 27% 43% % of patients with > 30 mg/dL decrease centa, embryo/fetus, and offspring, the no-effect dose was from baseline 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC HbAlc (%) at the maximum recommended human daily dose. 8.5 8.8 8.2 8.3 Baseline (mean) Rosiglitazone reduced the number of uterine implantations 0.1 -0.4 -0.5 -0.7 Change from baseline (mean) and live offspring when juvenile female rats were treated at 0.5 0.2 Adjusted treatment difference8 40 mg/kg/day from 27 days of age through to sexual matu¬ (-0.2, 1.3) (-0.6, 0.9) (rosiglitazone-metformin)b (95% Cl) rity (approximately 68 times human AUC, at the maximum 31% 54% 52% 63% % of patients with > 0.7% decrease from recommended daily dose). The no-effect level was 2 mg/kg/ baseline day (approximately 4 times human AUC -it the maximum recommended daily dose). There was no effect on pre- or * Change from baseline means are least squares means adjusting for baseline HbAlc, gender, and region. post-natal survival or growth. b Positive values for the difference favor metformin. 8.2 Labor and Delivery The effect of rosiglitazone on labor and delivery in humans is not known. In the 4- to 6-year ADOPT trial, patients treated with 8.3 Nursing Mothers treated with AVANDIA (mean decreases in individual trials AVANDIA (4,954 patient-years exposure), glyburide (4,244 Drug-related material was detected in milk from lactating as much as 1.0 g/dL hemoglobin and as much as 3.3% he¬ patient-years exposure), or metformin (4,906 patient-years rats. It is not known whether AVANDIA is excreted in hu¬ matocrit). The changes occurred primarily during the first 3 exposure), as monotherapy, had the same rate of ALT in¬ man milk. Because many drugs are excreted in human months following initiation of therapy with AVANDIA or fol¬ crease to >3x upper limit of normal (0.3 per 100 patientmilk, a decision should be made whether to discontinue lowing a dose increase in AVANDIA. The time course and nursing or to discontinue AVANDIA, taking into account the years exposure). magnitude of decreases were similar in patients treated In the RECORD trial, patients randomized to AVANDIA in importance.of the drug to the mother. with a combination of AVANDIA and other hypoglycemic addition to metformin or sulfonylurea (10,849 patient-years 8.4 Pediatric Use agents or monotherapy with AVANDIA. Pre-treatment lev¬ After placebo run-in including diet counseling, children exposure) and to metformin plus sulfonylurea (10,209 els of hemoglobin and hematocrit were lower in patients in with type 2 diabetes mellitus, aged 10 to 17 years and with patient-years exposure) had a rate of ALT increase to >3x metformin combination trials and may have contributed to a baseline mean body mass index (BMI) of 33 kg/m2, were upper limit of normal of approximately 0.2 and 0.3 per 100 the higher reporting rate of anemia. In a single trial in pe¬ randomized to treatment with 2 mg twice daily of AVANDIA patient-years exposure, respectively. diatric patients, decreases in hemoglobin and hematocrit (n = 99) or 500 mg twice daily of metformin (n = 101) in a 6.3 Postmarketing Experience (mean decreases of 0.29 g/dL and 0.95%, respectively) were 24-week, double-blind clinical trial. As expected, FPG de¬ reported. Small decreases in hemoglobin and hematocrit In addition to adverse reactions reported from clinical tri¬ creased in patients naive to diabetes medication (n = 104) have also been reported in pediatric patients treated with als. the events described below have been identified during and increased in patients withdrawn from prior medication AVANDIA. White blood cell counts also decreased slightly in post-approval use of AVANDIA. Because these events are (usually metformin) (n = 90) during the run-in period. After adult patients treated with AVANDIA. Decreases in hema¬ reported voluntarily from a population of unknown size, it is at least 8 weeks of treatment, 49% of patients treated with tologic parameters may be related to increased plasma vol¬ not possible to reliably estimate their frequency or to al¬ AVANDIA and 55% of metformin-treated patients had their ume observed with treatment with AVANDIA. ways establish a causal relationship to drug exposure. dose doubled if FPG >126 mg/dL. For the overall intent-toLipids: Changes in serum lipids have been observed fol¬ In patients receiving thiazolidinedione therapy, serious ad¬ treat population, at Week 24. the mean change from base¬ lowing treatment with AVANDIA in adults [see Clinical verse events with or without a fatal outcome, potentially re¬ line in HbAlc was -0.14% with AVANDIA and -0.49% with Pharmacology (12.2)]. Small changes in serum lipid param¬ lated to volume expansion (e.g., congestive heart failure, metformin. There was an insufficient number of patients in eters were reported in children treated with AVANDIA for pulmonary edema, and pleural effusions) have been re¬ this trial to establish statistically whether these observed 24 weeks. ported [see Boxed Warning, Warnings and Precautions mean treatment effects were similar or different. Treatment Serum Transaminase Levels: In pre-approval clinical tri¬ (5.1)], effects differed for patients naive to therapy with antidia¬ als in 4.598 patients treated with AVANDIA (3,600 patientThere are postmarketing reports with AVANDIA of hepati¬ betic drugs and for patients previously treated with antidi¬ years of exposure) and in a long-term 4- to 6-year trial in tis, hepatic enzyme elevations to 3 or more times the upper abetic therapy (Table 6). 1,456 patients treated with AVANDIA 14,954 patient-years limit of normal, and hepatic failure with and without fatal (See table 6 above] exposure), there was no evidence of drug-induced hepatotoxoutcome, although causality has not been established. Treatment differences depended on baseline BMI or weight icity. | There are postmarketing reports with AVANDIA of rash, such that the effects of AVANDIA and metformin appeared In pre-approval controlled trials, 0.2% of patients treated pruritus, urticaria, angioedema, anaphylactic reaction, j more closely comparable among heavier patients. The me¬ with AVANDIA had elevations in ALT >3x the upper limit of Stevens-Johnson syndrome [see Contraindications (4/], and dian weight gain was 2.8 kg with rosiglitazone and 0.2 kg normal compared with 0.2% on placebo and 0.5% on active new onset or worsening diabetic macular edema with de- I with metformin [see Warnings and Precautions (5.4)]. Fiftycomparators. The ALT elevations in patients treated with creased visual acuity /see Warnings and Precautions (5.6)1. four percent of patients treated with rosiglitazone and 32% AVANDIA were reversible. Hyperbilirubinemia was found 7 DRUG INTERACTIONS of patients treated with metformin gained 22 kg, and 33% of in 0.3% of patients treated with AVANDIA compared with 7.1 CYP2C8 Inhibitors and Inducers patients treated with rosiglitazone and 7% of patients 0.9% treated with placebo and 1% in patients treated with treated with metformin gained >5 kg on trial. An inhibitor of CYP2C8 (e.g., gemfibrozil i may increase the active comparators. In pre-approval clinical trials, there Adverse events observed in this trial are described in Ad¬ AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifam¬ were no cases of idiosyncratic drug reactions leading to he¬ pin) may decrease the AUC of rosiglitazone. Therefore, if an I verse Reactions 16.1). patic failure. /See Warnings and Precautions '5.5).]

CV death or CV hospitalization

321

323

0.99

0.85-1.16

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AVANDIA • GLAXOSMITHKLINE/863

Figure 2. Mean HbAlc Over Time in a 24-Week Trial of AVANDIA and Metformin in Pediatric Patients — Drug-naive Subgroup

Table 7. Summary of Mean Lipid Changes in 26-Week. Placebo-controlled and 52-Week, Glyburide-controlled Monotherapy Trials

90t

Placebo-controlled Trials Week 26 85-

Placebo

d

Parameter

if 2 8.0-

AVANDIA

Glyburide-controlled Trial Week 26 and Week 52 Glyburide Titration

AVANDIA 8 mg

4 mg Daily*

8 mg Daily*

Week 26

Week 52

Week 26

Week 52

207 18.1 +0.2%

428 17.5 -7.8%

436 17.9 -14.7%

181 26.4 -2.4%

168 26.4 -4.7%

166 26.9 -20.8%

145 26.6 -21.5%

190 123.7 +4.8%

400 126.8 +14.1%

374 125.3 +18.6%

175 142.7 -0.9%

160 141.9 -0.5%

161 142.1 +11.9%

133 142.1 +12.1%

208 44.1 +8.0%

429 44.4 +11.4%

436 43.0 +14.2%

184 47.2 +4.3%

170 47.7 +8.7%

170 48.4 +14.0%

145 48.3 + 18.5%

3.03 (0.87)

2.89 (0.71)

2.85 (0.69)

2.97 (0.81)

Free fatty acids

f

N Baseline (mean) % Change from baseline (mean)

7.5-

LDL -6 SC/MA

8.5

0

N Baseline (mean) % Change from baseline (mean)

6uc -H

Time ot Visit (Weeks)

Geriatric Use HDL

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see Clinical Pharmacology (12.3)]. There¬ fore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older (>65 years) and younger ( (117) (92) Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of TW 3.16 3.37 3.15 359 rosiglitazone has been demonstrated in animal models of (hr (0.72) (0.39) (0.63) (0.70) type 2 diabetes in which hyperglycemia and/or impaired

CIVF (L/h)

AUC = area under the curve; Cm„ = maximum concentration; Tw = terminal half-life; CL/F = Oral clearance. Absorption: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food re¬ sulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmns and a delay in Tmax (1.75 hours). These changes are not likely to be clini¬ cally significant; therefore, AVANDIA may be administered with or without food. Distribution: The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30'S» liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma pro¬ teins, primarily albumin. Metabolism: Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to con¬ tribute to the insulin-sensitizing activity of rosiglitazone. In vitro data demonstrate that rosiglitazone is predomi¬ nantly metabolized by Cytochrome P450 (CYPl isoenzyme 2C8. with CYP2C9 contributing as a minor pathway. Excretion: Following oral or intravenous administration of [l,C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of |uC)related material ranged from 103 to 158 hours. Population Pharmacokinetics in Patients With Type 2 Dia¬ betes: Population pharmacokinetic analyses from 3 large clinical trials including 642 men and 405 womeh with type 2 diabetes (aged 35 to 80 years) showed that the pharmacoki¬ netics of rosiglitazone are not influenced by age, race, smok¬ ing, or alcohol consumption. Both oral clearance >CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses 150 to 150 kg), the range of predicted CIVF and Vss/F values varied by 0.7% decrease from baseline

8.9 0.8 9%

-

“P 30 mg/dL decrease from baseline HbAlc(%) Baseline (mean) Change from baseline (mean) Difference from metformin alone (adjusted mean) % of patients with > 0.7% decrease from baseline " P 2.5x upper limit of normal) at baseline/see Warnings and Precautions (5.5)]. Pediatric: Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population phar¬ macokinetic analysis with sparse data from 96 pediatric pa¬ tients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 IVh and 13.5 L, re¬ spectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis. Renal Impairment: There are no clinically relevant differ¬ ences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysisdependent patients compared with subjects with normal re¬ nal function. No dosage adjustment is therefore required in such patients receiving AVANDIA. Since metformin is con¬ traindicated in patients with renal impairment, coadminis¬ tration of metformin with AVANDIA is contraindicated in these patients. Race: Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic ori¬ gins indicate that race has no influence on the pharmacoki¬ netics of rosiglitazone. 12.4 Drug-drug Interactions Drugs That Inhibit, Induce, or are Metabolized by Cyto¬ chrome P450: In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P45Q en¬

zymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabo¬ lized by CYP2C8, and to a lesser extent, 2C9. AVANDIA (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contra¬ ceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4. Gemfibrozil: Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared with the administra¬ tion of rosiglitazone (4 mg once daily) alone. Given the po¬ tential for dose-related adverse events with rosiglitazone, a decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced [see Drug Interactions (7.1)]. Rifampin: Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared with the administra¬ tion of rosiglitazone (8 mg) alone [see Drug Interactions (7.1)]}

Glyburide: AVANDIA (2 mg twice daily) taken concomi¬ tantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concen¬ trations in diabetic patients stabilized on glyburide therapy. Repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in gly¬ buride AUC and CmM of approximately 30%. In Japanese subjects, glyburide AUC and CmH> slightly increased follow¬ ing coadministration of AVANDIA. Glimepiride: Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of AVANDIA. No clinically significant reductions in glimepiride AUC and Cmax were ob¬ served after repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult subjects. Metformin: Concurrent administration of AVANDIA (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state phar¬ macokinetics of either metformin or rosiglitazone. Acarbose: Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clini¬ cally relevant effect on the pharmacokinetics of a single oral dose of AVANDIA. Digoxin: Repeat oral dosing of AVANDIA (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Warfarin: Repeat dosing with AVANDIA had no clinically relevant effect on the steady-state pharmacokinetics of war¬ farin enantiomers. Ethanol: A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with AVANDIA. Ranitidine: Pre-treatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by in¬ creases in gastrointestinal pH. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility Carcinogenesis: A 2-year carcinogenicity study was con¬ ducted in Charles River CD-I mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approx¬ imately 12 times human AUC at the maximum recom¬ mended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively). Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses >1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dosei. In rats, there was a significant increase in the incidence of be¬ nign adipose tissue tumors (lipomas) at doses >0.3 mg/kg/ day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue. Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the pres¬ ence of metabolic activation. Impairment of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum rec¬ ommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of pro¬ gesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/ day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive per¬ formance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times hu¬ man AUC at the maximum recommended human daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; ap¬ proximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequen¬ tial reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mecha¬ nism for these effects appears to be direct inhibition of ovar¬ ian steroidogenesis. 13.2 Animal Toxicology Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respec¬ tively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion. 14 CLINICAL STUDIES Monotherapy In clinical trials, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by FPG and HbAlc, with a concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also re¬ duced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer. The maximum recommended daily dose is 8 mg. Dose¬ ranging trials suggested that no additional benefit was ob¬ tained with a total daily dose of 12 mg. Short-term Clinical Trials: A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or anti¬ diabetic medication! a), were treated with AVANDIA as monotherapy in 6 double-blind trials, which included two 26-week, placebo-controlled trials; one 52-week, glyburidecontrulled trial; and 3 placebo-controlled, dose-ranging tri-

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Look for PDR drug information and services in your EHR als of 8 to 12 weeks’ duration. Previous antidiabetic medi¬ cation! s) were withdrawn and patients entered a 2- to 4-week placebo run-in period prior to randomization. Two 26-week, double-blind, placebo-controlled trials, in pa¬ tients with type 2 diabetes (n = 1,401) with inadequate glycemic control [mean baseline FPG approximately 228 mg/dL (101 to 425 mg/dL) and mean baseline HbAlc 8.9% (5.2% to 16.2%)), were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbAlc compared with baseline and relative to placebo. Data from one of these trials are summarized in Table 9. [See table 9 at top of previous page! When administered at the same total daily dose, AVANDIA was generally more effective in reducing FPG and HbAlc when administered in divided doses twice daily compared with once-daily doses. However, for HbAlc, the difference between the 4 mg once-daily and 2 mg twice-daily doses was not statistically significant. Long-term Clinical Trials: Long-term maintenance of ef¬ fect was evaluated in a 52-week, double-blind, glvburidecontrolled trial in patients with type 2 diabetes. Patients were randomized to treatment with AVANDIA 2 mg twice daily (N = 195) or AVANDIA 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/day or 5.0 mg/day. The dosage was then titrated in 2.5-mg/day in¬ crements over the next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic control. Thereaf¬ ter, the glyburide dose was kept constant. The median titrated dose of glyburide was 7.5 mg. All treat¬ ments resulted in a statistically significant improvement in glycemic control from baseline (Figure 3 and Figure 4). At the end of Week 52, the reduction from baseline in FPG and HbAlc was -40.8 mg/dL and -0.53% with AVANDIA 4 mg twice daily; -25.4 mg/dL and -0.27% with AVANDIA 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbAlc, the difference between AVANDIA 4 mg twice daily and glyburide was not statistically significant at Week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time. The improvement in glycemic control seen with AVANDIA 4 mg twice daily at Week 26 was maintained through Week 52 of the trial. Figure 3. Mean FPG Over Time in a 52-Week, Glyburide-controlled Trial

AVANDIA • GLAXOSMfTHKLM/865 Table 11. Glycemic Parameters in 24- to 26-Week Combination Trials of AVANOIA Plus Sulfonylurea

Twice-Daily Divided Dosing (5 Trials)

Sulfonylurea

AVANDIA 2 mg Twice Daily ♦ Sulfonylurea

Sulfonylurea

AVANDIA 4 mg Twice Daily ♦ Sulfonylurea

N = 397

N = 497

N r 243

N = 346

204 11

198 -29 -42*

188 8 -

187 -43 -53*

17%

49%

15%

61%

9.4 0.2 —

9.5 -1.0 -1.1*

93 00

9.6 -1.6 -14*

21%

60%

23%

75%

Sulfonylurea

AVANDIA 4 mg Once Daily + Sulfonylurea

Sulfonylurea

AVANDtA 8 mg Once Daily ♦ Sulfonylurea

N= 172

N = 172

N = 173

N = 176

198 17 _

206 -25 -47*

188 17

192 -43 -66*

17%

48%

19%

55%

8.6 0.4

8.8 -0.5 -0.9*

8.9 0.1 —

8.9 -L2 -1.4*

11%

36%

20%

68%

FPG Img/dLI Baseline' mean) Change from baseline (mean! Difference from sulfonylurea alone 'adjusted mean) % of patients with > 30 mg/dL decrease from baseline

-

HbAlc(%) Baseline (mean) Change from baseline (mean) Difference from sulfonylurea alone (adjusted mean) % of patients with > 0.7% decrease from baseline

Once-Daily Dosing (3 Trials)

FPG (mg/dL) Baseline (mean) Change from baseline (mean) Difference from sulfonylurea alone (adjusted mean) % of patients with > 30 mg/dL decrease from baseline HbAlc 0.7% decrease from baseline * P 180 mg/dL after at least 6 weeks of treatment at the maxi¬ mum tolerated dose of study medication or time to inade¬ quate glycemic control, as determined by an independent adjudication committee. The cumulative incidence of the primary efficacy outcome at 5 years was 15% with AVANDIA, 21% with metformin, and 34% with glyburide . to patients inadequately controlled on a submaximal or maxi¬ mal dose of sulfonylurea In these trials, the combination of AVANDIA 4 mg or 8 mg daily 'administered a* single- or twice-daily divided doses'

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866/GLAXOSMITHKLINE • AVANDIA Table 12. Glycemic Parameters in a 26-Week Combination Trial of AVANDIA Plus Sulfonylurea and Metformin

Parameter

Sulfonylurea + Metformin

AVANDIA 2 mg Twice Daily + Sulfonylurea + Metformin

AVANDIA 4 mg Twice Daily + Sulfonylurea + Metformin

N = 273

N = 276

N = 277

189 14 -

190 -19 -30M

192 -4U -oz

16%

46%

62%

8.7 0.2 “

8.6 -0.4 -0.6"

8.7 -0.9 -1.1

16%

39%

63%

FPG (mg/dL) Baseline (mean) Change from baseline (mean) Difference from sulfonylurea plus metformin (adjusted mean) % of patients with >30 mg/dL decrease from baseline

'

HbAlc(%) Baseline (mean) Change from baseline (mean) Difference from sulfonylurea plus metformin (adjusted mean) % of patients with >0.7% decrease from baseline “ P 180 mg/dL) occurred in a significantly lower proportion of patients (2%) on AVANDIA plus glipizide compared with pa¬ tients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbAlc was durable over the 2-year trial period, with pa¬ tients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbAlc compared with no change on the glipi¬ zide arm. 14.3 Combination With Sulfonylurea Plus Metformin In two 24- to 26-week, double-blind, placebo-controlled tri¬ als designed to assess the efficacy and safety of AVANDIA in combination with sulfonylurea plus metformin, AVANDIA 4 mg or 8 mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maxi¬ mal dose of metformin (2g/day). A statistically significant improvement in FPG and HbAlc was observed in patients treated with the combinations of sulfonylurea plus met¬ formin and 4 mg of AVANDIA and 8 mg of AVANDIA versus patients continued on sulfonylurea plus metformin, as shown in Table 12. [See table 12 above! 15

REFERENCES

1. Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004;75:157-162. 16

HOW SUPPLIED/STORAGE AND HANDLING

Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg-pink, debossed with GSK on one side and 2 on the other; 4 mgorange, debossed with GSK on one side and 4 on the other; 8 mg-red-brown. debossed with GSK on one side and 8 on the other. 2 mg bottles of 60: NDC 0173-0861-18 4 mg bottles of 30: NDC 0173-0863-13 8 mg bottles of 30: NDC 0173-0864-13 Store at 25“C (77°Fi; excursions 15“ to 30“C (59° to 86°F>. Dispense in a tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

There are multiple medications available to treat type 2 di¬ abetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient. Patients should be informed of the following: • AVANDIA is not recommended for patients with symptom¬ atic heart failure. • A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with AVANDIA compared with placebo. Data from long-term clinical trials of AVANDIA versus other antidiabetes agents (metformin or sulfonylureas), including a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. • AVANDIA is not recommended for patients who are taking insulin. • Management of type 2 diabetes should include diet con¬ trol. Caloric restriction, weight loss, and exercise are es¬ sential for the proper treatment of the diabetic patient be¬ cause they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 di¬ abetes, but in maintaining the efficacy of drug therapy. • It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. It can take 2 weeks to see a reduction in blood glu¬ cose and 2 to 3 months to see the full effect of AVANDIA. • Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdomi¬ nal pain, fatigue, anorexia, or dark urine should immedi¬ ately report these symptoms to their physician. • Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician. • AVANDIA can be taken with or without meals. • When using AVANDIA in combination with other hypogly¬ cemic agents, the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its develop¬ ment should be explained to patients and their family members. • Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation in some premenopausal anovula¬ tory women. As a result, these patients may be at an in¬ creased risk for pregnancy while taking AVANDIA. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specif¬ ically investigated in clinical trials so the frequency of this occurrence is not known. AVANDIA and TILTAB are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 62014, the GSK group of companies. All rights reserved. AVD:32PI

MEDICATION GUIDE AVANDIA® (ah-VAN-dee-a) (rosiglitazone maleate) tablets Read this Medication Guide carefully before you start tak¬ ing AVANDIA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about AVANDIA, ask your doctor or pharmacist. What is the most important information I should know about AVANDIA? AVANDIA may cause serious side effects, including: New or worse heart failure • The risk of heart failure may be higher in people who take AVANDIA with insulin. Most people who take insulin should not also take AVANDIA. • AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough. • If you have severe heart failure, you cannot start AVANDIA. • If you have heart failure with symptoms (such as short¬ ness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you. Call your doctor right away if you have any of the following: • swelling or fluid retention, especially in the ankles or legs • shortness of breath or trouble breathing, especially when you lie down • an unusually fast increase in weight • unusual tiredness AVANDIA can have other serious side effects. Be sure to read the section below “What are possible side effects of AVANDIA?” What is AVANDIA? AVANDIA is a prescription medicine used with diet and ex¬ ercise to treat adults with type 2 (“adult-onset” or “non¬ insulin dependent") diabetes mellitus (“high blood sugar”). AVANDIA helps to control high blood sugar. AVANDIA may be used alone or with other diabetes medicines. AVANDIA can help your body respond better to insulin made in your body. AVANDIA does not cause your body to make more in¬ sulin. AVANDIA is not for people with type 1 diabetes mellitus or to treat a condition called diabetic ketoacidosis. It is not known if AVANDIA is safe and effective in children younger than 18 years old. , Who should not take AVANDIA? Many people with heart failure should not start taking AVANDIA. See “What should I tell my doctor before taking AVANDIA?” Do not take AVANDIA if you are allergic to rosiglitazone or any of the ingredients in AVANDIA. See the end of this leaf¬ let for a complete list of ingredients in AVANDIA. Symptoms of a severe allergic reaction with AVANDIA may include: • swelling of your face, lips, tongue, or throat • problems with breathing or swallowing • skin rash or itching • raised red areas on your skin (hives) • blisters on your skin or in your mouth, nose, or eyes • peeling of your skin • fainting or feeling dizzy • very rapid heartbeat What should I tell my doctor before taking AVANDIA? Before starting AVANDIA, ask your doctor about what the choices are for diabetes medicines, and what the expected benefits and possible risks are for you in particular. Before taking AVANDIA, tell your doctor about all of your medical conditions, including if you: • have heart problems or heart failure. • have type 1 ("juvenile") diabetes or had diabetic ketoaci¬ dosis. These conditions should be treated with insulin. • have a type of diabetic eye disease called macular edema (swelling of the back of the eye). • have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. • had liver problems while taking REZULIN™ (troglitazone), another medicine for diabetes. • are pregnant or plan to become pregnant. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your dia¬ betes during pregnancy. If you are a premenopausal woman (before the “change of life”) who does not have reg¬ ular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. 'Dell your doc¬ tor right away if you become pregnant while taking AVANDIA. are breastfeeding or planning to breastfeed. It is not known if AVANDIA passes into breast milk. You and your doctor should decide if you will take AVANDIA or breast¬ feed. You should not do both.

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Look for PDR drug information and services in your EHR Ttell your doctor about all of the medicines you take includ¬ ing prescription and non-prescription medicines, vitamins or herbal supplements. AVANDIA and certain other medi¬ cines can affect each other and may lead to serious side ef¬ fects including high or low blood sugar, or heart problems. Especially tell your doctor if you take: • insulin. • any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is alright to take AVANDIA with other medicines. How should I take AVANDIA? • Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is 4 mg a day taken one time each day or 2 mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better com trolled. • AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled. • Take AVANDIA with or without food. • It can take 2 weeks for AVANDIA to start lowering blood sugar. It may take 2 to 3 months to see the full effect on your blood sugar level. • If you miss a dose of AVANDIA, take it as soon as you re¬ member, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for a missed dose. • If you take too much AVANDIA, call your doctor or poison control center right away. • Test your blood sugar regularly as your doctor tells you. • Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA. • Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for exam¬ ple, “A1C”) to monitor your response to AVANDIA. What are possible side effects of AVANDIA? AVANDIA may cause serious side effects including: • New or worse heart failure. See “What is the most impor¬ tant information I should know about AVANDIA?” • Heart attack. AVANDIA may increase the risk of a heart attack. Talk to your doctor about what this means to you. Symptoms of a heart attack can include the following: ° chest discomfort in the center of your chest that lasts for more than a few minutes, or that goes away or comes back ° chest discomfort that feels like uncomfortable pressure, squeezing, fullness, or pain ° pain or discomfort in your arms, back, neck, jaw, or stom¬ ach " shortness of breath with or Without chest discomfort a breaking out in a cold sweat o nausea or vomiting ° feeling lightheaded Call your doctor or go to the nearest hospital emergency room right away if you think you are having a heart at¬ tack. • Swelling (edema). AVANDIA can cause swelling due to fluid retention. See “What is the most important informa¬ tion I should know about AVANDIA?” • Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people, with certain conditions in¬ cluding heart problems. See “What is the most important information I should know about AVANDIA?” • Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doc¬ tor right away if you have unexplained symptoms such as: ° nausea or vomiting ° stomach pain ° unusual or unexplained tiredness °loss of appetite • dark urine ° yellowing of your skin or the whites of your eyes. • Macular edema a diabetic eye disease with swelling in the back of the eye). Tfell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have had vi¬ sion changes due to swelling in the back of the eye while taking AVANDIA. • Fractures (broken bones), usually in the hand, upper arm. or foot. Talk to your doctor for advice on how to keep your bones healthy. • Low red blood cell count (anemia). • Low blood sugar (hypoglycemia). Lightheadedness, dizzi¬ ness, shakiness or hunger may mean that your blood

AVODART • GLAXOSMITHKLINE/867 sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you. • Ovulation (release of egg from an ovary in a woman) lead¬ ing to pregnancy. Ovulation may happen in premenopau¬ sal women who do not have regular monthly periods. This can increase the chance of pregnancy. See “What should I tell my doctor before taking AVANDIA?” The most common side effects of AVANDIA reported in clin¬ ical trials included cold-like symptoms and headache. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AVANDIA? • Store AVANDIA at room temperature, 59°F to 86°F (15°C to 30°C). Keep AVANDIA in the container it comes in. • Safely, throw away AVANDIA that is out of date or no longer needed. • Keep AVANDIA and all medicines out of the reach of chil¬ dren. General information about AVANDIA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AVANDIA for a condition for which it was not prescribed. Do not give AVANDIA to other people, even if they have the same symp¬ toms you have. It may harm them. This Medication Guide summarizes important information about AVANDIA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AVANDIA that is written for healthcare professionals. You can also find out more about AVANDIA by calling 1-888-825-5249. What are the ingredients in AVANDIA? Active Ingredient: rosiglitazone maleate. Inactive Ingredients: hypromellose 2910, lactose monohy¬ drate, magnesium stearate, microcrystalline cellulose, poly¬ ethylene glycol 3000, sodium starch glycolate, titanium di¬ oxide, triacetin, and 1 or more of the following: synthetic red and yellow iron oxides ahd talc. Always check to make sure that the medicine you are taking is the correct one. AVANDIA tablets are triangles with rounded corners and look like this: 2 mg - pink with “GSK” on one side and “2” on the other. 4 mg - orange with “GSK” on one side and “4” on the other. 8 mg - red-brown with “GSK” on one side and “8” on the other. AVANDIA is a registered trademark of the GSK group of companies. REZULIN is a trademark of its respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products. This Medication Guide has been approved by the U S. Food and Drug Administration. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. Mav 2014 AVD:8MG

AVODART

I{

\au'd dart]

(dutasteride) soft gelatin capsules HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AVODART safely and effectively. See full prescribing information for AVODART. AVODART (dutasteride) soft gelatin capsules Initial U S. Approval: 2001 -INDICATIONS AND USAGEAVODART is a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: (1.1) • improve symptoms, • reduce the risk of acute urinary retention, and • reduce the risk of the need for BPH-related surgery. AVODART in combination with the alpha-adrenergic antag¬ onist, tamsulosin, is Indicated for the treatment of symp¬ tomatic BPH in men with an enlarged prostate. (1.2) Liitiitations of Use: AVODART is not approved for the pre¬ vention of prostate cancer. Vl.3) -DOSAGE AND ADMINISTRATIONMonotherapy: 0.5 mg once daily. (2.1) Combination with tamsulosin: 0.5 mg once daily and tam¬ sulosin 0.4 mg once daily. (2.2) Dosing considerations: Swallow whole. May take with or without food. (2) -DOSAGE FORMS AND STRENGTHS0.5-mg soft gelatin capsules (3)

-CONTRAINDICATIONS• Pregnancy and women of childbearing potential. 14, 5.4, 8.1) • Pediatric patients. (4) • • Patients with previously demonstrated, clinically signifi¬ cant hypersensitivity (e.g., serious skin reactions, angioedema) to AVODART or other 5 alpha-reductase inhibi¬ tors. (4) -WARNINGS AND PRECAUTIONS• AVODART reduces serum prostate-specific antigen (PSA) concentration by approximately 50'?, However, any con¬ firmed increase in PSA while on AVODART may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for un¬ treated men. (5.1) • AVODART may increase the risk of high-grade prostate cancer. (5.2, 6.1) • Prior to initiating treatment with AVODART, consider¬ ation should be given to other urological conditions that may cause similar symptoms. (5.3) • Women who are pregnant or could become pregnant should not handle AVODART Capsules due to potential risk to a male fetus. (5.4, 8.1) • Patients should not donate blood until 6 months after their last dose of AVODART. (5.5) -ADVERSE REACTIONSThe most common adverse reactions, reported in 51% of subjects treated with AVODART and more commonly than in subjects treated with placebo, are impotence, decreased libido, ejaculation disorders, and breast disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch. -DRUG INTERACTIONSUse with caution in patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir). (7) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 9/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Monotherapy 1.2 Combination with Alpha-adrenergic Antago¬ nist 1.3 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Monotherapy 2.2 Combination with Alpha-adrenergic Antago¬ nist 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Prostate-specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection 5.2 Increased Risk of High-grade Prostate Can¬ cer 5.3 Evaluation for Other Urological Diseases 6.4 Exposure of Women—Risk to Male Fetus 5.5 Blood Donation 5.6 Effect on Semen Characteristics 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Cytochrome P450 3A Inhibitors 7.2 Alpha-adrenergic Antagonists * 7.3 Calcium Channel Antagonists 7.4 Cholestyramine 7.5 Digoxin 7.6 Warfarin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Tbxicologv and/or Pharmacology 14 CLINICAL STUDIES 14.1 Monotherapy 14.2 Combination with Alpha-blocker Therapy (CombATi

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868/GLAXOSMITHKUNE • AVODART

Table 1. Adverse Reactions Reported in >1% of Subjects over a 24-Month Period and More Frequently in the Group Receiving AVODART than the Placebo Group (Randomized, Double-blind, Placebo-controlled Trials Pooledl by Time of Onset Adverse Reaction Time of Onset Months 19-24 (n = 1,605) (n = 1,555)

Months 0-6 (n = 2,167) (n = 2,158)

Months 7-12 (n = 1,901) (n = 1,922)

Months 13-18 (n = 1,725) (n = 1,714)

Impotence* 1 2 3 AVODART Placebo

4.7% 1.7%

1.4% 1.5%

1.0% 0.5%

0.8% 0.9%

Decreased libido3 5 * * * * * AVODART Placebo

3.0% 1.4%

0.7% 0.6%

0.3% 0.2%

0.3% 0.1%

Ejaculation disorders" AVODART Placebo

1.4% 0.5%

0.5% 0.3%

0.5% 0.1%

0.1% 0.0%

Breast disorders11 AVODART Placebo

0.5% 0.2%

0.8% 0.3%

1.1% 0.3%

0.6% 0.1%

Adverse Reaction AVODART (n) Placebo (n)

“These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tarnsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this rersistence is unknown. Tncludes breast tenderness and breast enlargement. PSA values in subjects with symptomatic BPH, although it may vary in individuals. AVODART may also cause de¬ creases in serum PSA in the presence of prostate cancer. To -• interpret serial PSAs in men taking AVODART, a new PSA baseline should be established at least 3 months after start¬ ing treatment and PSA monitored periodically thereafter. FULL PRESCRIBING INFORMATION Any confirmed increase from the lowest PSA value while on 1 INDICATIONS AND USAGE AVODART may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the 1.1 Monotherapy AVODART® (dutasteride) soft gelatin capsules are indicated normal range for men not taking a 5 alpha-reductase inhib¬ for the treatment of symptomatic benign prostatic hyperpla¬ itor. Noncompliance with AVODART may also affect PSA sia (BPH) in men with an enlarged prostate to: test results. To interpret an isolated PSA value in a man treated with • improve symptoms, • reduce the risk of acute urinary retention (AUR), and AVODART for 3 months or more, the PSA value should be • reduce the risk of the need for BPH-related surgery. doubled for comparison with normal values in untreated 1.2 Combination with Alpha-adrenergic Antagonist men.The free-to-total PSA ratio (percent free PSA) remains AVODART in combination with the alpha-adrenergic antag¬ constant, even under the influence of AVODART. If clini¬ onist, tamsulosin, is indicated for the treatment of symp¬ cians elect to use percent free PSA as an aid in the detection tomatic BPH in men with an enlarged prostate. of prostate cancer in men receiving AVODART, no adjust¬ 1.3 Limitations of Use ment to its value appears necessary. AVODART is not approved for the prevention of prostate Coadministration of dutasteride and tamsulosin resulted in cancer. similar changes to serum PSA as dutasteride monotherapy. 5.2 Increased Risk of High-grade Prostate Cancer 2 DOSAGE AND ADMINISTRATION In men aged 50 to 75 years with a prior negative biopsy for The capsules should be swallowed whole and not chewed or prostate cancer and a baseline PSA between 2.5 ng/mL and opened, as contact with the capsule contents may result in 10.0 ng/mL taking AVODART in the 4-year Reduction by irritation of the oropharyngeal mucosa. AVODART may be Dutasteride of Prostate Cancer Events (REDUCE) trial, administered with or without food. there was an increased incidence of Gleason score 8-10 pros¬ 2.1 Monotherapy tate cancer compared with men taking placebo (AVODART The recommended dose of AVODART is 1 capsule (0.5 mg) 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), taken once daily. Adverse Reactions (6.1)]. In a 7-year placebo-controlled clin¬ 2.2 Combination with Alpha-adrenergic Antagonist ical trial with another 5 alpha-reductase inhibitor (finas¬ The recommended dose of AVODART is 1 capsule (0.5 mg) teride 5 mg, PROSCAR®), similar results for Gleason score taken once daily and tamsulosin 0.4 mg taken once daily. 8-10 prostate cancer were observed (finasteride 1.8% versus 3 DOSAGE FORMS AND STRENGTHS placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of devel¬ 0.5-mg, opaque, dull yellow, gelatin capsules imprinted with opment of high-grade prostate cancer. Whether the effect of “GX CE2” in red ink on one side. 5 alpha-reductase inhibitors to reduce prostate volume or 4 CONTRAINDICATIONS trial-related factors impacted the results of these trials has AVODART is contraindicated for use in: not been established. • Pregnancy. In animal reproduction and developmental 5.3 Evaluation for Other Urological Diseases toxicity studies, dutasteride inhibited development of Prior to initiating treatment with AVODART, consideration male fetus external genitalia. Therefore, AVODART may should be given to other urological conditions that may cause fetal harm when administered to a pregnant cause similar symptoms. In addition, BPH and prostate woman. If AVODART is used during pregnancy or if the cancer may coexist. patient becomes pregnant while taking AVODART, the pa¬ 5.4 Exposure of Women—Risk to Male Fetus tient should be apprised of the potential hazard to the fe¬ AVODART Capsules should not be handled by a woman tus [see Warnings and Precautions (5.4), Use in Specific who is pregnant or who could become pregnant. Dutasteride Populations (8.1)]. is absorbed through the skin and could result in unintended • Women of childbearing potential [see Warnings and Pre¬ fetal exposure. If a woman who is pregnant or who could cautions (5.4). Use in Specific Populations (8.1)]. become pregnant comes in contact with leaking dutasteride • Pediatric patients /see Use in Specific Populations 7.5 mg/day at baseline. The pro¬ portion of patients able to reduce their average prednisone dose by at least 25% to 12, was calculated for both Trials 2 and 3. The propor¬ tion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for BENLYSTA relative to placebo in both trials. In Trial 2, 18% of patients receiving BENLYSTA 10 mg/kg and 16% of patients receiv¬ ing BENLYSTA 1 mg/kg had a severe flare compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, had a severe flare. 16

HOW SUPPLIED/STORAGE AND HANDLING

BENLYSTA is a sterile, preservative-free, lyophilized pow¬ der for reconstitution, dilution, and intravenous infusion provided in single-use glass vials with a rubber stopper (not

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Look for PDR drug information and services in your EHR made with natural rubber latex) and a flip-off seal. Each 5-mL vial contains 120 mg of belimumab. Each 20-mL vial contains 400 mg of belimumab. BENLYSTA is supplied as follows:

120 mg belimumab in a 5-mL single-use vial 400 mg belimumab in a 20-mL single-use vial

NDC 49401-101-01 NDC 49401-102-01

Store vials of BENLYSTA refrigerated between 2° to 8°C (36° to 46°F). Vials should be protected from light and stored in the original carton until use. Do not freeze. Avoid exposure to heat. Do not use beyond the expiration date. 17

PATIENT COUNSELING INFORMATION

See the FDA-approved patient labeling (Medication Guide). 17.1

Advice for the Patient

Give patients the Medication Guide for BENLYSTA and pro¬ vide them an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be dis¬ cussed. Mortality: Advise patients that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions (5.D1. Serious Infections: Advise patients that BENLYSTA may decrease their ability to fight infections. Ask patients if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precau¬ tions (5.2)]. Instruct patients to tell their healthcare pro¬ vider if they develop signs or symptoms of an infection. Progressive Multifocal Leukoencephalopathy (PML); Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warn¬ ings and Precautions (5.2)]. Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of hypersensi¬ tivity and infusion reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an al¬ lergic reaction during or after the administration of BENLYSTA. Inform patients to tell their healthcare pro¬ vider about possible reactions that may include a combina¬ tion of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling and may occur after administration of BENLYSTA [see Warnings and Precau¬ tions (5.4, 5.5)]. Depression: Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes [see Warnings and Precautions (5.6)]. Immunizations: Inform patients that they should not re¬ ceive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA /see Warn¬ ings and Precautions (5.7)]. Pregnancy and Nursing Mothers: Inform patients that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, be¬ come pregnant, or are thinking about becoming pregnant [see Use in Specific Populations (8.1)1. Encourage pregnant patients to enroll in the pregnancy registry for BENLYSTA [see Use in Specific Populations (8.1)]. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations (8.3)]. BENLYSTA is a registered trademark of the GSK group of companies. Manufactured by GlaxoSmithKline Manufacturing SpA

43056 S. Polo di 'Ibrrile (PR). Italy Manufactured for Human Genome Sciences, Inc.

(a subsidiary of GlaxoSmithKline) Rockville, Maryland 20850 US License No. 1820 Marketed by: GlaxoSmithKline

Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. BNL:3PI MEDICATION GUIDE BENLYSTA® (ben-UST-ah) (belimumab! Injection for intravenous use

Read this Medication Guide before you start receiving BENLYSTA and before each treatment. There may be new

BENLYSTA • GLAXOSMITHKLINE/879 information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about BENLYSTA?

BENLYSTA can cause serious side effects. Some of these side effects may cause death. It is not known if BENLYSTA causes these serious side effects. Tell your healthcare pro¬ vider right away if you have any of the symptoms listed be¬ low while receiving BENLYSTA. 1 Infections. Symptoms of an infection can include: • fever • chills • pain or burning with urination • urinating often • bloody diarrhea • coughing up mucus 2. Heart Problems. Symptoms of heart problems can in¬ clude: • chest discomfort or pain • shortness of breath • cold sweats • nausea • dizziness • discomfort in other areas of the upper body 3. Mental health problems and suicide. Symptoms of men¬ tal health problems can include: • thoughts of suicide or dying • attempt to commit suicide • trouble sleeping (insomnia) • new or worse anxiety • new or worse depression • acting on dangerous impulses • other unusual changes in your behavior or mood • thoughts of hurting yourself or others What is BENLYSTA?

BENLYSTA is a prescription medicine used to treat adults with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines. BENLYSTA contains belimumab which is in a group of medicines called monoclonal antibodies. Lupus is a disease of the immune system (the body system that fights infec¬ tion). People with active lupus often have high levels of a certain protein in their blood. BENLYSTA binds to and lim¬ its the activity of the protein. When given together with other medicines for lupus, BENLYSTA decreases lupus dis¬ ease activity more than other lupus medicines alone. • It is not known if BENLYSTA is safe and effective in peo¬ ple with severe active lupus nephritis or severe active cen¬ tral nervous system lupus. • It is not known if BENLYSTA is safe and effective in chil¬ dren. Who should not receive BENLYSTA? Do not receive BENLYSTA if you:

• are allergic to belimumab or any of the ingredients in BENLYSTA. See the end of this Medication Guide for a complete list of ingredients in BENLYSTA. What should I tell my healthcare provider before receiving BENLYSTA?

Before you receive BENLYSTA, tell your healthcare pro¬ vider if you: • think you have an infection or have infections that keep coming hack. You should not receive BENLYSTA if you have an infection unless your healthcare provider tells you to. See "What is the most important information I should know about BENLYSTA?"

• have or have had mental health problems such as depres¬ sion or thoughts of suicide • have recently received a vaccination or if you think you may need a vaccination. If you are receiving BENLYSTA, you should not receive live vaccines. • are allergic to other medicines • are receiving other biologic medicines, monoclonal anti¬ bodies or IV infusions of cyclophosphamide (Cytoxan®) • have or have had any type of cancer • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if BENLYSTA will harm your unborn baby. Tfell your healthcare provider if you become pregnant during your treatment with BENLYSTA. • If you become pregnant while receiving BENLYSTA, talk to your healthcare provider about enrolling in the BENLYSTA Pregnancy Registry. You can enroll in this reg¬ istry by calling 1-877-681-6296. The purpose of this regis¬ try is to monitor the health of you and your baby. • are breastfeeding or plan to breastfeed. It is not known if BENLYSTA passes into your breast milk. You and your healthcare provider should decide if you will receive BENLYSTA or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medi¬ cines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of your medicines with you to show to your healthcare provider and pharma¬ cist when you get a new medicine.

How will I receive BENLYSTA?

• You will be given BENLYSTA by a healthcare provider through a needle placed in a vein (IV infusion). It takes about 1 hour to give you the full dose of BENLYSTA. • Your healthcare provider will tell you how often you should receive BENLYSTA. • Your healthcare provider may give you medicines before you receive BENLYSTA to help reduce your chance of hav¬ ing a reaction. A healthcare provider will watch you closely while you are receiving BENLYSTA and after your infusion for signs of a reaction. What are the possible side effects of BENLYSTA? BENLYSTA can cause serious side effects. • See "What is the most important information I should know about BENLYSTA?"

• Cancer. BENLYSTA may reduce the activity of your im¬ mune system. Medicines that affect the immune system may increase your risk of certain cancers. • Allergic (hypersensitivity) and infusion reactions. Serious allergic or infusion reactions can happen on the day of or days after receiving BENLYSTA and may cause death. Your healthcare provider will watch you closely while you are receiving BENLYSTA and after your infusion for signs of a reaction. Allergic reactions can sometimes be delayed; tell your healthcare provider right away if you have any of the following symptoms of an allergic or infusion reaction: • itching • swelling of the face, lips, mouth, tongue, or throat • trouble breathing • anxiousness • low blood pressure • dizziness or fainting • headache • nausea • skin rash, redness, or swelling • Progressive multifocal leukoencephalopathy (PMLI. PML is a serious and life-threatening brain infection. Your chance of getting PML may be higher if you are treated with medicines that weaken your immune system, includ¬ ing BENLYSTA. PML can result in death or severe dis¬ ability. If you notice any new or worsening medical prob¬ lems such as those below, tell your healthcare provider right away: • memory loss • trouble thinking • dizziness or loss of balance • difficulty talking or walking • loss of vision The most common side effects of BENLYSTA include:

• nausea • diarrhea • fever • stuffy or runny nose • sore throat • cough (bronchitis) • trouble sleeping • leg or arm pain • depression • headache (migraine) • urinary tract infection • decreased white blood cell count (leukopenia • vomiting • stomach pain Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of BENLYSTA. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA*-1088. General information about the safe and effective use of BENLYSTA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BENLYSTA for a condition for which it was not prescribed. This Medication Guide summarizes the most important in¬ formation about BENLYSTA. For more information about BENLYSTA, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for in¬ formation about BENLYSTA that is written for healthcare professionals. For more information about BENLYSTA, go to www.BENLYSTA.com or call 1-877-423-6597 What are the ingredients in BENLYSTA?

belimumab. Inactive ingredients: citric acid, polysorbate 80, sodium citrate, sucrose. BENLYSTA is a registered trademark of the GSK group of companies. Manufactured by GlaxoSmithKline Manufacturing SpA 43056 S. Polo di Torrile i PR), Italy Manufactured for Human Genome Sciences. Inc (a subsidiary of GlaxoSmithKline) Rockville, Maryland 20850 Active ingredient:

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880/GLAXOSMITHKLINE

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

• BENLYSTA

US License No. 1820 Marketed by GlaxoSmithKline

Research Triangle Park, NC 27709 This Medication Guide has been approved by the U.S. Food and Drug Administration. ©2014, the GSK group of companies. All rights reserved. October 2014 BNL:3MG

• In subjects 19 to 64 years of age, lower levels for antibod¬ ies to FHA and pertactin were observed when BOOSTRIX was administered concomitantly with an inactivated influ¬ enza vaccine as compared to BOOSTRIX alone. (7.1) • Do not mix BOOSTRIX with any other vaccine in the same syringe or vial. (7.1)

There are no data to support repeat administration of BOOSTRIX. Five years should elapse between the last dose of the rec¬ ommended series of Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and/or Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine and the administration of BOOSTRIX.

-USE IN SPECIFIC POPULATIONS-

2.3 Additional Dosing Information

• Safety and effectiveness of BOOSTRIX have not been es¬ tablished in pregnant women. (8.1) • Register women who receive BOOSTRIX while pregnant in the pregnancy registry by calling 1-888-452-9622. (8.1)

Primary Series: The use of BOOSTRIX as a primary scries or to complete the primary series for diphtheria, tetanus, or pertussis has not been studied. Wound Management: If tetanus prophylaxis is needed for wound management, BOOSTRIX may be given if no previ¬ ous dose of any Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap) has been administered.

See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2013

BOOSTRIX [boos' trix\

FULL PRESCRIBING INFORMATION: CONTENTS*

(Tetanus Toxoid, Reduced Diphtheria Toxoid and

1 2

Acellular Pertussis Vaccine, Adsorbed) Suspension for Intramuscular injection HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BOOSTRIX safely and effectively. See full prescribing

3 4

information for BOOSTRIX. BOOSTRIX (Tetanus Toxoid, Reduced Diphtheria Toxoid

5

and Acellular Pertussis Vaccine, Adsorbed) Suspension for Intramuscular Injection Initial U.S. Approval: 2005

-INDICATIONS AND USAGEBOOSTRIX is a vaccine indicated for active booster immu¬ nization against tetanus, diphtheria, and pertussis. BOOSTRIX is approved for use as a single dose in individu¬ als 10 years of age and older. (1) -DOSAGE AND ADMINISTRATION-

6

A single intramuscular injection (0.5 mL). (2.2) -DOSAGE FORMS AND STRENGTHSSingle-dose vials and prefilled syringes containing a 0.5-mL suspension for injection. (3) -CONTRAINDICATIONS• Severe allergic reaction (e.g., anaphylaxis) after a previous dose of any tetanus toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine or to any component of BOOSTRIX. (4.1) • Encephalopathy (e.g., coma, decreased level of conscious¬ ness, prolonged seizures) within 7 days of administration of a previous pertussis antigen-containing vaccine. (4.2)

7 8

11 12 13

-WARNINGS AND PRECAUTIONS• The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latexsensitive individuals. (5.1) • If Guillain-Barre syndrome occurred within 6 weeks of re¬ ceipt of a prior vaccine containing tetanus toxoid, the risk of Guillain-Barre syndrome may be increased following a subsequent dose of tetanus toxoid-containing vaccine, in¬ cluding BOOSTRIX. (5.2) • Syncope (fainting) can occur in association with adminis¬ tration of injectable vaccines, including BOOSTRIX. Pro¬ cedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. (5.3) • Progressive or unstable neurologic conditions are reasons to defer vaccination with a pertussis-containing vaccine, including BOOSTRIX. (5.4) • Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoidcontaining vaccine should not receive BOOSTRIX unless at least 10 years have elapsed since the last dose of a tetanus toxoid-containing vaccine. (5.5) -ADVERSE REACTIONS• Common solicited adverse events (>15%) in adolescents (10 to 18 years of age) were pain, redness, and swelling at the injection site, increase in arm circumference of in¬ jected arm, headache, fatigue, and gastrointestinal symp¬ toms. (6.1) • Common solicited adverse events (>15%) in adults (19 to 64 years of age) were pain, redness, and swelling at the injection site, headache, fatigue, and gastrointestinal symptoms. (6.1) • The most common solicited adverse event (£15%) in the elderly (65 years of age and older) was pain at the injec¬ tion site. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-8227967 or www.vaers.hhs.gov.

-DRUG INTERACTIONS• In subjects 11 to 18 years of age, lower levels for antibod¬ ies to pertactin were observed when BOOSTRIX was ad¬ ministered concomitantly with meningococcal conjugate vaccine iserogroups A. C, Y, and W-135) as compared to BOOSTRIX administered first. (7.1)

14

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Dose and Schedule 2.3 Additional Dosing Information DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Encephalopathy WARNINGS AND PRECAUTIONS 5.1 Latex 5.2 Guillain-Barre Syndrome and Brachial Neu¬ ritis 5.3 Syncope 5.4 Progressive or Unstable Neurologic Disorders 5.5 Arthus-Type Hypersensitivity 5.6 Altered Immunocompetence 5.7 Prevention and Management of Acute Aller¬ gic Reactions ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience DRUG INTERACTIONS 7.1 Concomitant Vaccine Administration 7.2 Immunosuppressive Therapies USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1

Efficacy of INFANRIX

14.2 Immunological Evaluation in Adolescents 14.3 Immunological Evaluation in Adults (19 to 64 Years of Age) 14.4 Immunological Evaluation in the Elderly (65 Years of Age and Older) 14.5 Concomitant Vaccine Administration 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

3

DOSAGE FORMS AND STRENGTHS

BOOSTRIX is a suspension for injection available in 0.5-mL single-dose vials and prefilled TLP-LOK® syringes.

4

CONTRAINDICATIONS

4.1

Hypersensitivity

A severe allergic reaction (e.g., anaphylaxis) after a previ¬ ous dose of any tetanus toxoid-, diphtheria toxoid-, or pertussis antigen-containing vaccine or any component of this vaccine is a contraindication to administration of BOOSTRIX [see Description (11)]. Because of the uncer¬ tainty as to which component of the vaccine might be re¬ sponsible, none of the components should be administered. Alternatively, such individuals may be referred to an aller¬ gist for evaluation if immunization with any of these com¬ ponents is considered. 4.2

Encephalopathy

Encephalopathy (e.g., coma, decreased level of conscious¬ ness, prolonged seizures) within 7 days of administration of a previous dose of a pertussis antigen-containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis antigencontaining vaccine, including BOOSTRIX.

5 5.1

WARNINGS AND PRECAUTIONS Latex

The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latexsensitive individuals. 5.2

Guillain-Barre Syndrome and Brachial Neuritis

If Guillain-Barre syndrome occurred within 6 weeks of re¬ ceipt of a prior vaccine containing tetanus toxoid, the risk of Guillain-Barre syndrome may be increased following a sub¬ sequent dose of tetanus toxoid-containing vaccine, including BOOSTRIX. A review by the Institute of Medicine (IOM) found evidence for a causal relationship between receipt of tetanus toxoid and both brachial neuritis and GuillainBarre syndrome.* 1 2 5.3

Syncope

Syncope (fainting) can occur in association with administra¬ tion of injectable vaccines, including BOOSTRIX. Syncope can be accompanied by transient neurological signs such as visual disturbance, paresthesia, and tonic-clonic limb move¬ ments. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. 5.4

Progressive or Unstable Neurologic Disorders

approved for use as a single dose in individuals 10 years of age and older.

Progressive or unstable neurologic conditions (e.g., cerebro¬ vascular events and acute encephalopathic conditions! are reasons to defer vaccination with a pertussis-containing vaccine, including BOOSTRIX. It is not known whether ad¬ ministration of BOOSTRIX to persons with an unstable or progressive neurologic disorder might hasten manifesta¬ tions of the disorder or affect the prognosis. Administration of BOOSTRIX to persons with an unstable or progressive neurologic disorder may result in diagnostic confusion be¬ tween manifestations of the underlying illness and possible adverse effects of vaccination.

2

5.5

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE BOOSTRIX® is indicated for active booster immunization against tetanus, diphtheria, and pertussis. BOOSTRIX is

2.1

DOSAGE AND ADMINISTRATION Preparation for Administration

Shake vigorously to obtain a homogeneous, turbid, white suspension before administration. Do not use if resuspen¬ sion does not occur with vigorous shaking. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solu¬ tion and container permit. If either of these conditions ex¬ ists, the vaccine should not be administered. For the prefilled syringes, attach a sterile needle and ad¬ minister intramuscularly. For the rials, use a sterile needle and sterile syringe to withdraw the 0.5-mL dose and administer intramuscularly. Changing needles between drawing vaccine from a rial and injecting it into a recipient is not necessary unless the nee¬ dle has been damaged or contaminated. Use a separate ster¬ ile needle and syringe for each individual. Do not administer this product intravenously, intradermally, or subcutaneously. 2.2 Dose and Schedule BOOSTRIX is administered as a single 0.5-mL intramuscuI lar injection into the deltoid muscle of the upper arm.

Arthus-Type Hypersensitivity

Persons who experienced an Arthus-type hypersensitivity reaction following a prior dose of a tetanus toxoidcontaining vaccine usually have a high serum tetanus anti¬ toxin level and should not receive BOOSTRIX or other tetanus toxoid-containing vaccines unless at least 10 years have elapsed since the last dose of tetanus toxoid-containing vaccine. 5.6

Altered Immunocompetence

As with any vaccine, if administered to immunosuppressed persons, including individuals receiving immunosuppres¬ sive therapy, the expected immune response may not be ob¬ tained. 5.7

Prevention and Management of Acute Allergic Re¬

actions

Prior to administration, the healthcare provider should re¬ view the immunization history for possible vaccine sensitiv¬ ity and previous vaccination-related adverse reactions to al¬ low an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur.

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Look for PDR drug information and services in your EHR 6 6.1

ADVERSE REACTIONS Clinical Trials Experience

BOOSTRIX • GLAXOSMITHKLINE/881 The primary safety endpoint was the incidence of grade 3 pain (spontaneously painful and/or prevented normal activ¬ ity) at the injection site within 15 days of vaccination. Grade 3 pain was reported in 4.6% of those who received BOOSTRIX compared with 4.0% of those who received the Td vaccine. The difference in rate of grade 3 pain was within the pre-defined clinical limit for non-inferiority (upper limit of the 95% Cl for the difference [BOOSTRIX minus Td|

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of BOOSTRIX could reveal ad¬ 20 mm 4.1 3.9 dose of BOOSTRIX and 1,034 received the comparator Td Redness, 250 mm 1.7 1.6 vaccine, manufactured by MassBioLogics. There were no substantive differences in demographic characteristics be¬ Swelling, any 21.1 20.1 tween the vaccine groups. Among BOOSTRIX and compar¬ Swelling, >20 mm 5.3 4.9 ator vaccine recipients, approximately 75% were 10 to 14 Swelling, 250 mm 2.5 3.2 years of age and approximately 25% were 15 to 18 years of age. Approximately 98% of participants in this study had Arm circumference increase, 28.3 29.5 received the recommended series of 4 or 5 doses of either >5 mm11 Diphtheria and Tetanus Toxoids and Pertussis Vaccine Arm circumference increase. 2.0 2.2 Adsorbed (DTwP) or a combination of DTwP and DTaP in >20 mmd childhood. Subjects were monitored for solicited adverse Arm circumference increase. 0.5 0.3 events using standardized diary cards (day 0-14). Unsolic¬ >40 mmd ited adverse events were monitored for the 31-day period following vaccination (day 0-30). Subjects were also moni¬ General tored for 6 months post-vaccination for non-routine medical visits, visits to an emergency room, onset of new chronic ill¬ Headache, anv 43.1 41.5 ness, and serious adverse events. Information regarding Headache, grade 2 or 3b 15.7 12.7 late onset adverse events was obtained via a telephone call Headache, grade 3 3.7 2.7 6 months following vaccination. At least 97% of subjects completed the 6-month follow-up evaluation. Fatigue, any 36.7 37.0 In a study conducted in Germany, BOOSTRIX was admin¬ Fatigue, grade 2 or 3 14.4 12.9 istered to 319 children 10 to 12 years of age previously vac¬ Fatigue, grade 3 3.7 3.2 cinated with 5 doses of acellular pertussis antigencontaining vaccines; 193 of these subjects had previously Gastrointestinal symptoms. 26.0 25.8 received 5 doses of INFANRIX® (Diphtheria and Tetanus any1' Toxoids and Acellular Pertussis Vaccine Adsorbed). Adverse Gastrointestinal symptoms. 9.7 9.8 events were recorded on diary cards during the 15 days fol¬ grade 2 or 3*' lowing vaccination. Unsolicited adverse events that Gastrointestinal symptoms, 3.0 3.2 occurred within 31 days of vaccination (day 0-30) were re¬ grade 3*' corded on the diary card or verbally reported to the investi¬ gator. Subjects were monitored for 6 months post¬ Fever, 299.5°F (37.5°C)f 13.5 13.1 vaccination for physician office visits, emergency room 4.7 5.0 Fever. >100.4“F 102.2*F (39.0*0/ 1.4 1.0 events. The 6-month follow-up evaluation, conducted via telephone interview, was completed by 90% of subjects. Td = Tetanus and Diphtheria Toxoids Adsorbed For Adult The US adult (19 to 64 years of age) study, a randomized, Use manufactured by MassBioLogics. observer-blinded study, evaluated the safety of BOOSTRIX N = Number of subjects in the total vaccinated cohort with (N = 1,522) compared with ADACEL® (Tetanus Toxoid, local/general symptoms sheets completed. Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Grade 2 = Local: painful when limb moved; General: Adsorbed) (N = 762). a Tdap vaccine manufactured by interfered with normal activity. Sanofi Pasteur SA. Vaccines were administered as a single Grade 3 = I .oral: spontaneously painful and/or prevented dose. There were no substantive differences in demographic normal activity; General: prevented normal activity. characteristics between the vaccine groups. Subjects were “ Day of vaccination and the next 14 days. monitored for solicited adverse events using standardized b Statistically significantly higher IP 20 mm

17.6

Swelling, >50 mm

14.0

Fever, >99.5°F (37.5°C)b

8.8

Fever, >100.4°F (38.0*0)b

4.1

Fever, >102.2°F (39.0*C)b

1.0

N = Number of subjects with local/general symptoms sheets completed. Grade 2 = Painful when limb moved. Grade 3 = Spontaneously painful and/or prevented normal activity. “Day of vaccination and the next 14 days. bOral temperatures or axillary temperatures. Solicited Adverse Events in the US Adult (19 to 64 Years of Age) Study: Table 3 presents solicili-JlucaFadverse reac¬ tions and general adverse events w ithin 15 days of vaccina¬ tion with BOOSTRIX or the comparator Tdap vaccine for the total vaccinated cohort. Table 3. Rates of Solicited Local Adverse Reactions or General Adverse Events Within the 15-day* Post-Vaccination Period in Adults 19 to 64 Years of Age (Total Vaccinated Cohort)

(N = 1,480)

BOOSTRIX

Tdap (N = 741)

%

%

Pain, any Pain, grade 2 or 3 Pain, grade 3

61.0

69.2

35.1 1.6

44.4

Redness, anv Redness, >20 mm Redness, >50 mm

21.1 4.0 1.6

27.1 6.2 2.3

Swelling, any Swelling, >20 mm Swelling, >50 mm

17.6 3.9 1.4

25.6 6.3 2.8

Local

2.3

.

General

Headache, any Headache, grade 2 or 3 Headache, grade 3

30.1 11.1 2.2

31.0 10.6 1.5

Fatigue, any Fatigue, grade 2 or 3 Fatigue, grade 3

28.1 9.1 2.5

28.9 9.4 1.2

Gastrointestinal symptoms, any® Gastrointestinal symptoms, grade 2 or 3b Gastrointestinal symptoms, grade 3b

15.9

17.6

4.3

5.7

1.2

1.3

Fever, £99.5*F (37.5*0* Fever, >100.4°F (38.0*0* Fever, >102.2*P f39.(TCf

5.5 1.0 0.1

8.0 1.5 04

Tdap = Tetanus Toxoid. Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed, a Tdap vaccine manufactured by Sanofi Pasteur SA.

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882/GLAXOSMITHKLINE • BOOSTRIX Table 5. Rates of Solicited Local Adverse Reactions or General Adverse Events Reported Within the 4-day Post-Vaccination Period following Administration of BOOSTRIX in Individuals 11 to 18 Years of Age (Total Vaccinated Cohort) B00STRIX+MCV49

BOOSTRIX—>MCV4b

MCV4—>BOOSTRIXc

(N = 441)

(N = 432-433)

(N = 441)

%

%

%

Pain, any

70.1

70.4

47.8

Redness, any

22,7

25.7

17.9

Swelling, any

17.7

18.1

12.0

Fatigue

34.0

32.1

20.4

Headache

34.0

30.7

17.0

Gastrointestinal symptoms'1

15.2

14.5

7.7

Fever, >99.5°F (37.5°C)e

5.2

3.5

2.3

Local (at injection site for BOOSTRIX)

General (following administration of BOOSTRIX)

6.2

MCV4 = MENACTRA (Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine), Sanofi Pasteur SA. N = number of subjects in the total vaccinated cohort with local/general symptoms sheets completed. a BOOSTRIX+MCV4 = concomitant vaccination with BOOSTRIX and MENACTRA. b BOOSTRIX—>MCV4 = BOOSTRIX followed by MCV4 1 month later. c MCV4->BOOSTRIX = MCV4 followed by BOOSTRIX 1 month later. d Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. 9 Oral temperatures.

N = Number of subjects in the total vaccinated cohort with local/general symptoms sheets completed. Grade 2 = Local: painful when limb moved; General: interfered with normal activity. Grade 3 = Local/General: prevented normal activity. * Day of vaccination and the next 14 days. b Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. c Oral temperatures. Unsolicited Adverse Events in the US Adult (19 to 64 Years of Age) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.8% and 22.2% for BOOSTRIX and Tdap vaccine, respectively). Solicited Adverse Events in the US Elderly (65 Years of Age and Older) Study: Table 4 presents solicited local adverse reactions and general adverse events within 4 days of vac¬ cination with BOOSTRIX or the comparator Td vaccine for the total vaccinated cohort. Table 4. Rates of Solicited Local Adverse Reactions or General Adverse Events Within 4 Days9 of Vaccination in the Elderly 65 Years of Age and Older (Total Vaccinated Cohort) BOOSTRIX

Td

%

%

(N = 882)

(N = 444)

Pain, any Pain, grade 2 or 3 Pain, grade 3

21.5 7.5 0.2

27.7 10.1 0.7

Redness, any Redness, >20 mm Redness, £50 mm

10.8 1.4 0.6

12.6 2.5 0.9

Local

7.5 2.2 0.7

11.7 3.4 0.7

(N = 882)

(N = 445)

Fatigue, any Fatigue, grade 2 or 3 Fatigue, grade 3

12.5 2.5 0.7

14.8 2.9 0.7

Headache, any Headache, grade 2 or 3 Headache, grade 3

11.5 1.9 0.6

11.7 2.2 0.0

Gastrointestinal symptoms, anyb Gastrointestinal symptoms, grade 2 or 3b

7.6

9.2

1.7

1.8

Swelling, any Swelling, >20 mm Swelling, £50 mm General

Polysaccharide Diphtheria Toxoid Conjugate Vaccine), (Sanofi Pasteur SA), or each vaccine administered sepa¬ rately 1 month apart I see Drug Interactions (7.1) and Clin¬ ical Studies (14.5)1. Safety was evaluated in 446 subjects who received BOOSTRIX administered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects who received BOOSTRIX followed by meningo¬ coccal conjugate vaccine 1 month later, and 449 subjects who received meningococcal conjugate vaccine followed by BOOSTRIX 1 month later. Solicited local adverse reactions and general adverse events were recorded on diary cards for 4 days (day 0-3) following each vaccination. Unsolicited ad¬ verse events were monitored for the 31-day period following each vaccination (day 0-30). Table 5 presents the percent¬ ages of subjects experiencing local reactions at the injection site for BOOSTRIX and solicited general events following BOOSTRIX. The incidence of unsolicited adverse events re¬ ported in the 31 days after any vaccination was similar fol¬ lowing each dose of BOOSTRIX in all cohorts. [See table 5 above]

Gastrointestinal symptoms, grade 3b

0.3

0.4

Fever, £99.5°F (37.5°C)C Fever, >100.4°F (38.0°C)C Fever, >102.2°F (39.0°C)C

2.0 0.2 0.0

2.5 0.2 0.0

Td = Tetanus and Diphtheria Toxoids Adsorbed, a US-licensed Td vaccine, manufactured by Sanofi Pasteur SA. N = Number of subjects with a documented dose. Grade 2 = Local: painful when limb moved; General: interfered with normal activity. Grade 3 = Local/General: prevented normal activity. 9 Day of vaccination and the next 3 days. b Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain. c Oral temperatures. Unsolicited Adverse Events in the US Elderly (65 Years of Age and Older) Study: The incidence of unsolicited adverse events reported in the 31 days after vaccination was comparable between the 2 groups (17.1% and 14.4% for BOOSTRIX and Td vaccine, respectively). Serious Adverse Events (SAEs): In the US and German adolescent safety studies, no serious adverse events were reported to occur within 31 days of vaccination. During the 6-month extended safety evaluation period, no serious ad¬ verse events that were of potential autoimmune origin or new onset and chronic in nature were reported to occur. In non-US adolescent studies in which serious adverse events were monitored for up to 37 days, one subject was diagnosed with insulin-dependent diabetes 20 days following adminis¬ tration of BOOSTRIX. No other serious adverse events of potential autoimmune origin or that were new onset and chronic in nature were reported to occur in these studies. In the US adult (19 to 64 years of age) study, serious adverse events were reported to occur during the entire study period 1 (0-6 months) by 1.4% and 1.7% of subjects who received BOOSTRIX and the comparator Tdap vaccine, respectively. During the 6-month extended safety evaluation period, no serious adverse events of a neuroinflammatory nature or with information suggesting an autoimmune etiology were reported in subjects who received BOOSTRIX. In the US el¬ derly (65 years of age and older) study, serious adverse events were reported to occur by 0.7% and 0.9% of subjects who received BOOSTRIX and the comparator Td vaccine, respectively, during the 31-dav period after vaccination. Se¬ rious adverse events were reported to occur by 4.2% and 2.2% of subjects who received BOOSTRIX and the compar| ator Td vaccine, respectively, during the 6-month period afj ter vaccination. Concomitant Vaccination With Meningococcal Conjugate Vaccine in Adoleacents: In a randomized study in the US, 1,341 adolescents (11 to 18 years of age) received either BOOSTRIX administered concomitantly with MENACTRA* 'Meningococcal 'Groups A, C, Y, and W-1351

Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for BOOSTRIX in per¬ sons 10 years of age and older since market introduction of this vaccine are listed below. This list includes serious events or events which have causal connection to compo¬ nents of this or other vaccines or drugs. Because these events are reported voluntarily from a population of uncer¬ tain size, it is not possible to reliably estimate their fre¬ quency or establish a causal relationship to the vaccine. Blood and Lymphatic System Disorders: Lymphadenitis, lymphadenopathy. Immune System Disorders: Allergic reactions, including anaphylactic and anaphylactoid reactions. Cardiac Disorders: Myocarditis. General Disorders and Administration Site Conditions: Extensive swelling of the injected limb, injection site induration, injection site inflammation, injection site mass, in¬ jection site pruritus, injection site nodule, injection site warmth, injection site reaction. Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, myalgia. Nervous System Disorders: Convulsions (with and without fever), encephalitis, facial palsy, loss of consciousness, paraesthesia, syncope. Skin and Subcutaneous Tissue Disorders: Angioedema, exanthem, Henoch-Schonlein purpura, rash, urticaria. 7 7.1

DRUG INTERACTIONS Concomitant Vaccine Administration

BOOSTRIX was administered coftcomitanlly with MENACTRA in a clinical study of subjects 11 to 18 years of age/see Clinical Studies (14.5)]. Post-vaccination geometric mean antibody concentrations (GMCs) to pertactin were lower following BOOSTRIX administered concomitantly with meningococcal conjugate vaccine compared to BOOSTRIX administered first. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to pertac¬ tin. BOOSTRIX was administered concomitantly with FLUARIX® (Influenza Virus Vaccine) in a clinical study of subjects 19 to 64 years of age [see Clinical Studies (14.5)1. Lower GMCs for antibodies to the pertussis antigens fila¬ mentous hemagglutinin (FHA) and pertactin were observed when BOOSTRIX was administered concomitantly with FLUARIX as compared with BOOSTRIX alone. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to FHA and pertactin. When BOOSTRIX is administered concomitantly with other injectable vaccines or Tetanus Immune Globulin, they should be given with separate syringes and at different in¬ jection sites. BOOSTRIX should not be mixed with any other vaccine in the same syringe or vial. 7.2

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, anti¬ metabolites, alkylating agents, cytotoxic drugs, and cortico¬ steroids (used in greater than physiologic doses), may re¬ duce the immune response to BOOSTRIX. 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B A developmental toxicity study has been performed in fe¬ male rats at a dose approximately 40 times the human dose (on a mIVkg basis) and revealed no evidence of harm to the fetus due to BOOSTRIX. Animal fertility studies have not been conducted with BOOSTRIX. There are no adequate and well-controlled studies in pregnant women. Because an¬ imal reproduction studies are not always predictive of hu¬ man response, BOOSTRIX should be given to a pregnant woman only if clearly needed. In a developmental toxicity study, the effect of BOOSTRIX on embryo-fetal and pre-weaning development was evalu¬ ated in pregnant rats. Animals were administered INFANRIX by intramuscular injection once prior to gesta¬ tion and BOOSTRIX by intramuscular injection during the period of organogenesis 'gestation days 6, 8, 11, and 15), 0.1 mL/rat/occasion (approximately 40-fold excess relative to the projected human dose of BOOSTRIX on a body weight basis). The antigens in INFANRIX are the same as those in

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Look for PDR drug information and services in your EHR BOOSTRIX, but INFANRIX is formulated with higher quantities of these antigens. No adverse effects on preg¬ nancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were observed There were no vaccine-related fetal malformations or other evidence of teratogenesis. Pregnancy Registry: GlaxoSmithKline maintains a sur¬ veillance registry to collect data on pregnancy outcomes and newborn health status outcomes following vaccination with BOOSTRIX during pregnancy. Women who receive BOOSTRIX during pregnancy should be encouraged to con¬ tact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622. 8.3

Nursing Mothers

It is not known whether BOOSTRIX is excreted in human milk. Because many drugs are excreted in human milk, cau¬ tion should be exercised when BOOSTRIX is administered to a nursing woman. 8.4

Pediatric Use

BOOSTRIX is not indicated for use in children younger than 10 years of age. Safety and effectiveness of BOOSTRIX in this age group have not been established. 8.5

Geriatric Use

In clinical trials, 1,104 subjects 65 years of age and older received BOOSTRIX; of these subjects, 299 were 75 years of age and older. In the US elderly (65 years and older) study, immune responses to tetanus and diphtheria toxoids follow¬ ing BOOSTRIX were non-inferior to the comparator Td vaccine. Antibody responses to pertussis antigens following a single dose of BOOSTRIX in the elderly were non-inferior to those observed with INFANRIX administered as a 3-dose series in infants [see Clinical Studies (14.4)]. Solicited ad¬ verse events following BOOSTRIX were similar in fre¬ quency to those reported with the Comparator Td vaccine [see Adverse Reactions (6.1)].

11

Table 6. Antibody Responses to Tetanus and Diphtheria Toxoids Following BOOSTRIX Compared With Td Vaccine in Adolescents 10 to 18 Years of Age (ATP Cohort for Immunogenicity) N

% £0.1 IU/mL* (95% CD

% £10 IU/mL* (95% Cl)

% Booster Response*1

97.7 (97.1,98.3) 100 (99.8, 100)'

36.8 (34.9, 38.7) 99.5 (99.1, 99.7)"

89.7 (88.4. 90.8f

96.8 (95.4, 97.9) 100 (99.6, 100)

39.9 (36.5, 43.4) 99.8(99.1, 100)

92.5 (90.5. 94.2)

85.8 (84.3, 87.1) 99.9 (99.7, 100)'

17.1 (15.6, 18.6) 97.3 (96.6, 97.9^

90.6(89.4. 91.If

84.8 (82.1, 87.2) 99.9 (99.3, 100)

19.5 (16.9, 22.4) 99.3 (98.4, 99.7)

95.9 (94.4, 97.2)

(95% Cl)

Anti-Tetanus

BOOSTRIX Pre-vaccination Post-vaccination

2,469-2,516

Td Pre-vaocination Post-vacci nation

817-834

Anti-Diphtheria

BOOSTRIX Pre-vaccination Post-vaccination

2,463-2,515

Td Pre-vaccination Post-vaccination

814-834

Td manufactured by MassBioLogics. ATP = according-to-protocol; Cl = Confidence Interval. "Measured by ELISA. bBooster response: In subjects with pre-vaccination 0.4 IU/mL. In subjects with pre-vaccination concentration >0.1 IU/mL, an increase of at least 4 times the pre-vaccination concentration. 'Seroprotection rate or booster response rate to BOOSTRIX was non-inferior to Td (upper limit of two-sided 95% Cl on the difference for Td minus BOOSTRIX 1.0 IU/mL by ELISA have been associated with long-term protection.3 Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the dif¬ ferent components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

BOOSTRIX has not been evaluated for carcinogenic or mu¬ tagenic potential, or for impairment of fertility.

14

CLINICAL STUDIES

The efficacy of the tetanus and diphtheria toxoid compo¬ nents of BOOSTRIX is based on the immunogenicity of the individual antigens compared to US-licensed vaccines using established serologic correlates of protection. The efficacy of the pertussis components of BOOSTRIX was evaluated by comparison of the immune response of adolescents and adults following a single dose of BOOSTRIX to the immune response of infants following a 3-dose primary scries of INFANRIX. In addition, the ability of BOOSTRIX to induce a booster response to each of the antigens was evaluated. 14.1

14.2

Immunological Evaluation in Adolescents

In a multicenter, randomized, controlled study conducted in the United States, the immune responses to each of the an¬ tigens contained in BOOSTRIX were evaluated in sera ob¬ tained approximately 1 month after administration of a sin¬ gle dose of vaccine to adolescent subjects (10 to 18 years of age). Of the subjects enrolled in this study, approximately 76% were 10 to 14 years of age and 24% were 15 to 18 years of age. Approximately 98% of participants in this study had received the recommended series of 4 or 5 doses of either DTwP or a combination of DTwP and DTaP in childhood. The racial/ethnic demographics were as follows: white 85.8%, black 5.7%, Hispanic 5.6%, Oriental 0.8%, and other 2.1%. Response to Tetanus and Diphtheria Toxoids: The anti¬ body responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with Td vaccine are shown in Table 6. One month after a single dose, anti-tetanus and anti¬ diphtheria seroprotective rates (>0.1 IU/mL by ELISA) and booster response rates were comparable between BOOSTRIX and the comparator Td vaccine. ISee table 6 above) Response to Pertussis Antigens: The booster response rates of adolescents to the pertussis antigens are shown in Table 7. For each of the pertussis antigens the lower limit of the two-sided 95% Cl for the percentage of subjects with a booster response exceeded the pre-defined lower limit of 80% for demonstration of an acceptable booster response. Table 7. Booster Responses to the Pertussis Antigens Following BOOSTRIX in Adolescents 10 to 18 Years of Age (ATP Cohort for Immunogenicity) N

Efficacy of INFANRIX

The efficacy of a 3-dose primary series of INFANRIX in in¬ fants has been assessed in 2 clinical studies: A prospective efficacy trial conducted in Germany employing a household contact study design and a double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial con¬ ducted in Italy sponsored by the National Institutes of Health (NIH) ifor details see INFANRIX prescribing infor¬ mation). Serological data from a subset of infants immu¬ nized with INFANRIX in the household contact study were compared with the sera of adolescents and adults immu¬ nized with BOOSTRIX [see Clinical Studies (14.2, 14.3)]. In the household contact study, the protective efficacy of INFANRIX. in infants, against \VHO-defined pertussis 7 days of paroxvsmai cough was 81% (95% Cl: 68%, 89%) (for’details see INFANRIX pre¬ scribing information >.

BOOSTRIX % Booster Response* (95% Cl)

Anti-PT

2.677

84.5 (83.0, 85.9)

Anti-FHA

2,744

95.1 (94.2. 95.9)

Anti-pertactin

2,752

95.4 194.5, 96.1)

ATP = according-to-protocol; Cl = Confidence Interval. "Booster response: In initially seronegative subjects (20 EL.UVmL. In initially seropositive subjects with pre-vaccination antibody concentrations £5 EL.LVmL and 20 EL.l.VmL, an increase of at least 2 tunes the pre-vaccination antibody concentration. The GMCs to each of the pertussis antigens 1 month follow¬ ing a single dose of BOOSTRIX in the US adolescent study (K = 2,941-2,979) wen- compared with the GMCs observed in infants following a 3-dose primary aeries of INFANRIX

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884/GLAXOSMITHKLINE • BOOSTRIX

Table 9. Antibody Responses to Tetanus and Diphtheria Toxoids Following One Dose of BOOSTRIX Compared With the Comparator Tdap Vaccine in Adults 19 to 64 Years of Age (ATP Cohort for Immunogenicity)

One Dose of BOOSTRIX in Adults 19 to 64 Years of Age Compared With 3 Doses of INFANRIX in Infants (Total

% il .O IU/mL" (95% Cl)

% >0.1 IU/mL“ (95% Cl)

N

Table 11. Ratio of GMCs to Pertussis Antigens Following

Immunogenicity Cohort) GMC Ratio: BOOSTRIX/INFANRIX (95% Cl)

Anti-Tetanus

BOOSTRIX Pre-vaccination Post-vaccination

1,445-1,447

Tdap Pre-vaccination Post-vaccination

727-728

95.9 (94.8, 96.9) 99.6 (99.1, 99.8)b

71.9 (69.5, 74.2) 98.3 (97.5, 98.9)b

97.2 (95.8, 98.3) 100 (95.5, 100)

74.7 (71.4, 77,8) 99.3 (98.4. 99.8)

85.2 (83.3, 87.0) 98.2 (97.4, 98.8)b

23.7 (21.5, 26.0) 87.9 (86.1, 89.5f

89.2 (86.7, 91.3) 98.6 (97.5, 99.3)

26.5 (23.3, 29.9) 92.0 (89.8, 93.9)

Anti-Diphtheria

BOOSTRIX Pre-vaccination Post-vaccination

1,440-1,444

Tdap Pre-vaccination Post-vaccination

720-727

Tdap = Tetanus Toxoid. Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed manufactured by Sanofi Pasteur SA. ATP = according-to-protocol; Cl = Confidence Interval. "Measured by ELISA. '’Seroprotection rates for BOOSTRIX were non-inferior to the comparator Tdap vaccine (lower limit of 95% Cl on the difference of BOOSTRIX minus Tdap >-10%). cNon-inferiority criteria not prospectively defined for this endpoint.

Anti-PT

1.39 (1.32, 1.47)“

Anti-FHA

7.46 (6.86, 8.12f

Anti-pertactin

3.56 (3.10, 4.08V*

GMC = geometric mean antibody concentration; Cl = Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 1,460, anti-FHA = 1,472, and anti-pertactin = 1,473. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. “BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% Cl for the GMC ratio of BOOSTRIX/INFANRIX >0.67). 14.4

Immunological Evaluation in the Elderly (65 Years

of Age and Older)

The US elderly (65 years of age and older) study, a random¬ ized, observer-blinded study, evaluated the immunogenicity of BOOSTRIX (N = 887) compared with a US-licensed com¬ parator Td vaccine (N = 445) (Sanofi Pasteur SA). Vaccines were administered as a single dose to subjects who had not received a tetanus-diphtheria booster within 5 years. Among all vaccine recipients, the mean age was approxi¬ mately 72 years of age; 54% were female and 95% were white. The immune responses to each of the antigens con¬ tained in BOOSTRIX were evaluated in sera obtained ap¬ proximately 1 month after administration. Response to Tetanus and Diphtheria Toxoids and Pertussis Antigens: Immune responses to tetanus and diphtheria toxoids and pertussis antigens were measured 1 month af¬ ter administration of a single dose of BOOSTRIX or a com¬ parator Td vaccine. Anti-tetanus and anti-diphtheria sero¬ protective rates (>0.1 IU/mL) were comparable between BOOSTRIX and the comparator Td vaccine (Table 12).

administered at 3, 4, and 5 months of age (N = 631-2,884). Table 8 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen; the major¬ ity of subjects in the study of INFANRIX had anti-PT serol¬ ogy data only). These infants were a subset of those who formed the cohort for the German household contact study in which the efficacy of INFANRIX was demonstrated [see Clinical Studies (14.1)1. Although a serologic correlate of protection for pertussis has not been established, anti-PT, anti-FHA, and anti-pertactin antibody concentrations ob¬ served in adolescents 1 month after a single dose of BOOSTRIX were non-inferior to those observed in infants following a primary vaccination series with INFANRIX.

are shown in Table 9. One month after a single dose, anti¬ tetanus and anti-diphtheria seroprotective rates (>0.1 IU/mL by ELISA) were comparable between BOOSTRIX and the comparator Tdap vaccine. [See table 9 above] Response to Pertussis Antigens: Booster response rates to the pertussis antigens are shown in Table 10. For the FHA and pertactin antigens, the lower limit of the 95% Cl for the booster responses exceeded the pre-defined limit of 80% demonstrating an acceptable booster response following BOOSTRIX. The PT antigen booster response lower limit of the 95%' Cl (74.9%) did not exceed the pre-defined limit of 80%.

Table 8. Ratio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in Adolescents 10 to 18 Years of

Table 10. Booster Responses to the Pertussis Antigens

Toxoids Following BOOSTRIX or Comparator Td Vaccine

Following One Dose of BOOSTRIX in Adults 19 to 64

in the Elderly 65 Years of Age and Older (ATP Cohort for

Age Compared With 3 Doses of INFANRIX in Infants

Years of Age (ATP Cohort for Immunogenicity)

Immunogenicity)

Table 12. Immune Responses to Tetanus'and Diphtheria

(Total Immunogenicity Cohort) BOOSTRIX % Booster Response"

GMC Ratio: BOOSTRIX/INFANRIX (95% Cl)

Anti-PT

1.90(1.82, 1.99)"

Anti-FHA

7.35 (6.85, 7.89)“

Anti-pertactin

4.19(3.73, 4.71)"

Anti-PT Anti-FHA Anti-pertactin

GMC = geometric mean antibody concentration, measured in ELISA units; Cl Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 2,941, anti-FHA = 2,979, and anti-pertactin = 2,978. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. “GMC following BOOSTRIX was non-inferior to GMC following INFANRIX (lower limit of 95% Cl for the GMC ratio of BOOSTRIX/INFANRIX >0.67). 14.3

immunological Evaluation in Adults (19 to 64 Years

N

(95% Cl)

1,419 1,433 1,441

77.2 (74.9, 79.3)b 96.9 (95.8, 97.7)c 93.2 (91.8, 94.4)'

ATP = according-to-protocol; Cl = Confidence Interval. “Booster response: In initially seronegative subjects (20 EL.U./mL. In initially seropositive subjects with pre-vaccination antibody concentrations >5 EL.U./mL and 20 EL.U./mL, an increase of at least 2 times the pre-vaccination antibody concentration. hThe PT antigen booster response lower limit of the 95% Cl did not exceed the pre-defined limit of 80%. 'The FHA and pertactin antigens booster response lower limit of the 95% Cl exceeded the pre-defined limit of 80%.

of Age)

The GMCs to each of the pertussis antigens 1 month follow¬ A multicenter, randomized, observer-blinded study, con¬ ducted in the United States, evaluated the immunogenicity ing a single dose of BOOSTRIX in the US adult (19 to 64 of BOOSTRIX compared with the licensed comparator Tdap years of age) study were compared with the GMCs observed vaccine (Sanofi Pasteur SA). Vaccines were administered as in infants following a 3-dose primary series of INFANRIX a single dose to subjects (N = 2,284) who had not received a administered at 3,4, and 5 months of age. Table 11 presents tetanus-diphtheria booster within 5 years. The immune re¬ the results for the total immunogenicity cohort in both stud¬ sponses to each of the antigens contained in BOOSTRIX ies (vaccinated subjects w’ith serology data available for at were evaluated in sera obtained approximately 1 month af¬ least one pertussis antigen). These infants were a subset of ter administration. Approximately 33% of patients were 19 those who formed the cohort for the German household con¬ to 29 years of age, 33% were 30 to 49 years of age and 34% tact study in which the efficacy of INFANRIX was demon¬ were 50 to 64 years of age. Among subjects in the combined vaccine groups, 62% were female; 84% of subjects were ) strated lsee Clinical Studies (14.1)]. Although a serologic white, 8% black, 1% Asian, and 7% were of other racial/ ! correlate of protection for pertussis has not been estab¬ lished, anti-PT, anti-FHA, and anti-pertactin antibody con¬ ethnic groups. centrations observed in adults 1 month after a single dose of Response to Tetanus and Diphtheria Tbxoids: The anti¬ BOOSTRIX were non-inferior to those observed in infants body responses to the tetanus and diphtheria toxoids of BOOSTRIX compared with the comparator Tdap vaccine i following a primary vaccination series with INFANRIX.

Anti-T % >0.1 IU/mL (95% Cl) % >1.0 IU/mL (95% Cl) Anti-D % >0.1 IU/mL (95% Cl) % >1.0 IU/mL (95% Cl)

Td

BOOSTRIX (N = 844-864)

(N = 430-439)

96.8 (95.4, 97.8)* 88.8 186.5, 90.8)*

97.5 (95.6. 98.7) 90.0 (86.8, 92.6)

84.9 (82.3, 87.2)* 52.0 (48.6, 55.4 )b

86.6 (83.0, 89.6) 51.2 (46.3, 56.0)

Td = Tbtanus and Diphtheria Tbxoids Adsorbed, a US-licensed Td vaccine, manufactured bv Sanofi Pasteur SA. ATP = according-to-protocol; Cl = Confidence Interval. "Seroprotection rates for BOOSTRIX were non-inferior to the comparator Td vaccine (lower limit of 95% Cl on the difference of BOOSTRIX minus Td >-10%). bNon-inferiority criteria not prospectively defined for this endpoint. The GMCs to each of the pertussis antigens 1 month follow¬ ing a single dose of BOOSTRIX were compared with the GMCs of infants following a 3-dose primary series of INFANRIX administered at 3, 4. and 5 months of age. Table 13 presents the results for the total immunogenicity cohort in both studies (vaccinated subjects with serology data available for at least one pertussis antigen >. These infants were a subset of those who formed the cohort for the Ger¬ man household contact study in which the efficacy of INFANRIX wTas demonstrated [see Clinical Studies 114.01. Although a serologic correlate of protection for pertussis has not been established. anti-PT. anti-FHA. and anti-pertactin antibody concentrations in the elderly 165 years of age and older) 1 month after a single dose of BOOSTRIX were nonmfenor to those of infants following a primary vaccination series with INFANRIX.

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Look for PDR drug information and services in your EHR Table 13. Ratio of GMCs to Pertussis Antigens Following One Dose of BOOSTRIX in the Elderly 65 Years of Age and Older Compared With 3 Doses of INFANRIX in Infants (Total Immunogenicity Cohort) GMC Ratio: BOOSTRIX/INFANRIX (95% Cl)

Anti-PT

1.07(1.00, 1.15)"

Anti-FHA

8.24 (7.45, 9.12)"

Anti-pertactin

0.93(0.79, 1.10)“

GMC = geometric mean antibody concentration; Cl = Confidence Interval. Number of subjects for BOOSTRIX GMC evaluation: Anti-PT = 865, anti-FHA = 847, and anti-pertactin = 878. Number of subjects for INFANRIX GMC evaluation: Anti-PT = 2,884, anti-FHA = 685, and anti-pertactin = 631. “BOOSTRIX was non-inferior to INFANRIX (lower limit of 95% Cl for the GMC ratio of BOOSTRIX/INFANRIX >0.67). 14.5

Concomitant Vaccine Administration

Concomitant Administration With Meningococcal Conju¬ gate Vaccine: The concomitant use of BOOSTRIX and a tetravalent meningococcal (groups A, C, Y, and W-135) con¬ jugate vaccine (Sanofi Pasteur SA) was evaluated in a ran¬ domized study in healthy adolescents 11 to 18 years of age. A total of 1,341 adolescents were vaccinated with BOOSTRIX. Of these, 446 subjects received BOOSTRIX ad¬ ministered concomitantly with meningococcal conjugate vaccine at different injection sites, 446 subjects received BOOSTRIX followed by meningococcal conjugate vaccine 1 month later, and 449 subjects received meningococcal con¬ jugate vaccine followed by BOOSTRIX 1 month later. Immune responses to diphtheria and tetanus toxoids (% of subjects with anti-tetanus and anti-diphtheria antibodies >1.0 IU/mL by ELISA), pertussis antigens (booster re¬ sponses and GMCs), and meningococcal antigens (vaccine responses) were measured 1 month (range 30 to 48 days) after concomitant or separate administration of BOOSTRIX and meningococcal conjugate vaccine. For BOOSTRIX given concomitantly with meningococcal conjugate vaccine com¬ pared to BOOSTRIX administered first, non-inferiority was demonstrated for all antigens, with the exception of the anti-pertactin GMC. The lower limit of the 95% Cl for the GMC ratio was 0.54 for anti-pertactin (pre-specified limit SO.67). For the anti-pertactin booster response, noninferiority was demonstrated. It is not known if the efficacy of BOOSTRIX is affected by the reduced response to pertactin. There was no evidence that BOOSTRIX interfered with the antibody responses to the meningococcal antigens when measured by serum bactericidal assays (rSBA) when given concomitantly or sequentially (meningococcal conjugate vaccine followed by BOOSTRIX or BOOSTRIX followed by meningococcal conjugate vaccine. Concomitant Administration With FLUARIX (Influenza Virus Vaccine): The concomitant use of BOOSTRIX and FLUARIX was evaluated in a multicenter, open-label, ran¬ domized, controlled study of 1,497 adults 19 to 64 years of age. In one group, subjects received BOOSTRIX and FLUARIX concurrently (n = 748). The other group received FLUARIX at the first visit, then 1 month later received BOOSTRIX (n = 749). Sera was obtained prior to and 1 month following concomitant or separate administration of BOOSTRIX and/or FLUARIX, as well as 1 month after the separate administration of FLUARIX. Immune responses following concurrent administration of BOOSTRIX and FLUARIX were non-inferior to separate administration for diphtheria (seroprotection defined as £0.1 IU/mL), tetanus (seroprotection defined as >0.1 IU/mL and based on concentrations £1.0 IU/mL), pertussis toxin (PT) antigen (anti-PT GMC) and influenza antigens (per¬ cent of subjects with hemagglutination-inhibition IHI] anti¬ body titer £1:40 and £4-fold rise in HI titer'. Non-inferiority criteria were not met for the anti-pertussis antigens FHA and pertactin. The lower limit of the 95% Cl of the GMC ratio was 0.64 for anti-FHA and 0.60 for anti-pertactin and the pre-specified limit was >0.67. It is not known if the ef¬ ficacy of BOOSTRIX is affected by the reduced response to FHA and pertactin. 15 REFERENCES 1. Institute of Medicine (lOM). Stratton KR, Howe CJ. Johnston RB. eds. Adverse events associated with child¬ hood vaccines. Evidence bearing on causality. Washing¬ ton, DC: National Academy Press; 1994. 2. Wassilak SGF. Roper MH. Kretsinger K. and Orenstein WA. Ihtanus Thxoid. In: Plotkin SA, Orenstein WA, and Offit PA. eds. Vaccines. 5th ed. Saunders; 2008:805-839.

BREO ELLIPTA • GLAXOSMITHKLINE/885 3. Vitek CR and Wharton M. Diphtheria Ihxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:139-156. 16 HOW SUPPLIED/STORAGE AND HANDLING BOOSTRIX is available in O.p-rnL single-dose vials and dis¬ posable prefilled TIP-LOK syringes (packaged without needles): NDC 58160-842-01 Vial in Package of 10: NDC 58160842-11 NDC 58160-842-05 Syringe in Package of 1: NDC 58160842-34 NDC 58160-842-43 Syringe in Package of 10: NDC 58160842-52 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. 17 PATIENT COUNSELING INFORMATION The patient, parent, or guardian should be: • informed of the potential benefits and risks of immuniza¬ tion with BOOSTRIX. • informed about the potential for adverse reactions that have been temporally associated with administration of BOOSTRIX or other vaccines containing similar compo¬ nents. • instructed to report any adverse events to their healthcare provider. • informed that safety and efficacy have not been estab¬ lished in pregnant women. Register women who receive BOOSTRIX while pregnant in the pregnancy registry by calling 1-888-452-9622. • given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines). BOOSTRIX, FLUARIX, INFANRIX, and TIP-LOK are reg¬ istered trademarks of the GlaxoSmithKline group of compa¬ nies. The following are registered trademarks of their re¬ spective owners: ADACEL and DECAVAC/Sanofi Pasteur Limited; MENACTRA/Connaught Technology Corporation. Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License 1617, and Novartis Vaccines and Diagnostics GmbH

Marburg, Germany, US License 1754 Distributed by GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline group of companies. All rights re¬ served. BTX:26PI BREO ELLIPTA 100/25

IJ

(fluticasone furoate 100 meg and vilanterol 25 meg inhalation powder) for oral inhalation

and step down therapy (e g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS Do not use BREO ELLIPTA for patients whose asthma is ade¬ quately controlled on low- or medium-dose ICS.(1.2, 5.11

REGENT MAJOR CHANGES

Boxed Warning Indications and Usage. Treatment of Asthma (1.2)

Dosage and Administration (2, 2.21 Contraindications l4' Warnings and Precautions. Asthma-Related Death (5.1) Warnings and Precautions, Deterioration of Disease and Acute Episodes (5.2) Warnings and Precautions, Effect on Growth (5.17)

4/2015 4/2015 4/2015 4/2015 4/2015 4/2015 4/2015

-INDICATIONS AND USAGEBREO ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS), and vilanterol, a long-acting beta2-adrenergic agonist (LABA), indicated for: • Long-term, once-daily. maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). il l) • Once-daily treatment of asthma in patients aged 18 years and older. (1.2) Important limitation: Not indicated for relief of acute bronchospasm. (1.1, 1.2. 5.2) -DOSAGE AND ADMINISTRATION• For oral inhalation only. (2) • Maintenance treatment of COPD: 1 inhalation of BREO ELLIPTA 100/25 once daily. (2.1) • Asthma: 1 inhalation of BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 once daily. (2.2) -DOSAGE FORMS AND STRENGTHSInhalation Powder. Inhaler containing 2 foil blister strips of powder formulation for oral inhalation. One strip contains fluticasone furoate 100 or 200 meg per blister and the other contains vilanterol 25 meg per blister. (3) -CONTRAINDICATIONS• Primary treatment of status asthmaticus or acute epi¬ sodes of COPD or asthma requiring intensive measures. (4) • Severe hypersensitivity to milk proteins or any ingredi¬ ents. (4)

BREO ELLIPTA for patients not adequately con¬

-WARNINGS AND PRECAUTIONS• LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recom¬ mended patient populations. (5.1) • Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. 15.21 • Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3) • Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. 15.41 • Increased risk of pneumonia in patients with^COPD Mon¬ itor patients for signs and symptoms of pneumonia. (5.5) • Potential worsening of infections le.g., existing tuberculo¬ sis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex'. Use with caution in patients with these infections. More senous or even fatal course of chickenpox or measles ran occur in susceptible patients. (5.6) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from sys¬ temic corticosteroids if transferring to BREO ELLIPTA. (5.7) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. (5.8) • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. (5.10) • Use w ith caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. (5.12) • Assess for decrease in bone mineral density initially and periodically thereafter. (5.13)

trolled on a long-term asthma control medication,

• Close monitonng for glaucoma and cataracts is warranted

BREO ELLIPTA 200/25 (fluticasone furoate 200 meg and vilanterol 25 meg inhalation powder) for oral inhalation HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BREO* * ELLIPTA* safely and effectively. See full pre¬ scribing information for BREO ELLIPTA. BREO ELLIPTA 100/25 (fluticasone furoate 100 meg and vilanterol 25 meg inhalation powder), for oral inhalation BREO ELLIPTA 200/25 (fluticasone furoate 200 meg and vilanterol 25 meg inhalation powder), for oral inhalation Initial U S. Approval: 2013

WARNING:

ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning. • Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA

Available data

from controlled clinical trials suggest that LABA in¬ crease the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) • When treating patients with asthma, only prescribe

such as an ICS, or whose disease severity clearly

(5.14)

warrants initiation of treatment with both an ICS

• Use with caution in patients with convulsive disorders,

and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals

• Be alert to hvpokalemia and hyperglycemia (UH

thyrotoxicosis, diabetes raellitus. and ketoacidosis. (5.15)

Free mobile PDR app for fast drug references on Apple or Android devices

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

886/GLAXOSMITHKLINE • BREO ELLIPTA -ADVERSE REACTIONS• COPD: Most common adverse reactions (incidence greater than or equal to 3*^) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.

6.11

11 12

DESCRIPTION CLINICAL PHARMACOLOGY 12.1 12.2 12.3

• Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral can¬ didiasis, headache, influenza, upper respiratory tract in¬ fection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-

WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA), such

2.1

as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death.

BREO ELLIPTA 100/25 should be administered as 1 inhalation once daily. The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 100/25 once daily, the only strength indicated for the treatment of COPD. If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief.

NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14

CLINICAL STUDIES 14.1 14.2

16 17

Chronic Obstructive Pulmonary Disease Asthma

HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

1088 or www.fda.gov/medwatch.

-DRUG INTERACTIONS• Strong cytochrome P450 3A4 inhibitors (e,g., ketoconazole): Use with caution. May cause systemic corticoster¬ oid and cardiovascular effects. (7.1) • Monoamine oxidase inhibitors and tricyclic antidepres¬ sants: Use with extreme caution. May potentiate effect of vilanterol on vascular system. (7.2) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. (7.3) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with nonpotassium-sparing diuretics may worsen with concomitant beta-agonists. (7.4)

FULL PRESCRIBING INFORMATION

Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects re¬ ceiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of

-USE IN SPECIFIC POPULATIONS-

asthma-related death from LABA. Available data from

Hepatic impairment: Fluticasone furoate exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. (8.6, 12.3)

controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric

See 17 for PATIENT COUNSELING INFORMATION

and adolescent patients.

and Medication Guide.

Therefore, when treating patients with asthma, phy¬ sicians should only prescribe BREO ELLIPTA for pa¬

Revised: 4/2015

tients not adequately controlled on a long-term asthma control medication, such as an inhaled corti¬ costeroid, or whose disease severity clearly warrants

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ASTHMA-RELATED DEATH 1 INDICATIONS AND USAGE 1.1 Maintenance Treatment of Chronic Obstruc¬ tive Pulmonary Disease 1.2 Treatment of Asthma 2 DOSAGE AND ADMINISTRATION 2.1 Chronic Obstructive Pulmonary Disease 2.2 Asthma 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death 5.2 Deterioration of Disease and Acute Episodes 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists 5.4 Local Effects of Inhaled Corticosteroids 5.5 Pneumonia 5.6 Immunosuppression 5.7 Transferring Patients from Systemic Cortico¬ steroid Therapy 5.8 Hypercorticism and Adrenal Suppression 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors 5.10 Paradoxical Bronchospasm 5.11 Hypersensitivity Reactions, Including Ana¬ phylaxis 5.12 Cardiovascular Effects 5.13 Reduction in Bone Mineral Density 5.14 Glaucoma and Cataracts 5.15 Coexisting Conditions 5.16 Hypokalemia and Hyperglycemia 5.17 Effect on Growth 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Chronic Ob¬ structive Pulmonary’ Disease 6.2 Clinical Trials Experience in Asthma 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants 7.3 Beta-Adrenergic Receptor Blocking Agents 74 Non-Potassium-Sparing Diuretics 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 10.1 Fluticasone Furoate 1012 Vilanterol

2 DOSAGE AND ADMINISTRATION BREO ELLIPTA should be administered once daily every day by the orally inhaled route only. BREO ELLIPTA should be taken at the same time every day. Do not use BREO ELLIPTA more than 1 time every 24 hours. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. More frequent administration or a greater number of inha¬ lations (more than 1 inhalation daily) of the prescribed strength of BREO ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses. Patients using BREO ELLIPTA should not use additional LABA for any reason. [See Warnings and Pre¬ cautions (5.3, 5.5, 5.8, 5.12).]

13

(

Mechanism of Action Pharmacodynamics Pharmacokinetics

Important Limitation of Use BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm.

initiation of treatment with both an inhaled cortico¬ steroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular inter¬ vals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma con¬ trol medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose in¬ haled corticosteroids [see Warnings and Precau¬ tions 15.1)].

1 1.1

INDICATIONS AND USAGE Maintenance Treatment of Chronic Obstructive Pul¬

monary Disease

BREO® ELLIPTA® 100/25 is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/ LABA) indicated for the long-term, once-daily. maintenance treatment of airflow obstruction in patients with chronic ob¬ structive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA 100/25 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. BREO ELLIPTA 100/25 once daily is the only strength indicated for the treatment of COPD. Important Limitation of Use BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm. 1.2

Treatment of Asthma

BREO ELLIPTA is a combination ICS/LABA indicated for the once-daily treatment of asthma in patients aged 18 years and older. LABA. such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precau¬ tions (5.1), Adverse Reactions (6.2), Use in Specific Popula¬ tions (8.4)1. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for pa¬ tients not adequately controlled on a long-term asthma con¬ trol medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the pa¬ tient at regular intervals and step down therapy (e.g., dis¬ continue BREO ELLIPTA* if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticoster¬ oid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

2.2

Chronic Obstructive Pulmonary Disease

Asthma

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta-2-agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief. The recommended starting dosage is BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 administered as 1 inhalation once daily. The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 once daily. The starting dosage is based on patients' asthma severity. For patients previously treated with low- to mid-dose corti¬ costeroid-containing treatment, BREO ELLIPTA 100/25 should be considered. For patients previously treated with mid- to high-dose corticosteroid-containing treatment, BREO ELLIPTA 200/25 should be considered. The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV1), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to BREO ELLIPTA 100/25, increasing the dose to BREO ELLIPTA 200/25 may provide additional improvement in asthma con¬ trol. If a previously effective dosage regimen of BREO ELLIPTA fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and addi¬ tional therapeutic options (e.g., replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, initiating oral corticoster¬ oids) should be considered.

3

DOSAGE FORMS AND STRENGTHS

Inhalation powder: Disposable light grey and pale blue plastic inhaler containing 2 foil blister strips of powder in¬ tended for oral inhalation only. One strip contains fluticasone furoate (100 or 200 meg per blisteri, and the other strip contains vilanterol (25 meg per blister).

4

CONTRAINDICATIONS

The use of BREO ELLIPTA is contraindicated in the follow¬ ing conditions: • Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required /see Warnings and Precautions (5.2)]. • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions '5.11). De¬ scription (11)].

5 5.1

WARNINGS AND PRECAUTIONS Asthma-Related Death

LABA. such as vilanterol. one of the active ingredients in BREO ELLIPTA. increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long¬ term asthma control medication, such as an inhaled corti¬ costeroid, or whose disease severity clearly warrants initi¬ ation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down ther-

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Look for PDR drug information and services in your EHR apy (e g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long¬ term asthma control medication, such as an inhaled corti¬ costeroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjectsreceiving salmeterol (13/13,176 in subjectstreated with salmeterol vs. 3/13,179 in subjectstreated with placebo; relative risk; 4.37 [95% Cl: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial ade¬ quate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. 5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening epi¬ sodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation. Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the pa¬ tient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Pa¬ tients should not use more than 1 inhalation once daily of BREO ELLIPTA. BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the health¬ care provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists BREO ELLIPTA should not be used more often than recom¬ mended, at higher doses than recommended, or in conjunc¬ tion with other medicines containing I-ABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine contain¬ ing a LABA (e.g.. salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appro¬ priate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water with¬ out swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia An increase in the incidence of pneumonia has been ob¬ served in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased inci¬ dence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacer¬ bations.

BREO ELLIPTA • GLAXOSMITHKUNE/887 In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 meg/ 25 meg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 meg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/ vilanterol 50 mcg/25 meg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group). 5.6 Immunosuppression Persons who are using drugs that suppress the immune sys¬ tem are more susceptible to infections than healthy indi¬ viduals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with var¬ icella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled in¬ tramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been trans¬ ferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) func¬ tion. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most suscep¬ tible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to re¬ sume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These pa¬ tients should also be instructed to carry a warning card in¬ dicating that they may need supplementary systemic corti¬ costeroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV|Or peak expiratory flow), beta-agonist use. and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal in¬ sufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhi¬ nitis, conjunctivitis, eczema, arthritis, eosinophilic condi¬ tions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticoster¬ oid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with tho therapeutic doses

of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction /see Warnings and Precautions (5.9), Drug Interactions (7.1)1. Because of the possibility of significant: systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particu¬ lar care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hy¬ percorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with ac¬ cepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered. 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadmin¬ istration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corti¬ costeroid and increased cardiovascular adverse effects may occur /see Drug Interactions (7.1), Clinical Pharmacology (12.3)1. 5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA can pro¬ duce paradoxical bronchospasm, which may be life threat¬ ening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alterna¬ tive therapy should be instituted. 5.11 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such re¬ actions occur. There have been reports of anaphylactic reac¬ tions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA/see Contraindications (4)1. 5.12 Cardiovascular Effects Vilanterol, like other beta2-agomsts, can produce a clinically significant cardiovascular effect in some patients as mea¬ sured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraven¬ tricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardio¬ graphic changes, such as flattening of the T wave, prolon¬ gation of the QTt interval, and ST segment depression, al¬ though the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic ex¬ posure than seen in subjects with COPD or asthma, respec¬ tively) have been associated with clinically significant pro¬ longation of the QTt interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been ob¬ served with long-term administration of products contain¬ ing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture iB unknown. Patients with major risk fac¬ tors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmeno¬ pausal status, tobacco use. advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anti¬ convulsants. oral corticosteroids) should be monitored and treated with established standards of care Since patients with COPD often have multiple risk factors for reduced BMD. assessment of BMD is recommended prior to initiat¬ ing BREO ELLIPTA and periodically thereafter. If signifi¬ cant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteopo¬ rosis should be strongly considered 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma fol¬ lowing the long-term administration of inhaled corn coster-

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888/GLAXOSMITHKLINE • BREO ELLIPTA

Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Fluticasone Furoate 100 meg

Placebo

(n = 410)

(n = 412)

%

%

%

9 7 5

10 5 2

8 4 3

8 3 2

7

9

7

5

BREO ELLIPTA

Vilanterol

100/25 (n = 4101

25 meg (n = 408)

%

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasis * Nervous system disorders Headache

Adverse Reaction

0 Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.

Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1!

100/25

Fluticasone Furoate 100 meg

Placebo

(n = 201)

(n = 205)

(n = 203)

%

%

%

Infections and infestations N asopharyngi tis Oral candidiasis"

10 2

7 2

7 0

Nervous system disorders Headache

5

4

4

Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain Dysphonia

2 2

2 1

1 0

BREO ELLIPTA

Adverse Reaction

” Includes oral candidiasis and oropharyngeal candidiasis.

Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >2% Incidence in Subjects with Asthma (Trial 2) BREO ELLIPTA

200/25

100/25

100 meg

(n = 346)

(n = 346)

(n = 347)

Nervous system disorders Headache Infections and infestations Nasopharyngitis Influenza Upper respiratory tract infection Sinusitis Bronchitis Respiratory, thoracic and mediastinal disorders Oropharyngeal pain Cough oids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intra¬ ocular pressure, glaucoma, and/or cataracts. Coexisting Conditions

BREO ELLIPTA, like all medicines containing sympathomi¬ metic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when ad¬ ministered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellu¬ lar shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Betaagonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potas¬ sium. 5.17

Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adoles¬ cents. I See Use in Specific Populations (8.4).]

6

ADVERSE REACTIONS

LABA. such as vilanterol, one of the active ingredients in BREO ELLIPTA. increase the risk of asthma-related death

6.2

Clinical Trials Experience in Asthma

BREO ELLIPTA for the treatment of asthjna was studied in 18 double-blind, parallel-group, controlled trials ill with placebo) of 4 to 76 weeks’ duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied 9 8 8 in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were in¬ cluded in these trials, BREO ELLIPTA is not approved for 7 6 7 use in this age-group [see Use in Specific Populations (8.4)/. 1 3 3 The safety data described below are based on two 12-week 3 2 2 efficacy trials, one 24-week efficacy trial, and two long-term For oral suspension: 125 mg/5 mL and 250 mg/5 mL (3) Pediatric Patients (3 months to 12 years) Dosage Guidelines for CEFTIN for Oral Suspension

-CONTRAINDICATIONSKnown hypersensitivity (e.g., anaphylaxis) to CEFTIN or to other (i-lactams (e.g., penicillins and cephalosporins). (4) -WARNINGS AND PRECAUTIONS• Serious hypersensitivity (anaphylactic) reactions: In the event of a serious reaction, discontinue CEFTIN and insti¬ tute appropriate therapy. (5.1) • Clostridium difficile-associated diarrhea (CDAD): If di¬ arrhea occurs, evaluate patients for CDAD. (5.2) -ADVERSE REACTIONSThe most common adverse reactions (>3%) for CEFTIN tablets are diarrhea, nausea/vomiting, Jarisch-Herxheimer reaction and vaginitis (early Lyme disease). (6.1) The most common adverse reactions 02%) for CEFTIN for oral suspension are diarrhea, dislike of taste, diaper rash, and nausea/vomiting. (6.1)

Duration Recommended Daily Dose*

Maximum Daily Dose

(Days)

Pharyngitis/tonsillitis

20 mg/kg

500 mg

10

Acute bacterial otitis media

30 mg/kg

1,000 mg

10

Acute bacterial maxillary sinusitis (mild to moderate)

30 mg/kg

1,000 mg

10

Impetigo

30 mg/kg

1,000 mg

10

Infection

1 Total daily dose given twice daily divided in equal doses.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch.

-DRUG INTERACTIONS• Oral Contraceptives: Effects on gut flora may lower es¬ trogen reabsorption and reduce efficacy of oral contracep¬ tives. (7.1) • Drugs that reduce gastric acidity may lower the bioavail¬ ability of CEFTIN. (7.2) • Co-administration with probenecid increases systemic ex¬ posure to CEFTIN and is therefore not recommended. (7.3) See 17 for PATIENT COUNSELING INFORMATION. Revised: 7/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1

2

INDICATIONS AND USAGE 1.1 Pharyngiti.s/Ibnsillitis 1.2 Acute Bacterial Otitis Media 1.3 Acute Bacterial Maxillary Sinusitis 1.4 Acute Bacterial Exacerbations of Chronic Bronchitis and Secondary Bacterial Infections of Acute Bronchitis 1.5 Uncomplicated Skin and Skin-structure In¬ fections 1.6 Uncomplicated Urinary Tract Infections 1.7 Uncomplicated Gonorrhea 1.8 Early Lyme Disease (erythema migrans) 1.9 Impetigo 1.10 Usage DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Dosage for CEFTIN Tablets 2.3 Dosage for CEFTIN for Oral Suspension 2.4 Preparation and Administration of CEFTIN for Oral Suspension

10 11 12

13

14

2.5 Dosage in Patients with Impaired Renal Function DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Anaphylactic Reactions 5.2 Clostridium difficile-associated Diarrhea 5.3 Potential for Microbial Overgrowth 5.4 Development of Drug-resistant Bacteria 5.5 Phenylketonuria 5.6 Interference with Glucose Tests ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience DRUG INTERACTIONS 7.1 Oral Contraceptives 7.2 Drugs that Reduce Gastric Acidity 7.3 Probenecid 7.4 Drug/Laboratory Thst Interactions USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1 Acute Bacterial Maxillary Sinusitis 14.2 Early Lyme Disease 14.3 Secondary Bacterial Infections of Acute Bronchitis

15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

1.1

Pharyngitis/Tonsillitis

CEFTIN* tablets are indicated for the treatment of adult patients and pediatric patients (13 years and older) with mild-to-moderate pharyngitis/tonsillitis caused by suscepti¬ ble strains of Streptococcus pyogenes. CEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 yearn with mildto-moderate pharyngitis/tonsillitis caused by susceptible strains of Streptococcus pyogenes. Limitations of Use • The efficacy of CEFTIN in the prevention of rheumatic fe¬ ver was not established in clinical trials. • The efficacy of CEFTIN in the treatment of penicillinresistant strains of Streptococcus pyogenes has not been demonstrated in clinical trials. 1.2

Acute Bacterial Otitis Media

CEFTIN tablets are indicated for the treatment of pediatric patients (who can swallow tablets whole) with acute bacte¬ rial otitis media caused by susceptible strains of Streptococ¬ cus pneumoniae. Haemophilus influenzae (including ]} lacta¬ mase-producing strains), Uoraxella catarrhalis (including (J-lactamase-producing strains), or Streptococcus pyogenes. CEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years with acute bacterial otitis media caused by susceptible strains of Strep tococcus pneumoniae, Haemophilus influenzae i including ^•lactamase-producing strains), Moraxella catarrhalis (in¬ cluding ^-lactamase-producing strains), or Streptococcus pyogenes

1.3 Acute Bacterial Maxillary Sinusitis CEFTIN tablets are indicated for the treatment of adult and pediatric patients (13 years and older) with mild-to-

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898/GLAXOSMITHKLINE • CEFTIN Table 1. Adult Patients and Pediatric Patients Dosage Guidelines for CEFTIN Tablets

Table 3. Amount of Water Required for Reconstitution of Labeled Volumes of CEFTIN for Oral Suspension Duration (Days)

Dosage

Infection Adults and Adolescents (13 years and older)

Amount of Water Oral Suspension

Pharyngitis/tonsillitis (mild to moderate) Acute bacterial maxillary sinusitis (mild to moderate) Acute bacterial exacerbations of chronic bronchitis (mild to moderate) Secondary bacterial infections of acute bronchitis Uncomplicated skin and skin-structure infections Uncomplicated urinary tract infections Uncomplicated gonorrhea Early Lyme disease

10 10 10a 5 to 10 10 7 to 10 single dose 20

250 mg every 12 hours 250 mg every 12 hours 250 or 500 mg every 12 hours 250 or 500 mg every 12 hours 250 or 500 mg every 12 hours 250 mg every 12 hours 1,000 mg 500 mg every 12 hours

Pediatric Patients younger than 13 years (who can swallow tablets whole)b

10 10

250 mg every 12 hours 250 mg every 12 hours

Acute bacterial otitis media Acute bacterial maxillary sinusitis

a The safety and effectiveness of CEFTIN administered for less than 10 days in patients with acute exacerbations of chronic bronchitis have not been established. b When crushed, the tablet has a strong, persistent bitter taste. Therefore, patients who cannot swallow the tablet whole should receive the oral suspension.

125 mg/5 mL

Required for

Labeled Volume after

Reconstitution

Reconstitution

37 mL

100 mL

19 mL

50 mL

35 mL

100 mL

250 mg/5 mL

• Shake the oral suspension well before each use. • Replace cap securely after each opening. • Store the reconstituted suspension refrigerated between 2° and 8°C (36° and 46°F). • Discard the reconstituted suspension after 10 days. 2.5 Dosage in Patients with Impaired Renal Function

A dosage interval adjustment is required for patients whose creatinine clearance is 30

No dosage adjustment

10 to See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 2/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1

2

3 4 5

6

CERVARIX

fy

[serr’-a/i-rtx] [Human Papillomavirus Bivalent (Types 16 and 181

7

Vaccine, Recombinant] Suspension for Intramuscular Injection

8 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CERVARIX safely and effectively. See full prescribing information for CERVARIX. CERVARIX [Human Papillomavirus Bivalent (Types 16 and 18| Vaccine, Recombinant] Suspension for Intramuscular Injection

11 12

Initial U.S. Approval: 2009

-INDICATIONS AND USAGECERVARIX is a vaccine indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18: • cervical cancer.

13

14

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INDICATIONS AND USAGE 1.1 Indications 1.2 Limitations of Use and Effectiveness DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Dose and Schedule DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Syncope 5.2 Latex 5.3 Preventing and Managing Allergic Vaccine Reactions ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience DRUG INTERACTIONS 7.1 Concomitant Vaccine Administration 7.2 Hormonal Contraceptives 7.3 Immunosuppressive Therapies USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Immunocompromised Individuals DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action NONCUNICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES 14.1 Prophylactic Efficacy Against HPV Types 16 and 18

CERVARIX • GLAXOSMITHKLINE/903

Look for PDR drug information and services in your EHR 14.2 Efficacy Against HPV Types 16 and 18, Re¬ gardless of Current Infection or Prior Exposure to HPV-16 or HPV-18 14.3 Efficacy Against Cervical Disease Irrespec¬ tive of HPV Type, Regardless of Current or Prior In¬ fection with Vaccine or Non-Vaccine HPV Types 14.4 Immunogenicity 14.5 Bridging of Efficacy from Women to Adoles¬ cent Girls 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed.

Table 1. Rates of Solicited Local Adverse Reactions and General Adverse Events in Females 9 Through 25 Years of Age Within 7 Days of Vaccination (Total Vaccinated Cohort*) AIIOHtj (15-25 years)

(15-25 years)

%

%

%

N = 6.669

N = 3,079

N = 1,027

N = 549

Pain

91.9

78.0

64.2

87.2

Redness

48.4

27.6

25.2

24.4

FULL PRESCRIBING INFORMATION

Swelling

44.3

19.8

17.3

21.3

1

General Adverse Event

N = 6,670

N = 3,079

N = 1,027

N s 549

Fatigue

54.6

53.7

42.3

53.6

Headache

53.4

51.3

45.2

61.4

GF

27.9

27.3

24.6

32.8

Fever (>99.5°F)

12.9

10.9

16.0

13.5

Rash

9.5

8.4

6.7

10.0

N = 6,119

N = 3,079

N = 1,027

—

Myalgiaf

48.8

44.9

33.1

—

Arthralgiaf

20.7

17.9

19.9

—

7.2

7.9

5.4

—

INDICATIONS AND USAGE

1.1

Limitations of Use and Effectiveness

CERVARIX does not provide protection against disease due to all HPV types [see Clinical Studies (14.3)1. CERVARIX has not been demonstrated to provide protec¬ tion against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity [see Clinical Studies (14.2)]. Females should continue to adhere to recommended cervical cancer screening procedures [see Patient Counseling Infor¬ mation (17)1 Vaccination with CERVARIX may not result in protection in all vaccine recipients. 2 2.1

DOSAGE AND ADMINISTRATION Preparation for Administration

Shake syringe well before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. With thor¬ ough agitation, CERVARIX is a homogeneous, turbid, white suspension. Do not administer if it appears otherwise. Attach a sterile needle and administer intramuscularly. Do not administer this product intravenously, intradermally, or subcutaneously. 2.2

Dose and Schedule

Immunization with CERVARIX consists of 3 doses of 0.5-mL each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of admin¬ istration is the deltoid region of the upper arm. 3

DOSAGE FORMS AND STRENGTHS

CERVARIX is a suspension for intramuscular injection available in 0.5-mL single-dose prefilled TIP-LOK® syrin¬ ges. 4

CONTRAINDICATIONS

Severe allergic reactions (e.g., anaphylaxis) to any compo¬ nent of CERVARIX /see Description (11)]. 5 5.1

WARNINGS AND PRECAUTIONS Syncope

Because vaccinees may develop syncope, sometimes result¬ ing in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes asso¬ ciated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with CERVARIX. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. 5.2

Latex

The tip caps of the prefilled syringes may contain natural rubber latex which may cause allergic reactions in latexsensitive individuals. 5.3

Preventing and Managing Allergic Vaccine Reac¬

tions

Prior to administration, the healthcare provider should re¬ view the immunization history for possible vaccine hyper¬ sensitivity and previous vaccination-related adverse reac¬ tions to allow an assessment of benefits and risks. Appropriate medical treatment and supervision should be readily available in case of anaphylactic reactions following administration of CERVARIX. 6

(9-25 years) %

Indications

CERVARIX® is indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18/see Clinical Studies (14)1: • cervical cancer, • cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and • cervical intraepithelial neoplasia (CIN) grade 1. CERVARIX is approved for use in females 9 through 25 years of age. 1.2

HAV 720b

Control**

HAV 360' (10-14 years)

Local Adverse Reaction

CERVARIX

ADVERSE REACTIONS

The most common local adverse reactions t£20% of subjects* were pain, redness, and swelling at the injection site.

Urticaria1

“Total vaccinated cohort included subjects with at least one documented dose (N). bHAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 meg AllOHlJ. CHAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 meg of AKOHlJ. dAl(OH)3 Control = control containing 500 meg Al(OH)3. “GI = Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and/or abdominal pain. fAdverse events solicited in a subset of subjects.

The most common general adverse events (>20% of subjects) were fatigue, headache, myalgia, gastrointestinal symp¬ toms, and arthralgia. 6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of CERVARIX could reveal adverse reactions not observed in clinical trials. Studies in Females 9 Through 25 Years of Age: The safety of CERVARIX was evaluated by pooling data from con¬ trolled and uncontrolled clinical trials involving 23,952 fe¬ males 9 through 25 years of age in the pre-licensure clinical development program. In these studies, 13.024 females (9 through 25 years of age) received at least one dose of CERVARIX and 10,928 females received at least one dose of a control [Hepatitis A Vaccine containing 360 EL.U. (10 through 14 years of age), Hepatitis A Vaccine containing 720 EL.U. (15 through 25 years of age), or Al(OH)3 (500 meg, 15 through 25 years of age)l. Data on solicited local and general adverse events were col¬ lected by subjects or parents using standardized diary cards for 7 consecutive days following each vaccine dose (i.e., day of vaccination and the next 6 days). Unsolicited adverse events were recorded with diary cards for 30 days following each vaccination (day of vaccination and 29 subsequent days). Parents and/or subjects were also asked at each study visit about the occurrence of any adverse events and in¬ structed to immediately report serious adverse events throughout the study period. These studies were conducted in North America. Latin America, Europe, Asia, and Austra¬ lia. Overall, the majority of subjects were white (69.5%), fol¬ lowed by Asian (25.9%), Hispanic (8.5%), black (3.4%), and other racial/ethnic groups (2.7%). Solicited Adverse Events: The reported frequencies of so¬ licited local injection site reactions (pain, redness, and swelling) and general adverse events (fatigue, fever, gastro¬ intestinal symptoms, headache, arthralgia, myalgia, and urticaria) within 7 days after vaccination in females 9 through 25 years of age are presented in Table 1. An anal¬ ysis of solicited local injection site reactions by dose is pre¬ sented in Table 2. Local reactions were reported more fre¬ quently with CERVARIX when compared with the control groups; in £76% of recipients of CERVARIX, these local re¬ actions were nuld to moderate in intensity. Compared with dose 1, pain was reported less frequently after doses 2 and 3 of CERVARIX, in contrast to redness and swelling where

there was a small increased incidence. There was no in¬ crease in the frequency of general adverse events with suc¬ cessive doses. [See table 1 abovel [See table 2 at top of next page] The pattern of solicited local adverse reactions and general adverse events following administration of CERVARIX was similar between the age cohorts (9 through 14 years and 15 through 25 years). Unsolicited Adverse Events: The frequency of unsolicited adverse events that occurred within 30 days of vaccination (>1% for CERVARIX and greater than any of the control groups) in females 9 through 25 years of age are presented in Table 3. [See table 3 at top of next pagel New Onset Autoimmune Diseases (NOADs): The pooled safety database, which included controlled and uncontrolled trials which enrolled females 9 through 25 years of age. was searched for new medical conditions indicative of potential new onset autoimmune diseases. Overall, the incidence of potential NOADs, as well as NOADs, in the group receiving CERVARIX was 0.8% (96/12,772) and comparable to the pooled control group (0.8%, 87/10,730) during the 4.3 years of follow-up (Table 4). . In the largest randomized, controlled trial (Study 2) which enrolled females 15 through 25 years of age and which in¬ cluded active surveillance for potential NOADs, the inci¬ dence of potential NOADs and NOADs was 0.8% among subjects who received CERVARIX (78/9,319) and 0.8% among subjects who received Hepatitis A Vaccine [720 EL.U. of antigen and 500 meg Al(OH) J control (77/9,325). [See table 4 at top of page 905) Serious Adverse Events: In the pooled safety database, inclusive of controlled and uncontrolled studies, which en¬ rolled females 9 through 72 years of age, 5.3% (864/16,381) of subjects who received CERV ARIX and 5.9% (814/13,811) of subjects who received control reported at least one seri¬ ous adverse event, without regard to causality, during the entire follow-up period (up to 7.4 years). Among females 9 through 25 years of age enrolled in these clinical studies, 6.3% of subjects who received CERVARIX and 7.2% of subjects who received the control reported at least one serious adverse event during the entire follow-up period (up to 7.4 years). Deaths: In completed and ongoing studies which enrolled 57,323 females 9 through 72 years of age, 37 deaths were reported during the 7.4 years of follow-up: 20 in subjects who received CERVARIX (0.06%, 20/33,623) and 17 in sub¬ jects who received control (0.07%, 17/23,700). Causes of

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904/GLAXOSMITHKLINE • CERVARIX

Table 2. Rates of Solicited Local Adverse Reactions in Females 9 Through 25 Years of Age by Dose Within 7 Days of Vaccination (Total Vaccinated Cohort*)

CERVARIX (9-25 years) %

HAV 720b (15-25 years) %

HAV 360c (10-14 years) %

AKOHIj Control*1 (15-25 years) %

Post-Dose

Post-Dose

Post-Dose

Post-Dose

1

2

3

1

2

3

1

2

3

1

2

3

N

6,653

6.428

6.168

3,070

2,919

2,758

1,027

1,021

1,011

546

521

500

Pain

87.0

76.4

78.5

65.6

54.4

56.1

48.5

38.5

36.9

79.1

66.8

72.4

7.5

5.6

7,7

2.0

1.4

2.0

0.8

0.2

1.6

9.0

6.0

8.6

Redness

28.4

30.1

35.7

16.6

15.2

16.1

15.6

13.3

12.1

11.5

11.5

15.6

Redness, >50 mm

0.2

0.5

1.0

0.1

0.1

0.0

0.1

0.2

0.1

0.2

0.0

0.0

Swelling

22.8

25.5

32.7

10.5

9.4

10.5

9.4

8.6

7.6

10.3

10.4

12.0

1.1

1.0

1.3

Q3

0.2

0.2

0.4

0.3

0.0

0.0

0.0

0.0

Pain. Grade 3'

Swelling, >50 mm

—

"Mai vaccinated cohort included subjects with at least one documented dose (N). bHAV 720 = Hepatitis A Vaccine control group 1720 EL.U. of antigen and 500 meg All OH y. 98% of subjects were seropositive for both HPV-16 IS8 EL.l'./mL, the limit of detection) and HPV-18 8 EL.U./mL' and HPV-18 (>7 EL.UVmL) antigens. The GMTs for anti-HPV-16 and anti-HPV-18 antibodies in initially seronegative sub¬ jects are presented in Table 9. [See table 9 above] In Study 4 (HPV 012), the immunogenicity of CERVARIX administered to girls 10 through 14 years of age was com¬ pared with that in females 15 through 25 years of age. The immune response in girls 10 through 14 years of age mea¬ sured one month post-dose 3 was non-inferior to that seen in females 15 through 25 years of age for both HPV-16 and HPV-18 antigens (Table 10). [See table 10 at top of next page] In Study 5, a post-hoc analysis compared the immunogenic¬ ity of CERVARIX administered to girls 9 through 14 years of age (n = 68) with that in females 15 through 25 years of age (n = 114). In these initially seronegative subjects, the im¬ mune response in girls 9 through 14 years of age measured one month post-dose 3 was non-inferior to that observed in females 15 through 25 years of age for both HPV-16 and HPV-18 antigens [lower limit of the 2-sided 95% Cl for the GMT ratio (9-14 year olds/15-25 year olds) was >0.5]. The GMTs for anti-HPV-16 and anti-HPV-18 antibodies at month 7 were 22,261.3 EL.U./mL and 7,398.8 EL.U./mL, re¬ spectively, in girls 9 through 14 years of age and 10,322.0 EL.U./mL and 4.261.5 EL.U./mL, respectively, in females 15 through 25 years of age. Based on these immunogenicity data, the efficacy of CERVARIX is inferred in girls 9 through 14 years of age. 16

HOW SUPPLIED/STORAGE AND HANDLING

CERVARIX is available in 0.5-mL single-dose disposable prefilled TIP-LOK syringes (packaged without needles): NDC 58160-830-05 Syringe in Package of 1: NDC 58160830-34 NDC 58160-830-43 Syringe in Package of 10: NDC 58160830-52 Store refrigerated between 2° and 8°C (36° and 46°F). Do not freeze. Discard if the vaccine has been frozen. Upon storage, a fine, white deposit with a clear, colorless super¬ natant may be observed. This does not constitute a sign of deterioration. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient Information). Patient labeling is provided as a tear-off leaflet at the end of this Full Prescribing Informa¬ tion. Provide the Vaccine Information Statements prior to immu¬ nization. These are required by the National Childhood Vaccine Injury Act of 1986 and are available free of charge at the Centers for Disease Control and Prevention iCDC) website (www.cdc.gov/vaccines). Inform the patient, parent, or guardian: • Vaccination does not substitute for routine cervical cancer screening. Women who receive CERVARIX should con¬ tinue to undergo con ical cancer screening per standard of care. • CERVARIX does not protect against disease from HPV types to which a woman has previously been exposed through sexual activity. • Since syncope has been reported following vaccination in young females, sometimes resulting in falling with injury, observation for 15 minutes after administration is recom¬ mended. • Safety has not been established in pregnant women. CERVARIX and TIP-LOK are registered trademarks of the GSK group of companies. Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License 1617 Distributed by GlaxoSmithKline Research Triangle Park, NC 27709 €>2015, the GSK group of companies. All rights reserved. CRX:11PI PATIENT INFORMATION CERVARIX*lSERV-ah-rix) [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine. Recombinant]

Read this Patient Information carefully before getting CERVARIX. You (the person getting CERVARIX i will need 3 doses of the vaccine. Read this information before each done

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COREG • GLAXOSMITHKLINE/909

Look for PDR drug information and services in your EHR

-CONTRAINDICATIONS• Bronchial asthma or related bronchospastic conditions. (4) • Second ''ord-d ree AV block tj • Sick ,i i i. (t • Sev hradvcardia (unless permanent pacemaker in place). 4) • Patient 1 -*/enic shock or decompensated heart failure requiring tlu- use of IV inotropic therapy. (41 • Severe hep .tic impairment (2.4. 4 • History of serious hypersensitivity reaction (eg., StevensJohnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol. (4)

Table 10. Geometric Mean Titers (GMTs) and Seropositivity Rates at Month 7 for Initially Seronegative Females 10 Through 14 Years of Age Compared With Females 15 Through 25 Years of Age (According To Protocol Cohort for Immunogenicity*) (Study 4) 15-25 Years of Age

10-14 Years of Age

Seropositivity GMTb EL.U./mL

Rate'

N

(95% Cl)

%

100

118

7,438.9 (6,324.6, 8,749.6)

100

100

116

3,070.1 (2,600.0, 3,625.4)

100

GMTb EL.U./mL

Seropositivity Ratec

N

(95% Cl)

%

Anti-HPV-16

143

17,272.5 (15,117.9, 19,734.1)

Anti-HPV-18

141

6,863.8 (5,976.3, 7,883.0)

Antibody Assay

“Subjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N). bNon-inferiority based on the upper limit of the 2-sided 95% Cl for the GMT ratio (15-25 year olds/10-14 year olds) was 5%): Dizziness To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

What are the ingredients in CERVARIX?

CERVARIX contains proteins of HPV types 16 and 18. The vaccine also contains 3-0-desacyl-4'-monophosphoryl lipid A (MPL), aluminum hydroxide, sodium chloride, and so¬ dium dihydrogen phosphate dehydrate. CERVARIX contains no preservatives. This is a summary of information about CERVARIX. If you would like more information, please talk with your health¬ care provider or visit www.cervarix.com. CERVARIX is a registered trademark of the GSK group of companies. Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License 1617 Distributed by GlaxoSmithKline Research Triangle Park, NC 27709 ©2015, the GSK group of companies. All rights reserved. February 2015 CRX:5PIL

COREG®

li

\kor' eg] (carvedilol)

-DRUG INTERACTIONS• CYP P450 2D6 enzyme inhibitors may increase and ri¬ fampin may decrease carvedilol levels. (7.1, 7.5) • Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidinei may increase the risk of hypotension and/or severe bradycardia. (7.2) • Cyclosporine or digoxin levels may increase. (7.3, 7.4' • Both digitalis glycosides and (J-blockers slow atrioventric¬ ular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. (7.4) • Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. (7.6) • Verapamil- or diltiazem-typc calcium channel blockers may affect ECG and/or blood pressure. (7.7) • Insulin and oral hvpoglvcemics action may be enhanced. (7.8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2013

tablets HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed

FULL PRESCRIBING INFORMATION CONTENTS*

1

to use COREG safely and effectively. See full prescribing in¬ formation for COREG. COREG (carvedilol) tablets Initial U.S. Approval: 1995

-INDICATIONS AND USAGECOREG is an alpha/beta-adrenergic blocking agent indi¬ cated for the treatment of: • Mild to severe chronic heart failure 3% in Subjects Treated With Carvedilol, Regardless of Causality)

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.10

Table 1. Adverse Events (%) Occurring More Frequently With COREG Than With Placebo in Subjects With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects With Severe Heart Failure in the

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome lIFIS) has been ob¬ served during cataract surgery in some patients treated with alpha-1 blockers (COREG is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to in¬ traoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydri¬ atic drugs, and potential prolapse of the iris toward the pha¬ coemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

Hyperglycemia Weight increase BUN increased NPN increased Hypercholesterolemia Edema peripheral Musculoskeletal

Arthralgia Respiratory

Cough increased Rales Vision

Vision abnormal

placebo-treated subjects with an incidence of >3% in sub¬ I Left Ventricular Dysfunction Following Myocardial Infarc¬ tion jects treated with carvedilol regardless of causality. Median 6.1 Clinical Studies Experience COREG has been evaluated for safety in survivors of an trial medication exposure was 6.3 months for both COREG has been evaluated for safety in subjects with heart acute myocardial infarction with left ventricular dysfunc¬ carvedilol and placebo subjects in the trials of mild-totion in the CAPRICORN trial which involved 969 subjects failure (mild, moderate, and severe), in subjects with left moderate heart failure, and 10.4 months in the trial of se¬ who received COREG and 980 who received placebo. Ap¬ ventricular dysfunction following myocardial infarction and vere heart failure subjects. The adverse event profile of proximately 7591 of the subjects received COREG for at in hypertensive subjects The observed adverse event profile COREG observed in the long-term COMET trial was gener¬ least 6 months and 5391 received COREG for at least was consistent with the pharmacology of the drug and the ally similar to that observed in the US Heart Failure Trials. 12 months. Subjects were treated for an average of health status of the subjects in the clinical trials. Adverse [See table 1 above] 12.9 months and 12.8 months with COREG and placebo, events reported for each of these patient populations are Cardiac failure and dyspnea were also reported in these tri¬ respectively. provided below. Excluded are adverse events considered too als, but the rates were equal or greater in subjects who re¬ The most common adverse events reported with COREG in general to be informative, and those not reasonably associ¬ ceived placebo. the CAPRICORN trial were consistent with the profile of ated with the use of the drug because they were associated The following adverse events were reported with a fre¬ the drug in the US heart failure trials and the COPERNIwith the condition being treated or are very common in the quency of >1% but 53% and more frequently with COREG | CUS trial. The only additional adverse events reported in treated population. Rates of adverse events were generally in either the US placebo-controlled trials in subjects with CAPRICORN in >391 of the subjects and more commonly on similar across demographic subsets (men and women, el¬ mild-to-moderate heart failure, or in subjects with severe carvedilol were dyspnea, anemia, and lung edema. The fol¬ derly and non-elderly, blacks and non-blacks). heart failure in the COPERNICUS trial. lowing adverse events were reported with a frequency of Heart Failure Incidence >1% to 53% >191 but 5391 and more frequently with COREG:flu syn¬ COREG has been evaluated for safety in heart failure in drome, cerebrovascular accident, peripheral vascular disor¬ Body as a Whole: Allergy, malaise, hypovolemia, fever, leg more than 4,500 subjects worldwide of whom more than der, hypotonia, depression, gastrointestinal pain, arthritis, edema. 2,100 participated in placebo-controlled clinical trials. Ap¬ and gout. The overall rates of discontinuations due to ad¬ Cardiovascular: Fluid overload, postural hypotension, ag¬ proximately 6091 of the total treated population in placeboverse events were similar in both groups of subjects. In this gravated angina pectoris, AV block, palpitation, hyperten¬ controlled clinical trials received COREG for at least database, the only cause of discontinuation >191, and occur¬ sion. 6 months and 3091 received COREG for at least 12 months. ring more often on carvedilol was hypotension (1.591 on Central and Peripheral Nervous System: Hypesthesia, In the COMET trial, 1,511 subjects with mild-to-moderate carvedilol, 0.291 on placebo). vertigo, paresthesia. heart failure were treated with COREG for up to 5.9 years | Hypertension Gastrointestinal: Melena, periodontitis. (mean: 4.8 years). Both in US clinical trials in mild-toCOREG has been evaluated for safety in hypertension in Liver and Biliary System: SGPT increased, SGOT in¬ moderate heart failure that compared COREG in daily more than 2,193 subjects in US clinical trials and in doses up to 100 mg (n = 765) with placebo tn = 437), and creased. 2,976 subjects in international clinical trials Approxiin a multinational clinical trial in severe heart failure Metabolic and Nutritional: Hyperuricemia, hypoglycemia, (COPERNICUS) that compared COREG in daily doses up to hyponatremia, increased alkaline phosphatase, glycosuria, [ mately 3691 of the total treated population received COREG for at least 6 months. Most adverse events reported during 50 mg (n = 1.156) with placebo (n = 1,133), discontinua¬ hypervolemia, diabetes mellitus, GGT increased, weight [ therapy with COREG were of mild to moderate severity. In tion rates for adverse experiences were similar in carvedilol loss, hyperkalemia, creatinine increased. ^ US controlled clinical trials directly comparing COREG in and placebo subjects. In placebo-controlled clinical trials, Musculoskeletal: Muscle cramps. doses up to 50 mg (n = 1,142) with placebo (n = 462), the only cause of discontinuation >191, and occurring more Platelet, Bleeding and Clotting: Prothrombin decreased, 4.991 of subjects receiving COREG discontinued for adverse often on carvedilol was dizziness 11.391 on carvedilol, 0.61* purpura, thrombocytopenia. ! events versus 5.291 of placebo subjects. Although there was on placebo in the COPERNICUS trial). Psychiatric: Somnolence. I no overall difference in discontinuation rates, discontinua¬ Table 1 shows adverse events reported in subjects with Reproductive, male: Impotence. tions were more common in the carvedilol group for postural mild-to-moderate heart failure enrolled in US placeboI hypotension 1191 versus 0). The overall incidence of adverse Special Senses: Blurred vision. controlled clinical trials, and with severe heart failure en¬ events in US placebo-controlled trials increased with inrolled in the COPERNICUS trial. Shown are adverse events ! Urinary System: Renal insufficiency, albuminuria, hemaI creasing dose of COREG. For individual advert* events this that occurred more frequently in drug-treated subjects than I turia.

6

ADVERSE REACTIONS

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912/GLAXOSMITHKLINE • COREG could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg. Table 2 shows adverse events in US placebo-controlled clin¬ ical trials for hypertension that occurred with an incidence of >1% regardless of causality, and that were more frequent in drug-treated subjects than placebo-treated subjects. Table 2. Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials (Incidence i1%. Regardless of Causality)' Body System/ Adverse Event

COREG

Placebo

(n = 1,142)

(n = 462)

7

Cardiovascular Bradycardia Postural hypotension Peripheral edema

2 2 1

— —

Central Nervous System Dizziness Insomnia

6 2

5 1

Gastrointestinal Diarrhea

2

1

Hematologic Thrombocytopenia

1

—

Metabolic Hypertriglyceridemia

1

—

“

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Aplastic anemia. Immune System Disorders" Hypersensitivity (e.g., ana¬ phylactic reactions, angioedema, urticaria). Renal and Urinary Disorders: Urinary incontinence. Respiratory, Thoracic and Mediastinal Disorders: Intersti¬ tial pneumonitis. Skin and Subcutaneous Tissue Disorders: Stevens-John¬ son syndrome, toxic epidermal necrolysis, erythema multi¬ forme.

Shown are events with rate >1% rounded to nearest integer.

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received pla¬ cebo. The following adverse events not described above were re¬ ported as possibly or probably related to COREG in world¬ wide open or controlled trials with COREG in subjects with hypertension or heart failure. Incidence >0.1% to S1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic en¬ zymes (0.2% of hypertension patients and 0.4% of heart fail¬ ure patients were discontinued from therapy because of in¬ creases in hepatic enzymes) [see Adverse Reactions (6.2)]. Psychiatric: Nervousness, sleep disorder, aggravated de¬ pression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see Contraindications (4)]. Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating in¬ creased. Metabolic and Nutritional: Hypokalemia, hypertriglyceri¬ demia. Hematologic: Anemia, leukopenia. The following events were reported in observed during controlled clinical trials have gen¬ erally been similar between subjects treated with COREG and those treated with placebo. However, transaminase el¬ evations, confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in se¬ vere heart failure, subjects treated with COREG had lower values for hepatic transaminases than subjects treated with placebo, possibly because improvements in cardiac function induced by COREG led to less hepatic congestion and/or im¬ proved hepatic blood flow. COREG has not been associated with clinically significant changes in serum potassium, total triglycerides, total cho¬ lesterol. HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials

DRUG INTERACTIONS

7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3)]. Retrospec¬ tive analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the a-blocking R(+) enantio¬ mer. 7.2 Hypotensive Agents Patients taking both agents with P-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with agents with p-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment' with agents with P-blocking properties and clonidine is to be terminated, the p-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage. 7.3 Cyclosporine Modest increases in mean trough cyclosporine concentra¬ tions were observed following initiation of carvedilol treat¬ ment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cy¬ closporine had to be reduced in order to maintain cyclospor¬ ine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variabil¬ ity in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initi¬ ation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate. 7.4 Digitalis Glycosides Both digitalis glycosides and p-blockers slow atrioventricu¬ lar conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitor¬ ing of digoxin is recommended when initiating, adjusting, or discontinuing COREG lsee Clinical Pharmacology (12.5)1. 7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in CmM [see Clinical Pharmacology (12.5)]. 7.6 Amiodarone Amiodarone, and its metabolite desethyl amiodarone, in¬ hibitors of CYP2C9 and P-glycoprotein, increased concen¬ trations of the S(-)-enantiomer of carvedilol by at least 2-fold [see Clinical Pharmacology (12.5)]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with COREG may enhance the P-blocking properties of carvedilol resulting in further slow¬ ing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, partic¬ ularly when one agent is added to pre-existing treatment with the other. 7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compro¬ mise) has been observed when COREG is co-administered with diltiazem. As with other agents with P-blocking prop¬ erties. if COREG is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recom¬ mended that ECG and blood pressure be monitored. 7.8 Insulin or Oral Hypoglycemics Agents with P-blocking properties may enhance the bloodsugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)]. 7.9 Anesthesia If treatment with COREG is to be continued perioperativelv. particular care should be taken when anesthetic

agents which depress myocardial function, such as ether, cy¬ clopropane, and trichloroethylene, are used [see Overdosage

(10)]. 8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Pregnancy Category C. Studies performed in pregnant rats and rabbits given carvedilol revealed increased post¬ implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD1 as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m21. which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during preg¬ nancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other p-blockers) cross the placental barrier and are excreted in breast milk. There was in¬ creased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (TO times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in hu¬ man milk and because of the potential for serious adverse reactions in nursing infants from p-blockers, especially bradycardia, a decision should be made whether to discon¬ tinue nursing or to discontinue the drug, taking into ac¬ count the importance of the drug to the mother. The effects of other a- and p-blocking agents have included perinatal and neonatal distress. 8.4 Pediatric Use Effectiveness of COREG in patients younger than 18 years has not been established. In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-IV. left ventricu¬ lar ejection fraction , dizziness (13% versus 2%), and dysp¬ nea (11% versus 0%). 8.5 Geriatric Use Of the 765 subjects with heart failure randomized to COREG in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to COREG in a long-term, placebo-controlled trial in severe heart failure, 47% ’547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving COREG in heart failure trials worldwide, 42% were 65 years of age or older. Of the 975 myocardial infarction subjects randomized to COREG in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older. Of the 2.065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with COREG, 21% '436) were 65 years of age or older. Of 3.722 subjects receiving COREG in hypertension clinical trials conducted world¬ wide. 24% were 65 years of age or older. With the exception of dizziness in hypertensive subjects i in¬ cidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Fig¬ ures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differ¬ ences in responses between the elderly and younger sub¬ jects, but greater sensitivity of some older individuals can¬ not be ruled out.

10

OVERDOSAGE

Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms. vomiting, lapses of consciousness, and generalized seizures may also occur. The patient should be placed in a supine position and. where necessary, kept under observation and treated under

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COREG • GLAXOSMITHKUNE/913

Look for PDR drug information and services in your EHR Left Ventricular Dysfunction Following Myocardial InfarcHon The basis for the beneficial effects of COREG in patients with left ventricular dysfunction following an acute myocar¬ dial infarction is not established. Hypertension The mechanism by which [i-blockade produces an antihy¬ pertensive effect has not been established. P-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) re¬ duces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant P-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration. aradrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascu¬ lar resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration. Due to the oq-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), in¬ cluding rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when COREG is ad¬ ministered with food at the recommended starting dose and titration increments are closely followed (see Dosage and Administration (2)]. In hypertensive patients with normal renal function, thera¬ peutic doses of COREG decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after COREG and placebo. COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly re¬ duce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.

intensive-care conditions. Gastric lavage or pharmacologi¬ cally induced emesis may be used shortly after ingestion. The following agents may be administered: For excessive bradycardia: Atropine. 2 mg IV. To support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infu¬ sion of 5 mg/hour; sympathomimetics idobutamine, isoprenaline, adrenaline) at doses according to body weight and effect. If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, (i-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recom¬ mended. NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be con¬ tinued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol. Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experi¬ enced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recov¬ ered. 11

DESCRIPTION

Carvedilol is a nonselective p-adrenergic blocking agent with a,-blocking activity. It is (±)-l-(Carbazol-4-yloxy)-3-[[2(o-methoxyphenoxy)ethyl]aminol-2-propanol. Carvedilol is a racemic mixture with the following structure:

H

12.3 Pharmacokinetics

COREG is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25-mg, 12.5-mg. and 25-mg tablets are TILTAB® tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide. Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practi¬ cally insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action COREG is a racemic mixture in which nonselective p-adrenoreceptor blocking activity is present in the S(-) en¬ antiomer and aradrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity. 12.2 Pharmacodynamics Heart Failure The basis for the beneficial effects of COREG in heart fail¬ ure is not established. Two placebo-controlled trials compared the acute hemody¬ namic effects of COREG with baseline measurements in 59 and 49 subjects with NYHAclass II-IV heart failure receiv¬ ing diuretics, ACE inhibitors, and digitalis. There were sig¬ nificant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable. These trials measured hemodynamic effects again at 12 to 14 weeks. COREG significantly reduced systemic blood pressure, pulmonary' artery pressure, right atrial pressure, systemic vascular resistance, and heart rate, while stroke volume index was increased. Among 839 subjects with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 US placebo-controlled tri¬ als, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving COREG and by 2 EF units in pla¬ cebo subjects at a target dose of 25 to 50 mg twice daily. The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg twice daily. 12.5 mg twice daily, and 25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively, each of these effects were nominally statisti¬ cally significant.

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COREG is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approxi¬ mately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When ad¬ ministered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma lev¬ els, with no significant difference in extent of bioavailability. Taking COREG with food should minimize the risk of ortho¬ static hypotension. Carvedilol is extensively metabolized. Following oral ad¬ ministration of radiolabelled carvedilol to healthy volun¬ teers, carvedilol accounted for only about 7% of the total ra¬ dioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabo¬ lites are further metabolized by conjugation via glucuroni¬ dation and sulfation. The metabolites of carvedilol are ex¬ creted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active me¬ tabolites with P-receptor blocking activity. Based on preclinical studies, the 4’-hydroxyphenyl metabolite is approxi¬ mately 13 times more potent than carvedilol for (i-blockade. Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the ac¬ tive metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R( + l-carvedilol approximately 2 to 3 times higher than S(-i-carvedilol following oral adminis¬ tration in healthy subjects. The mean apparent terminal elimination half-lives for R( + )-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the &-F enantiomer. The primary P450 enzymes responsible for the metabolism of both R(+) and S(-t-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4 - and 5 -hydroxylation of carvedilol. with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of St-F carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6i exhibiting 2- to 3-fold higher plasma concentraliuns of Ri +(-carvedilol compared with extensive metabolizers In contrast, plasma levels of S(- ^-carvedilol are increased only about 20% to 25% in poor metabolizers, mdieating this enantiomer is metabolized to a lesser extent by

cytochrome P450 2D6 than R( + Fcarvedilol. The pharma¬ cokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin 1 patients deficient in cyto¬ chrome P450 2C19). . Carvedilol is more than 98% bound to plasma proteins, pri¬ marily with albumin. The plasma-protein binding is inde¬ pendent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steadystate volume of distribution of approximately 115 L, indi¬ cating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min. 12.4

Specific Populations

Heart Failure Steady-state plasma concentrations of carv edilol and its en¬ antiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmll, values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 sub¬ jects with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects. Geriatric Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects. Hepatic Impairment Compared with healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment. Renal Impairment Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment com¬ pared to a control group of hypertensive subjects with nor¬ mal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma lev¬ els were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function. Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be cleared significantly by hemodialysis. 12.5

Drug-Drug Interactions

Since carvedilol undergoes substantial oxidative metabo¬ lism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes. Amiodarone In a pharmacokinetic trial conducted in 106 Japanese sub¬ jects with heart failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol re¬ sulted in at least a 2-fold increase in the steady-6tate trough concentrations of Si-i-carvedilol (see Drug Interactions (7.6)1. Cimetidine In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine (1,000 mg/day) increased the steadystate AUC of carvedilol by 30% with no change in Cm„ Isee Drug Interactions (7.5)). Digoxin Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily 1 for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive subjects (see Drug Interactions (7.4)]. Glyburide In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic inter¬ action for either compound. Hydrochlorothiazide A single oral dose of carvedilol 25 mg did not alter the phar¬ macokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 subjects with hypertension Likewise, hydro¬ chlorothiazide had no effect on the pharmacokinetics of carvedilol. Rifampin In a pharmacokinetic trial conducted in 8 healthy male sub¬ jects, rifampin (600 mg daily for 12 days) decreased the AUC and of carvedilol by about 70% (see Drug Interac¬ tions (7.5)7. Torse mide In a trial of 12 healthy subjects, combined oral administra¬ tion of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differ¬ ences in their pharmacokinetics compared with administra¬ tion of the drugs alone. Warfarin Carvedilol < 12.5 mg twice daily) did not have an effect on the steady-state prothrombin tune ratios and did not alter

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914/GLAXOSMITHKLINE • COREG Table 3. Results of COMET

Carvedilol N = 1,511

Metoprolol N = 1,518

Hazard ratio

(95% Cl)

All-cause mortality

34%

40%.

0.83

0.74 - 0.93

Mortality + all hospitalization

74%

76%

0.94

0.86 - 1.02

Cardiovascular death

30%

35%

0.80

0.70 - 0.90

14% 11% 0.9%

17% 13% 2.5%

0.81 0.83 0.33

0.68 - 0.97 0.67 - 1.02 0.18 - 0.62

End point

Sudden death Death due to circulatory failure Death due to stroke

Table 4. Results of COPERNICUS Trial in Subjects With Severe Heart Failure

Placebo (N = 1,133)

Carvedilol (N = 1,156)

Hazard ratio (95% Cl)

% Reduction

Nominal P value

Mortality

190

130

0.65 (0.52-0.81)

35

0.00013

Mortality + all hospitalization

507

425

0.76 (0.67 - 0.87)

24

0.00004

Mortality + CV hospitalization

395

314

0.73 (0.63 - 0.84)

27

0.00002

Mortality + HF hospitalization

357

271

0.69 (0.59-0.81)

31

0.000004

End point

Cardiovascular = CV; Heart failure = HF.

the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy vol¬ unteers. 13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronu¬ cleus and in vivo human lymphocyte cell tests for clastogenicity. At doses >200 mg/kg/day (>32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of success¬ ful matings, prolonged mating time, significantly fewer cor¬ pora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2). 14 14.1

CLINICAL STUDIES Heart Failure

A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol. Mild-to-Moderate Heart Failure Carvedilol was studied in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET trial) involv¬ ing subjects with mild-to-moderate heart failure. Four US multicenter, double-blind, placebo-controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class 11-111 heart failure and ejection fraction 70

S8P 2l20mmHg S6P 70 tricular dysfunction following myocardial infarction. Heart rate < 70 14.3 Hypertension SBP > 120 mm Hg A double-blind, randomized, placebo-controlled, 8-week trial SBP < 120 mm Hg evaluated the blood pressure lowering effects of COREG CR Spironolactone No spironolactone 20 mg, 40 mg, and 80 mg once daily in 338 subjects with es¬ All patients sential hypertension (sitting diastolic blood pressure [DBPj OO 0.5 1.0 1.5 2.0 >90 and were observed with each dose of COREG CR farction l within 21 days) and left ventricular ejection frac¬ compared with placebo. Placebo-subtracted mean changes tion of 90 mm Hg, a sitting heart | mean changes from baseline in mean trough i average of rate >60 beats/minute, and no contraindication to (J-blocker hours 20 to 24) SBP/DBP were -3.3/—2.8 mm Hg, -4.9/-

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COREG CR • GLAXOSMITHKLINE/923

Look for PDR drug information and services in your EHR

COREG CR only one time each day. Tb lessen possible side effects, your doctor might begin with a low dose and then slowly increase the dose. • Swallow COREG CR capsules whole Do not chew or crush COREG CR capsules. ' • If you have trouble swallowing COREG CR whole: • The capsule may lie carefully opened and the beads sprinkled over a spoonful of applesauce which should be eaten right away. The applesauce should not be warm. • Do not sprinkle beads on foods other than applesauce

• Patients should take COREG CR with food. • Diabetic patients should report any changes in blood sugar levels to their physician. • Contact lens wearers may experience decreased lacrimation. COREG CR and COREG are registered trademarks of the GSK group of companies. TOPROL-XL is a trademark of its respective owner and is not a trademark of the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. Mav 2014 CCR:17PI PHARMACIST—DETACH HERE AND GIVE INSTRUC¬ TIONS TO PATIENT

5.2 mm Hg. and -8.4/-7.4 mm Hg for COREG CR 20 mg. 40 mg, and 80 mg. respectively. The placebo-corrected trough to peak (3 to 7 h) ratio was approximately 0.6 for COREG CR 80 mg. In this trial, assessments of 24-hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period (Figure 5).

Figure 5. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM

• Do not stop taking COREG CR and do not change the amount of COREG CR you take without talking to your doctor.

PATIENT INFORMATION LEAFLET

• If you miss a dose of COREG CR, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time. • If you take too much COREG CR, call your doctor or poi¬ son control center right away.

COREG CR® (Co-REG)

What should I avoid while taking COREG CR?

(carvedilol phosphate)

COREG CR can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.

Extended-release Capsules

16

12

18

Read the Patient Information that comes with COREG CR before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medi¬ cal condition or your treatment. If you have any questions about COREG CR, ask your doctor or pharmacist.

24

Time after morning dose (hr} Lines smoothed using locally weighted regression smoothing methodology

COREG CR.See “What is the most important information I should know about COREG CR?” • slow heart beat. • low blood pressure (which may cause dizziness or faint¬

What is COREG CR?

• changes in your blood sugar. If you have diabetes, tell

directed by your doctor. If you stop taking COREG CR sud¬ denly, you could have chest pain and a heart attack. If your doctor decides that you should stop taking COREG CR, your doctor may slowly lower your dose over time before

your doctor if you have any changes in your blood sugar

COREG CR is a prescription medicine that belongs to a group of medicines called “beta-blockers”. COREG CR is used, often with other medicines, for the following condi¬ tions: • to treat patients with certain types of heart failure • to treat patients who had a heart attack that worsened how well the heart pumps • to treat patients with high blood pressure (hypertension) COREG CR is not approved for use in children under 18 years of age.

Hypertension With Type 2 Diabetes Mellitus

levels.

• masking (hiding) the symptoms of low blood sugar, espe¬ cially a fast heartbeat. • new or worsening symptoms of peripheral vascular dis¬ ease.

• leg pain that happens when you walk, but goes away when you rest • no feeling (numbness) in your legs or feet while you are resting • cold legs or feet • masking the symptoms of hyperthyroidism (overactive thyroid), such as a fast heartbeat. • worsening of severe allergic reactions. Medicines to treat a severe allergic reaction may not work as well while you are taking COREG CR. • rare but serious allergic reactions i including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing! have hap¬ pened in patients who were on COREG or COREG CR. These reactions can be life-threatening. In some cases, these reactions happened in patients who had been on COREG before taking COREG CR. Common side effects of COREG CR include shortness of breath, weight gain, diarrhea, and tiredness. If you wear contact lenses, you may have fewer tears or dry eyes that can become bothersome. Call your doctor if you have any side effects that bother you or don't go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Who should not take COREG CR?

Do not take COREG CR if you: • have severe heart failure and require certain intravenous medicines that help support circulation. • have asthma or other breathing problems. • have a slow heartbeat or certain conditions that cause your heart to skip a beat (irregular heartbeat). • have liver problems. • are allergic to any of the ingredients in COREG CR. See *What are the ingredients in COREG CR?”

HOW SUPPLIED/STORAGE AND HANDLING

What should I tell my doctor before taking COREG CR?

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient InformationI Patients taking COREG CR should be advised of the fol¬ lowing: • Patients should not interrupt or discontinue using COREG CR without a physician's advice. • Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. • Patients may experience a drop in blood pressure when standing, resulting in dizziness and. rarely, fainting. Pa¬ tients should sit or lie down when these symptoms of lowered blood pressure occur. • If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks. • Patients should consult a physician if they experience diz¬ ziness or faintness, in case the dosage should be adjusted. • Patients should not crush or chew COREG CR capsules

stopping it completely.

ing when you stand up). If these happen, sit or lie down, and tell your doctor right away. • worsening heart failure. Tell your doctor right away if you have signs and symptoms that your heart failure may be worse, such as weight gain or increased shortness of breath.

It is important for you to take your medicine every day as

The hard gelatin capsules are available in the following strengths: • 10 mg - white and green capsule shell printed with “GSK COREG CR" and “10 mg” • 20 mg - white and yellow capsule shell printed with “GSK COREG CR" and “20 mg’ • 40 mg - yellow and green capsule shell printed with “GSK COREG CR” and “40 mg" • 80 mg - white capsule shell printed with "GSK COREG CR" and “80 mg" • 10 mg 30’s: NDC 0007-3370-13 • 20 mg 30’s: NDC 0007-3371-13 . 40 mg 30’s: NDC 0007-3372-13 . 80 mg 30's: NDC 0007-3373-13 Store at 25°C (77°Ft; excursions 15° to 30°C 1 mlU/mL. month 8 (N = 122) with a GMT of 7,672 mlU/mL (N = 122, 13 NONCLINICAL TOXICOLOGY 95% Cl: 5,248, 10,965 ). 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ Persons 16 Through 65 Years of Age: Clinical, trials in tility healthy adult and adolescent subjects (16 through 65 years ENGERIX-B has not been evaluated for carcinogenic or mu¬ of age) have shown that following a course of 3 doses of tagenic potential, or for impairment of fertility. ENGERIX-B (20 mcg/1 mL) given at 0, 1, and 6 months, the seroprotection (antibody titers £10 mlU/mL) rate for all in¬ 14 CLINICAL STUDIES 14.1 Efficacy in Neonates dividuals was 79% at month 6 (5 months after second dose) Protective' efficacy with ENGERIX-B has been demon¬ and 96% at month 7 (1 month after third dose); the GMT for strated in a clinical trial in neonates at high risk of hepati¬ seroconverters was 2,204 mlU/mL at month 7 (N = 110). tis B infection.1’-7 8 * * 11 Fifty-eight neonatps born of mothers who An alternate 3-dose schedule (20 mcg/1 mL given at 0, 1, were both HBsAg-positive and hepatitis B “e” antigen and 2 months) designed for certain populations (e.g., indi¬ (HBeAgl-positive were given ENGERIX-B (10 mcg/0.5 mL) viduals who have or might have been recently exposed to at 0, 1, and 2 months, without concomitant hepatitis B im¬ the virus and travelers to high-risk areas) was also evalu¬ mune globulin (IIBIG). Two infants became chronic carriers ated. At month 3 (1 month after third dose), 99% of all in¬ in the 12-month follow-up period after initial inoculation. dividuals were seroprotected and remained protected Assuming an expected carrier rate of 70%, the protective ef¬ through month 12. On the alternate schedule, a fourth dose ficacy rate against the chronic carrier state during the first of ENGERIX-B (20 mcg/1 mL) at 12 months produced a 12 months of life was 95%. "* GMT of 9,163 mlU/mL at month 13 (1 month after fourth 14.2 Efficacy and Immunogenicity in Specific Popula¬ dose) (N = 373). tions Persons 40 Years of Age and Older: Among subjects 40 Homosexual Men: ENGERIX-B (20 mcg/1 mL) given at 0, years of age and older given ENGERIX-B (20 mcg/1 mL) at 1, and 6 months was evaluated in homosexual men 16 to 59 0,1, and 6 months, the seroprotection rate 1 month after the years of age. Four of 244 subjects became infected with hep¬ third dose was 88% and the GMT for seroconverters was atitis B during the period prior to completion of the 3-dose 610 mlU/mL (N = 50). In adults older than 40 years of age. immunization schedule. No additional subjects became in¬ ENGERIX-B produced anti-HBsAg antibody titers that fected during the 18-month follow-up period after comple¬ were lower than those in younger adults. tion of the immunization course. 14.5 Interchangeability With Other Hepatitis B Vaccines Adults with Chronic Hepatitis C: In a clinical trial of 67 A controlled study (N = 48) demonstrated that completion of adults 25 to 67 years of age with chronic hepatitis C, a course of immunization with 1 dose of ENGERIX-B ENGERIX-B (20 mcg/1 mL) was given at 0, 1, and 6 (20 mcg/1 mL) at month 6 following 2 doses of months. Of the subjects assessed at month 7 (N = 31), 100% RECOMBIVAX HB® (10 meg) at months 0 and 1 produced a responded with seroprotective titers. The geometric mean similar GMT (4,077 mlU/mL) to immunisation with 3 doses antibody titer (GMT) was 1,260 mlU/mL (95% Confidence of RECOMBIVAX HB (10 meg) at months 0, 1, and 6 (GMT: Interval [CD: 709, 2,237). 2,654 mlU/mL). Thus, ENGERIX-B can be used to complete Adults on Hemodialysis: Hemodialysis patients given hep¬ a vaccination course initiated with RECOMBIVAX HB.* * * * S atitis B vaccines respond with lower titers, which remain at 15 REFERENCES protective levels lor shorter durations than in normal sub¬ 1. Centers for Disease Control and Prevention. Hepatitis B. jects. In a clinical trial of 56 adults who had been on hemo¬ In: Atkinson W, Wolfe C, Humiston S, Nelson R, eds. Ep¬ dialysis for a mean period of 56 months, ENGERIX-B idemiology and Prevention of Vaccine-Preventable Dis¬ (40 mcg/2 mL given as two 1-mL doses) was given at 0, 1, 2, eases. 6th ed. Atlanta, GA: Public Health Foundation; and 6 months. Two months after the fourth dose, 67% 2000:207-229. (29/43) of patients had seroprotective antibody levels 2. Centers for Disease Control and Prevention. A Compre¬ (£10 mlU/mL) and the GMT among seroconverters was hensive Immunization Strategy to Eliminate Transmis¬ 93 mlU/mL. sion of Hepatitis B Virus Infection in the United States. 14.3 Immunogenicity in Neonates Recommendations of the Advisory Committee on Immu¬ In clinical studies, neonates were given ENGERIX-B nization Practices (ACIP). Part 1: Immunization of In¬ (10 mcg/0.5 mL) at 0. 1, and 6 months or at 0, 1, and 2 fants, Children, and Adolescents, MMWR 2005;54(RRmonths of age. The immune response to vaccination was 16); 1-23. evaluated in sera obtained one month after the third dose of 3. Ascherio A. Zhang SM, Herndn MA. et al. Hepatitis B ENGERIX-B. vaccination and the risk of multiple sclerosis. N Engl J Among infants administered ENGERIX-B at 0, 1, and 6 Med. 2001:344) 5):327-332. months, 100% of evaluable subjects (N = 52) seroconverted 4. Confavreux C, Suissa S, Saddier P, et al. Vaccination and by month 7. The GMT was 713 mlU/mL. Of these, 97% had the risk of relapse in multiple sclerosis. N Engl J Med. seroprotective levels (£10 mlU/mL). 2001-344(51:319-326. Among infants enrolled (N = 3811 to receive ENGERIX-B at 5. Centers for Disease Control and Prevention. A Compre 0, 1, and 2 months of age, 96% had seroprotective levels hensive Immunization Strategy to Eliminate Transmis¬ (£10 mlU/mL) by month 4. The GMT among seroconverters sion of Hepatitis B Virus Infection in the United States. (N = 311) (antibody titer £1 mlU/mLi was 210 mlU/mL. A Recommendations of the Advisory Committee on Immu¬ subset of these children received a fourth dose of nization Practices (ACIP). Part 2: Immunization of ENGERIX-B at 12 months of age. One month following this Adults, MMWR 2006;55(RR-16);l-25. dose, seroconverters (N = 126i had a GMT of 2,941 mlU/mL. 6. Andre FE, Safary A. Clinical experience with a yeast14.4 Immunogenicity in Children and Adults derived hepatitis B vaccine. In: Zuckerman AJ. ed. Viral Persons 6 Months Through 10 Years of Age: In clinical tri¬ Hepatitis and Liiier Diseuse. New York, NY: Alan R Liss, als, children (N = 2421 6 months through 10 years of age Inc., 1988:1025-1030. were given ENGERIX-B (10 mcg/0.5 mL) at 0. 1, and 6 7. Poovorawan Y, Sanpavat S, Pongpunlert W, et al. Protec¬ months. One to 2 months after the third dose, the seroprotive efficacy of a recombinant DNA hepatitis B vaccine in tection rate was 98% and the GMT of seroconverters was neonates of HBe antigen-positive mothers. JAMA. 4.023 mlU/mL. 1989;261(22):3278-3281. Persons [^Through 16 Years of Age: In a separate clinical 8. Bush LM, Moonsammy GI. Boscia JA. Evaluation of ini¬ trial including both children and adolescents 5 through 16 tiating a hepatitis B vaccination schedule with one years of age, ENGERIX-B (10 mcg/0.5 mL) was adminis¬ vaccine and completing it with another. Vaccine. tered at 0, 1, and 6 months (N = 181) or 0, 12, and 24 1991;9( U):807-809. months (N = 161). Immediately before the third dose of 16 HOW SUPPLIED/STORAGE AND HANDLING vaccine, seroprotection was achieved in 92 3% of subjects vaccinated on the 0-. 1-, and 6-month schedule and 88.8% of 1 ENGERIX-B is available in single-dose vials and prefilled subjects on the 0-, 12-. and 24-month schedule tGMT. ! disposable TIP-LOK syringes (packaged without needlesi 117.9 mlU/mL versus 162.1 mlU/mL. respectively, P = 0.18). I (Preservative Free Formulation):

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Look for PDR drug information and services in your EHR 10 mcg/0.5 ml, Pediatric/Adolescent Dose NDC 58160-820-01 Vial in Package of 10: NDC 58160820-11 NDC 58160-820-43 Syringe in Package of 10: NDC 58160820- 52 20 mcg/mL Adult Dose NDC 58160-821-01 Vial in Package of 10: NDC 58160821- 11 NDC 58160-821-05 Syringe in Package of 1: NDC 58160821-34 NDC 58160-821-43 Syringe in Package of 10: NDC 58160821-52 Store refrigerated between 2° and 8° C (36° and 46° F). Do not freeze; discard if product has been frozen. Do not dilute to administer. 17

PATIENT COUNSELING INFORMATION

EPIVIR-HBV • GLAXOSMITHKLINE/929 -INDICATIONS AND USAGE-

13

EPIVIR-HBV is a nucleoside analogue reverse transcrip¬ tase inhibitor indicated for the treatment of chronic hepa¬ titis B virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. (1)

14

-DOSAGE AND ADMINISTRATIONAdult patients: 100 mg, once daily. (2.2) Pediatric patients aged 2 to 17 years: 3 mg per kg once daily up to 100 mg once daily. Prescribe oral solution for pediatric patients requiring less than 100 mg daily. (2.3 > Patients with renal impairment: Doses of EPIVIR-HBV must be adjusted in accordance with renal function. (2.4) EPIVIR-HBV should not be used with other medications that contain lamivudine or emtricitabine. (2.5)

16 17

* Sections or subsections omitted from the full prescribing information are not listed

FULL PRESCRIBING INFORMATION

WARNING: RISK OF LACTIC ACIDOSIS, EX¬ ACERBATIONS OF HEPATITIS B UPON DIS¬ CONTINUATION OF EPIVIR-HBV®, AND RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION.

-DOSAGE FORMS AND STRENGTHS-

• Inform vaccine recipients and parents or guardians of the potential benefits and risks of immunization with ENGERIX-B. • Emphasize, when educating vaccine recipients and par¬ ents or guardians regarding potential side effects, that ENGERIX-B contains non-infectious purified HBsAg and cannot cause hepatitis B infection. • Instruct vaccine recipients and parents or guardians to re¬ port any adverse events to their healthcare provider. • Give vaccine recipients and parents or guardians the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are avail¬ able free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines). ENGERIX-B and TIP-LOK are registered trademarks of the GlaxoSmithKline group of companies. RECOMBIVAX HB is a registered trademark of Merck & Co. Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License No. 1617 Distributed by GlaxoSmithKline Research Triangle Park, NC 27709 ©2013; GlaxoSmithKline group of companies. All rights re¬ served. ENG:53PI

EPIVIR-HBV

• Tablets: 100 mg (3) • Oral Solution: 5 mg per mL (3) -CONTRAINDICATIONSPatients with previously demonstrated clinically significant hypersensitivity (y.g., anaphylaxis) to any of the compo¬ nents of the products. (4)

Lactic Acidosis and Severe Hepatomegaly:

tablets for oral use

EPIVIR-HBV (lamivudine) oral solution HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EPIVIR-HBV safely and effectively. See full prescrib¬ ing information for EPIVIR-HBV. EPIVIR-HBV (lamivudine) tablets for oral use EPIVIR-HBV (lamivudine) oral solution Initial U.S. Approval: 1995

WARNING:

RISK OF LACTIC ACIDOSIS, EXACER¬

BATIONS OF HEPATITIS B UPON DISCONTINUATION OF EPIVIR-HBV, AND RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOG¬ NIZED OR UNTREATED HIV-1 INFECTION. See full prescribing information for complete Boxed Warning. • Lactic acidosis and severe hepatomegaly with stea¬ tosis, including fatal cases, have been reported with the use of nucleoside analogues. Suspend treat¬ ment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.11 • Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti¬ hepatitis B therapy (including EPIVIR-HBV). Monitor hepatic function closely in these patients and, if ap¬ propriate, initiate anti-hepatitis B treatment. (5.2) • EPIVIR-HBV tablets and oral solution contain a lower

dose

of

the

same

active

ingredient

(lamivudine) as EPIVIR tablets and oral Solution used to treat HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B patients with unrec¬ ognized or untreated HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment. (5.3)

Lactic ac¬

idosis and severe hepatomegaly with steatosis, in¬ cluding fatal cases, have been reported with the use

-WARNINGS AND PRECAUTIONS-

of nucleoside analogues alone or in combination, in¬

• EPIVIR-HBV should not be used with other medications that contain lamivudine or with medications that contain emtricitabine. (5.4) • Emergence of Resistance-Associated HBV Substitu¬ tions: Monitor ALT and HBV DNA levels during lamivudine treatment to aid in treatment decisions if emergence of viral mutants or loss of therapeutic response is suspected. (2.6, 5.5) , ,

cluding EPIVIR-HBV. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur /see Warnings and Precautions 15.1)]. Exacerbations of Hepatitis B Upon Discontinuation of EPIVIR-HBV: Severe acute exacerbations of hepati¬ tis B have been reported in patients who have discon¬ tinued

anti-hepatitis

B

therapy

(including

EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for

-ADVERSE REACTIONS• The most common reported adverse reactions in those re¬ ceiving EPIVIR-HBV (incidence greater than or equal to 10% and reported at a rate greater than placejxi) were ear, nose and throat infections, sore throat, and diarrhea. (6.1)

at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted Isee Warnings and Precautions 15.211.

To report SUSPECTED ADVERSE REACTIONS, contact

Risk of HIV-1 Resistance if EPIVIR-HBV Is Used in Pa¬

GlaxoSmithKline at 1-888-825-5249 at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

tients With Unrecognized or Untreated HIV-1 Infec¬ tion:

EPIVIR-HBV is not approved for the treatment

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

of HIV-1 infection because the lamivudine dosage in

Revised: 12/2013

appropriate for the treatment of HIV-1 infection. HIV-1

EPIVIR-HBV is subtherapeutic and monotherapy is in¬

[ep’a-t’tr] (lamivudine)

NONCUNICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility , CLINICAL STUDIES 14.1 Clinical Studies of EPIVIR-HBV in Adult Patients 14.2 Clinical Studies of EPIVIR-IIBV in Pediat¬ ric Subjects HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION: CONTENTS* * WARNING: RISK OF LACTIC ACIDOSIS, EXACER¬ BATIONS OF HEPATITIS B UPON DISCONTINUA¬ TION OF EPIVIR-HBV®, AND RISK OF HIV-1 RESIS¬ TANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFEC¬ TION. 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 HIV Counseling and Testing 2.2 Dosage in Adult Patients 2.3 Dosage in Pediatric Patients 2.4 Dosage Adjustment in Adult Patients With Renal Impairment 2.5 Important Administration Instructions 26 Assessing Patients During Treatment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis and Severe Hepatomegaly With Steatosis 5.2 Exacerbation of Hepatitis After Discontinua¬ tion of Treatment 5.3 Risk of HIV-1 Resistance if EPIVIR-HBV Is Used in Patients With Unrecognized or Un¬ treated HTV-1 Infection 5.4 Coadministration With Other Medications Containing Lamivudine or Emtricitabine 5.5 Emergence of Resistance-Associated HBV Substitutions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients With Impaired Renal Function 8.7 Patients With Impaired Liver Function 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.4 Microbiology

resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infec¬ tion. Counseling and testing should be offered to all patients before beginning treatment with EPIVIRHBV and periodically during treatment /see Warnings and Precautions 15.3)1.

1

INDICATIONS AND USAGE

EPIVIR-HBV is indicated for the treatment of chronic hep¬ atitis B virus > HBVi infection associated with evidence of hepatitis B viral replication and active liver inflammation [see Clinical Studies (14.1, 14.21/. The following points should be considered when initiating therapy with EPIVIR-HBV: • Due to high rates of resistance development in treated pa¬ tients, initiation of treatment with EPIVIR-HBV should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate • EPIVIR-HBV has not been evaluated in patients co¬ infected with HIV, hepatitis C virus (HCV7, or hepatitis delta virus. • EPIVIR-HBV has not been evaluated in liver transplant recipients or in patients with chronic hepatitis B virus in¬ fection with decompensated liver disease. • EPIVIR-HBV has not been evaluated in pediatric patients younger than 2 years of age with chronic HBV infection. 2 DOSAGE AND ADMINISTRATION 2.1 HIV Counseling and Testing HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodi¬ cally during treatment because of the risk of emergence of resistant-HIV-1 and limitation of treatment options if EPIVIR-HBV is proscribed to treat chronic hepatitis B in¬ fection in a patient who has unrecognized HIV-1 infection or acquires HIV-1 infection during treatment /see Warnings and Precautions (5.3)1. 2.2

Dosage in Adult Patients

The recommended oral dosage of EPIVIR-HBV is 100 mg once daily. 2.3

Dosage in Pediatric Patients

The recommended oral dosage of EPIVIR-HBV for pediatric patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dusage of 100 mg The oral solution formu¬ lation should be prescribed for patients requiring a dusage less than 100 mg or if unable to swallow tablets.

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Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

930/GLAXOSMITHKLINE • EPIVIR-HBV 2.4 Dosage Adjustment in Adult Patients With Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1I see Clinical Pharma¬ cology (12.3)1. Table 1. Dosage of EPIVIR-HBV in Adult Patients With Renal Impairment Creatinine

Recommended Dosage of EPIVIR-HBV

Clearance (mL/min)

100 mg once daily 100 mg first dose, then 50 mg once daily 100 mg first dose, then 25 mg once daily 35 mg first dose, then 15 mg once daily 35 mg first dose, then 10 mg once daily

>50 30-49 15-29 5-14 were un¬ changed. There was no significant pharmacokinetic interac¬ tion between lamivudine and interferon alfa in this trial. Ribavirin: In vitro data indicate ribavirin reduces phos¬ phorylation of lamivudine. stavudine. and zidovudine. How¬ ever. no pharmacokinetic le g., plasma concentrations or in¬ tracellular triphosphorvlated active metabolite 1

concentrations) or pharmacodynamic (e.g., loss of HIV-1/ HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zi¬ dovudine (n = 6) were coadministered as part of a multidrug regimen to HIV-l/HCV co-infected subjects. Trimethoprim /Sulfamethoxazole: Lamivudine and tri¬ methoprim/sulfamethoxazole (TMP/SMX) were coadminis¬ tered to 14 HIV-positive subjects in a single-center, openlabel, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with con¬ comitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/ SMX with lamivudine resulted in an increase of 44% ± 23% (mean ± SD) in lamivudine AUC, a decrease of 29%. ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic proper¬ ties of TMP and SMX were not altered by coadministration with lamivudine. Zidovudine: Lamivudine and zidovudine were coadminis¬ tered to 12 asymptomatic HIV-positive adult subjects in a single-center, open-label, randomized, crossover trial. No significant differences were observed in AUC or total clear¬ ance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in C,nox of zidovudine. 12.4

Microbiology

Mechanism of Action: Lamivudine is a synthetic nucleo¬ side analogue. Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphos¬ phate, 3TC-TP. The principal mode of action of 3TC-TP is the inhibition of the RNA- and DNA- dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian a, (1, and y-DNA polymerases. Antiviral Activity: Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to re¬ duce the level of extracellular HBV DNA by 50%) varied from 0.01 pM (2.3 ng per mL) to 5.6 pM (1.3 meg per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the EPIV1R prescribing information for information re¬ garding activity of lamivudine against HIV Resistance: Lamivudine-resistant isolates were identified in subjects with virologic breakthrough, defined when using solution hybridization assay as the detection of HBV DNA in serum on 2 or more occasions after failing to detect HBV DNA on 2 or more occasions and defined when using PCR assay as a greater than 1 log,0 (10-fold) increase in serum HBV DNA from nadir during treatment in a subject who had an initial virulogic response.

Lamivudine-resistant HBV isolates develop rtM204V/l sub¬ stitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/l substitutions are fre¬ quently accompanied by other substitutions (rtV173L, rtLISOM) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions detected in lamivudineresistant HBV isolates include rtL80I and rtA181T. In 4 controlled clinical trials in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving EPIVIR-HBV 100 mg once daily for 52 weeks. The preva¬ lence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in subjects who continued 100 mg per day EPIVIR-HBV after one of these trials, YMDD substitutions further increased from 18% (10 of 57) at 1 year to 41% (20 of 49), 53% (27 of 51), and 69% (31 of 45) after 2, 3, and 4 years of treatment, respectively. Over the 5-year treatment period, the propor¬ tion of subjects who developed YMDD-mutant HBV at any time was 69% (40 of 58). In a controlled trial, treatment-naive subjects with HBeAgpositive CHB were treated with EPIVIR-HBV or EPIVIR-HBV plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV7 was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only EPIVIR-HBV In another controlled trial, combination therapy was evaluated in adult subjects with HBeAg-positive CHB who had YMDD-mutant HBV and di¬ minished clinical and virologic response to EPIVIR-HBV. Following 52 weeks of EPIVIR-HBV plus adefovir dipivoxil combination therapy (n = 46) or therapy with only EPIVIR-HBV (n = 49), YMDD-mutant HBV was detected less frequently in subjects receiving combination therapy, 62% versus 96%. A published trial suggested that the rates of lamivudine re¬ sistance in subjects treated for HBeAg-negative CHB ap¬ pear to be more variable (0% to 27% at 1 year and 10% to 56% at 2 years). Pediatric Subjects: In a controlled trial in pediatric sub¬ jects, YMDD-mutant HBV was detected in 31 of 166 19% : subjects receiving EPIVIR-HBV for 52 weeks. For a sub¬ group that remained on therapy with EPIVIR-HBV in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with EPIVIR-HBV. Cross-Resistance: HBV containing lamivudine resistanceassociated substitutions (rtL180M. rtM204I, rtM204V. rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (30 fold) and telbivudine (greater than 100 fold). The lamivudine resistanceassociated substitution rtA181T results in diminished re¬ sponse to adefovir and telbivudine. Similarly, HBV with en¬ tecavir resistance-associated substitutions (I169T/M250V and T184G/S202D have greater than 1,000-fold reductions in susceptibility to lamivudine. 13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

Carcinogenesis: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcino¬ genic potential at exposures up to 34 times unice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B. Mutagenesis: Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytoge¬ netic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg producing plasma levels of 60 to 70 times those in humans at the recommended dose for chronic hepatitis B. Impairment of Fertility: In a study of reproductive perfor¬ mance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 80 to 120 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and develop¬ ment to weaning of the offspring.

14 14.1

CLINICAL STUDIES Clinical Studies of EPIVIR-HBV in Adult Patients

The safety and efficacy of EPIVIR-HBV 100 mg once daily versus placebo were evaluated in 3 controlled trials in sub¬ jects with compensated chronic hepatitis B virus infection All subjects were aged 16 years or older and had chronic hepatitis B virus infection (serum HBsAg-pusitive for at least 6 months) accompanied by evidence of HBV replica¬ tion iserum HBeAg-positive and positive for serum HBV

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Look for PDR drug information and services in your EHR DNA) and persistently elevated ALT levels and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The results of these trials are sum¬ marized below. • Trial 1 was a randomized, double-blind trial of EPIVIR-HBV 100 mg once daily versus placebo for 52 weeks followed by a 16-week no-treatment period in 141 treatment-naive US subjects. • Trial 2 was a randomized, double-blind, 3-arm trial that compared EPIVIR-HBV 25 mg once daily versus EPIVIR-HBV 100 mg once daily versus placebo for 52 weeks in 358 Asian subjects. • Trial 3 was a randomized, partially-blind trial conducted primarily in North America and Europe in 238 subjects who had ongoing evidence of active chronic hepatitis B de¬ spite previous treatment with interferon alfa. The trial compared EPIVIR-HBV 100 mg once daily for 52 weeks, followed by either EPIVIR-HBV 100 mg or matching pla¬ cebo once daily for 16 weeks (Arm 1), versus placebo once daily for 68 weeks (Arm 2). Principal endpoint comparisons for the histologic and sero¬ logic outcomes in subjects receiving EPIVIR- HBV (100 mg daily) or placebo in these trials are shown in the following tables. ISee table 7 at top of previous page] [See table 8 above] Normalization of serum ALT levels was more frequent with EPIVIR-HBV treatment compared with placebo in Trials 1-3. The majority of subjects treated with EPIVIR-HBV showed a decrease of HBV DNA to below the assay limit early in the course of therapy. However, reappearance of assaydetectable HBV DNA during treatment with EPIVIR-HBV was observed in approximately one-third of subjects after this initial response. 14.2 jects

Clinical Studies of EPIVIR-HBV in Pediatric Sub¬

The safety and efficacy of EPIVIR-HBV were evaluated in a double-blind clinical trial in 286 subjects aged from 2 to 17 years, who were randomized (2:1) to receive 52 weeks of EPIVIR-HBV (3 mg per kg once daily to a maximum of 100 mg once daily) or placebo. All subjects had compensated chronic hepatitis B accompanied by evidence of hepatitis B virus replication (positive serum HBeAg and positive for serum HBV DNA by a research branched-chain DNA assay) and persistently elevated serum ALT levels. The combina¬ tion of loss of HBeAg and reduction of HBV DNA to below the assay limit of the research assay, evaluated at Week 52, was observed in 23% of subjects treated with EPIVIR-HBV and 13% of placebo-treated subjects. Normalization of serum ALT was achieved and maintained to Week 52 more frequently in subjects treated with EPIVIR-HBV compared with placebo (55% versus 13%). As in the adult controlled trials, most subjects treated with EPIVIR-HBV had de¬ creases in HBV DNA below the assay limit early in treat¬ ment, but about one third of subjects with this initial re¬ sponse had reappearance of assay-detectable HBV DNA during treatment. Adolescents (aged 13 to 17 years) showed less evidence of treatment effect than younger pediatric sub¬ jects. 16

HOW SUPPLIED/STORAGE AND HANDLING

EPIVIR-HBV tablets, 100 mg, are butterscotch-colored, film-coated, biconvex, capsule-shaped tablets imprinted with “GX CG5" on one side. Bottles of 60 tablets (NDC 0173-0662-00) with childresistant closures. Store at 25°C (77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

EPIVIR-HBV oral solution, a clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 5 mg of lamivudine in each 1 mL in plastic bottles of 240 mL. Bottles of 240 mL (NDC 0173-0663-00) with child-resistant closures. This product does not require reconstitution. Store at controlled room temperature of 20° to 25°C 168” to 77°F) (see USP) in tightly closed bottles.

EPIVIR-HBV • GLAXOSMITHKLINE/933 Table 8. HBeAg Seroconverters* at Week 52 Among Adult Subjects Receiving EPIVIR-HBV 100 mg Once Daily or Placebo Seroconversion

Trial 1

Trial 2

Trial 3

EPIVIR-HBV

Placebo

EPIVIR-HBV

Placebo

(n * 69)

(n = 140)

Placebo (n = 70)

EPIVIR-HBV

(n = 63)

(n = 108)

(n = 53)

17%

6%

16%

4%

15%

13%

Seroconverters

“ Three-component seroconversion was defined as Week 52 values showing loss of HBeAg, gain of HBeAb, and reduction of HBV DNA to below the solution-hybridization assay limit. Subjects with negative baseline HBeAg or HBV DNA assay were excluded from the analysis. • Inform patients that emergence of resistant hepatitis B vi¬ rus and worsening of disease can occur during treatment, and they should promptly report any new symptoms to their physician [see Warnings and Precautions (5.5)1. • Counsel patients on the importance of testing for HIV to avoid inappropriate therapy and development of resistant HIV. HIV counseling and testing should be offered before starting EPI\rIR-HBV and periodically during therapy. • Advise patients that EPIVIR-HBV' tablets and EPIVIR-HBV oral solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR tablets, EPIVIR oral solution, COMBIVIR tablets, EPZICOM tab¬ lets, and TRIZIVIR tablets. EPIVIR-HBV should not be taken concurrently with EPIVIR, COMBIVIR, EPZICOM, or TRIZIVIR [see Dosage and Administration (2.1), Warn¬

• • • • •

trouble breathing stomach pain with nausea and vomiting feel cold, especially in your arms and legs feel dizzy or light-headed have a fast or irregular heartbeat Severe liver problems.Severe liver problems can happen in people who take EPIVTR-HBV' or similar medicines. In some cases these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take EPIVIR-HBV Call your healthcare provider right away if you get any of the follow¬ ing signs of liver problems:

• your skin or the white part of your eyes turns yellow (jaun¬ dice) • dark “tea-colored” urine • light-colored bowel movements (stools) • loss of appetite for several days or longer • nausea • stomach pain

ings and Precautions (5.3, 5.4)]. • Advise patients not to take

EPIVTR-HBV with emtricitabine-containing medicines, such as ATRIPLA, COMPLERA. EMTRIVA, STRIBILD, or TRUVADA [see Warnings and Precautions (5.4)].

You may be more likely to get lactic acidosis or severe liver problems if you are female, very overweight, or have been

• Advise patients that treatment with EPIVTR-HBV' has not been shown to reduce the risk of transmission of HBV' to others through sexual contact or blood contamination [see

taking nucleoside analogue medicines for a long time. Worsening liver disease.Your

hepatitis B infection may be¬ come worse after stopping treatment with EPIVIR-HBV. Worsening liver disease can be serious and may lead to death. If you stop treatment with EPIVIR-HBV', your healthcare provider will need to check your health and do blood tests to check your liver for at least several months after you stop taking EPIVIR-HBV.

Use in Specific Populations (8.1)].

• Instruct patients to avoid doing things that can spread HBV infection to others. ® Do not share needles or other injection equipment. •Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

°

Always practice safe sex by using a latex or polyurethane con¬ dom to lower the chance of sexual contact with semen, vaginal secretions, or blood. • Advise diabetic patients that each 20-mL dose of EPIVIR-HBV oral solution contains 4 grams of sucrose Do not have any kind of sex without protection.

Risk of HIV-1 resistance in people with unknown HIV-1 in¬ fection or in people with untreated HIV-1 infection.If

you have or get HIV that is not being treated with medicines while taking EPIVIR-HBV, the HIV virus may develop re¬ sistance to certain HIV medicines and become harder to treat. • Your healthcare provider should offer you counseling and testing for HIV-1 infection before you start treatment for hepatitis B with EPIVIR-HBV and during treatment. • EPIVTR-HBV tablets and EPIVIR-HBV' oral solution con¬ tain a lower dose of lamivudine than other medicines that contain lamivudine and are used to treat HIV-1 infection. See “What should I tell my healthcare provider?” for a list of medicines you should not take with EPIVIR-HBV. Resistant Hepatitis B Virus (HBV).The hepatitis B virus can change (mutate) during your treatment with EPIVIR-HBV and become harder to treat (resistant). If this happens, your liver disease can become worse and may lead to death. Tell your healthcare provider right away if you have any new symptoms.

[see Description (11)].

EPIVIR-HBV is a registered trademark of the GlaxoSmith¬ Kline group of companies. EPIVIR, COMBIVIR. EPZICOM, and TRIZIVIR are regis¬ tered trademarks of the ViiV Healthcare group of compa¬ nies. The other brands listed are trademarks of their respective owners and are not trademarks of the GlaxoSmithKline group of companies. The makers of these brands are not af¬ filiated with and do not endorse the GlaxoSmithKline group of companies or its products. GlaxoSmithKline Research Triangle Park, NC 27709 Manufactured under agreement from Shire Pharmaceuticals Group pic

Basingstoke, UK ©2013, GlaxoSmithKline group of companies. All rights re¬ served. EPV:3PI PATIENT INFORMATION EPIVIR HBV® lEP-i-veer h-b-v* * (lamivudine) tablets EPIVIR HBV® (lamivudine) oral solution

(EP-i-veer h-b-vl

What is EPIVIR-HBV?

I

EPIVIR-HBV is a prescription medicine used to treat long¬ term (chronic) hepatitis B virus (HBVi when the disease is progressing and there is liver swelling (inflanlmation). . EPIVTR-HBV will not cure HBV. • EPIVIR-HBV may lower the amount of HBV in your body. • EPIVIR-HBV may lower the ability of HBV to multiply and infect new liver cells. • EPIVIR-HBV may improve the condition of your liver. • The long-term benefits of taking EPIVTR-HBV' for treat¬ ment of chronic hepatitis B infection are not known. It is not known if EPIVIR-HBV is safe and effective in: • people with chronic HBV who have a severely damaged liver that is unable to work properly (decompensated liver disease) • people with hepatitis C virus or hepatitis D (delta) virus • people who have had a liver transplant • children with chronic HBV less than 2 years of age

Read this Patient Information before you start taking : EPIVTR-HBV and each time you get a refill. There may be ; new information. This information does not take the place Adi'ise the patient to read the FDA-approved patient label¬ ! of talking with your healthcare provider about your medical ing (Patient Information). j Advice for the Patient condition or treatment. What is the most important information I should know • Advise patients to remain under the care of a physician j about EPIVIR-HBV? while taking EPIVIR-HBV and discuss any new symptoms EPIVIR-HBV can cause serious side effects, including: EPIVIR-HBV does not stop you from spreading HBV to oth¬ or concurrent medications with their physician. Build-up of an acid in your blood (lactic acidosisl.Lactic ac¬ ers by sex, sharing needles, or being exposed to your • Advise patients that EPIVIR-HBV is not a cure for hepa¬ blood Avoid doing things that can spread HBV infection to idosis can happen in some people who tuke EPIVTR-HBV or titis B. that the long-term treatment benefits of similar i nucleoside analogs * medicines. Lactic acidosis is a others. EPIVIR-HBV an* unknown at this time, and, in particu¬ serious medical emergency that can lead to death. • Do not share or re-use needles or other injection equip¬ lar, that the relationship of initial treatment response to Lactic acidosis can be hard to identify early because the ment. outcomes such as hepatocellular carcinoma and decom¬ symptoms could seem like symptoms of other health prob¬ • Do not share personal items that can have blood or body pensated cirrhosis is unknown [see Dosage and Adminis¬ lems. Call your healthcare provider right away H you get fluids on them, like toothbrushes and razor blades tration 12.6)1. any of the following symptoms that could be signs of lactic • Do not have any kind of sex without protection Always • Inform patients that deterioration of liver disease has acidosis: practice safer sex by using a latex or polyurethane condom occurred in some cases when treatment was discontinued. to lower the chance of sexual oontact with semen, vaginal • feel very weak or tired Instruct patients to discuss any changes in regimen with secretions, or blood. • unusual (not normal* muscle pain their physician /see Warnings and Precautions (5.2)1. 17

PATIENT COUNSELING INFORMATION

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934/GLAXOSMITHKLINE • EPIVIR-HBV A vaccine is available to protect people at risk for becoming infected with HBV. You can ask your healthcare provider for information about this vaccine. Who should not take EPIVIR-HBV?

Do not take EPIVIR-HBV if you are allergic to lamivudine or any of the ingredients in EPIVIR-HBV. See the end of this leaflet for a complete list • of ingredients in EPIVIR-HBV. What should I tell my healthcare provider before taking EPIVIR-HBV? Before you take EPIVIR-HBV, tell your healthcare provider if you:

• have HIV-1 infection. • have kidney problems • have diabetes. Each 20-mL dose (100 mg) of EPIVIR-HBV oral solution contains 4 grams of sucrose. • have any other medical condition • are pregnant or plan to become pregnant. It is not known if EPIVIR-HBV will harm your unborn baby. Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. EPIVIR-HBV can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take EPIVIR-HBV or breastfeed. Tell your healthcare provider about all the medicines you

including prescription and over-the-counter medi¬ cines, vitamins,and herbal supplements. take,

Do not take EPIVIR-HBV if you also take:

• other medicines that contain lamivudine (COMBIVIR®, EPIVIR®, EPZICOM®, TRIZIVIR®) • medicines that contain emtricitabine (ATRIPLA®, COMF1.ERA® EMTRIVA®, STRIBILD®, TRUVADA®) How should I take EPIVIR-HBV?

• Take EPIVIR-HBV exactly as your healthcare provider tells you to take it. • Do not change your dose or stop taking EPIVIR-HBV without talking with your healthcare provider. • EPIVIR-HBV is taken 1 time each day. • Your healthcare provider may prescribe a lower dose if you have problems with your kidneys. • For children 2 to 17 years of age, your healthcare provider will prescribe the right dose of EPIVIR-HBV based on your child’s body weight. • Take EPIVIR-HBV by mouth, with or without food. • Tell your healthcare provider if you have trouble swallow¬ ing tablets. EPIVIR-HBV also comes as a liquid (oral so¬ lution). • If you take too much EPIVIR-HBV, call your healthcare provider or go to the nearest hospital emergency room right away. • It is important to stay under your healthcare provider’s care while taking EPIVIR-HBV. Ttell your healthcare pro¬ vider about any new symptoms that you have.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch

What are the ingredients in EPIVIR-HBV? Active ingredient:

lamivudine.

Inactive ingredients: EPIVIR-HBVtablets:

hypromellose, macrogol 400. magne¬ sium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide, and yellow iron oxide. EPIVIR-HBV oral solution: artificial strawberry and ba¬ nana flavors, citric acid (anhydrous), methylparaben, pro¬ pylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg per mL). This Patient Information has been approved by the U.S. Food and Drug Administration. EPIVIR-HBV is a registered trademark of the GlaxoSmith¬ Kline group of companies. EPIVIR, COMBIVIR, EPZICOM, and TRIZIVIR are regis¬ tered trademarks of the ViiV Healthcare group of compa¬ nies. The other brands listed are trademarks of their respective owners and are not trademarks of the GlaxoSmithKline group of companies. The makers of these brands are not af¬ filiated with and do not endorse the GlaxoSmithKline group of companies or its products. GlaxoSmithKline Research Triangle Park, NC 27709 Manufactured under agreement from Shire Pharmaceuticals Group pic

Basingstoke, UK ©2013, GlaxoSmithKline group of companies. All rights re¬ served. Revised: December 2013 EPH:3PIL

FLOLAN® [flow-lan] (epoprostenol sodium) for injection, for intravenous use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLOLAN safely and effectively. See full prescribing information for FLOLAN. FLOLAN (epoprostenol sodium) for injection, for intrave¬ nous use Initial U.S. Approval: 1995

-RECENT MAJOR CHANGES-

Dosage and Administration (2.1 - 2.3)

4/2015

-INDICATIONS AND USAGE-

know about EPIVIR-HBV?”.

FLOLAN is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly (9790 patients with NYHA Functional Class II1-IV symptoms and etiologies of idiopathic or heritable PAH (4991) or PAH associated with connective tissue diseases (51%). (1)

The most common side effects of EPIVIR-HBV include:

-DOSAGE AND ADMINISTRATION-

What are the possible side effects of EPIVIR-HBV? EPIVIR-HBV may cause serious side effects, including:

See

‘What is the most important information I should

• ear, nose, and throat infections • sore throat • diarrhea Tbll your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of EPIVIR-HBV. For more information, ask your healthcare provider or phar¬ macist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store EPIVIR-HBV?

• Store EPIVIR-HBV tablets and oral solution at room tem¬ perature between 68°F to 77°F (20'C to 25°C). • Keep bottles of EPIVIR-HBV oral solution tightly closed.

• Initiate intravenous infusion through a central venous catheter at 2 ng/kg/min. (2.2, 2.3) • Change dose in 1-to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response. (2.2) • Avoid sudden large dose reductions. ( 2.2, 5.2) -DOSAGE FORMS AND STRENGTHS-

For injection: 0.5 mg or 1.5 mg epoprostenol freeze-dried powder in a single use vial for reconstitution with the sup¬ plied diluent. (3) -CONTRAINDICATIONS• Heart failure with reduced ejection fraction. i4) • Hypersensitivity to FLOLAN or any of its ingredients. (4)

Keep EPIVIR-HBV and all medicines out of the reach of chil¬

-WARNINGS AND PRECAUTIONS-

dren.

• Pulmonary edema: Discontinue therapy if pulmonary edema occurs. (5.1) • Rebound pulmonary hypertension: Do not abruptly dis¬ continue or decrease the dose. (5.2) • Vasodilation reactions: Monitor blood pressure and symp¬ toms regularlv during initiation and after dose change. (5.3) • Increased risk for bleeding Increased risk for hemor¬ rhagic complications, particularly for patients with other risk factors for bleeding. i5.4i

General information about the safe and effective use of EPIVIR-HBV

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet Do not use EPIVIR-HBV for a condition for which it was not pre¬ scribed. Do not give EPIVIR-HBV to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your health¬ care provider. You can ask your pharmacist or healthcare provider for information about EPIVIR-HBV that is written for health professionals. For more information, go to www.gsk.com or call 1-800-25-5249.

-ADVERSE REACTIONSThe most common adverse reactions are dizziness, jaw pain, headache, musculoskeletal pain, and nausea/vomiting, and are generally associated with vasodilation. (6l

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 4/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 2

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Reconstitution 2.2 Dosage 2.3 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Pulmonary Edema 5.2 Rebound Pulmonary Hypertension following Abrupt Withdrawal 5.3 Vasodilation 5.4 Increased Risk for Bleeding 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis. Impairment of Fertility 14 CLINICAL STUDIES 14.1 Chronic Infusion in Idiopathic or Heritable PAH 14.2 Chronic Infusion in PAH/SSD 14.3 Increased Mortality in Patients with Heart Failure Caused by Severe Left Ventricular Systolic Dysfunction 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION PATIENT INFORMATION * Sections or subsections omitted from the' full prescribing information are not listed. FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE FLOLAN * is indicated for the treatment of pulmonary ar¬ terial hypertension (PAHuWHO Group I) to improve exer¬ cise capacity. Trials establishing effectiveness included pre¬ dominantly (97%) patients with New York Heart Association (NYHA) Functional Class 1II-TV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH asso¬ ciated with connective tissue diseases (61%). 2 2.1

DOSAGE AND ADMINISTRATION Reconstitution

Each vial is for single use only; discard any unused diluent or unused reconstituted solution. Select a concentration for the solution of FLOIAN that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed below /see Dosage and Administration (2.4)1.

Using aseptic technique, reconstitute FLOIAN only with STERILE DILUENT Tor FLOLAN or pH 12 STERILE DIL¬ UENT for FLOLAN. Table 1 gives directions for preparing several different concentrations of FLOIAN. See Table 2 for storage and administration time limits for the reconstituted FLOLAN. ISee table 1 at top of next page] ISee table 2 at top of next page) 2.2 Dosage Initiate intravenous infusions of FLOLAN at 2 ng/kg/min. Alter the infusion by 1- to 2-ng/kg/min increments at inter¬ vals sufficient to allow assessment of clinical response. These intervals should be at least 15 minutes. During dose initiation, asymptomatic increases in pulmo¬ nary artery pressure coincident with increases in cardiacoutput may occur. In such cases, consider dose reduction, but such an increase dot's not imply that chronic treatment is contraindicated. Base changes in Llie chronic infusion rate on persistence, re¬ currence, or worsening of the patient's symptoms of pulmo¬ nary hypertension and the occurrence of adverse vasodila¬ tor) reactions. In general, expect progressive increases in duse. If dose-related adverse reactions occur, make dose decreases gradually in 2-ng/kg/min decrements every 15 minutes or

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FLOLAN • GLAXOSMITHKLINE/935

longer until the dose-limiting effects resolve/see Adverse Re¬ actions (6.1)]. Avoid abrupt withdrawal of FLOLAN or sud¬ den large reductions in infusion rates [see Warnings and Precautions (5.2)]. Following establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours. Taper doses of FLOLAN after initiation of cardiopulmonary bypass in patients receiving lung transplants.

Table 1. Reconstitution and Dilution Instructions for FLOLAN Using STERILE DILUENT for FLOLAN or pH 12 STERILE DILUENT for FLOLAN To make 100 mL of solution with final concentration of:

Directions:

3,000 ng/mL

Dissolve contents of one 0.5-mg vial with 5 mL of sterile diluent. Withdraw 3 mL and add to sufficient sterile diluent to make a total of 100 mL. Dissolve contents of one 0.5-mg vial with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. Dissolve contents of two 0.5-mg vials each with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. Dissolve contents of one 1.5-mg vial with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL.

5,000 ng/mL

2.3 Administration

Initiate FLOLAN in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discolor¬ ation is noted, do not use. Administer continuous chronic infusion of FLOLAN through a central venous catheter. Temporary peripheral in¬ travenous infusion may be used until central access is es¬ tablished. Do not administer bolus injections of FLOLAN. The ambulatory infusion pump used to administer FLOLAN should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have oc¬ clusion, end-of-infusion, and low-battery alarms, (4) be ac¬ curate to ±6% of the programmed rate, and (5) be positivepressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver FLOLAN. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Use a 60-inch microbore non-di-(2-ethylhexyl)phthalate (DEHP) extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22-micron filter. Tb avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous in¬ fusion sets. Do not administer or dilute reconstituted solutions' of FLOLAN with other parenteral solutions or medications. Consider a multi-lumen catheter if other intravenous ther¬ apies are routinely administered. Select a concentration for the solution of FLOLAN that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. When adminis¬ tered chronically, prepare FLOLAN in a drug delivery res¬ ervoir appropriate for the infusion pump with a total reser¬ voir volume of at least 100 mL, using 2 vials of Sterile Diluent for flolan or 2 vials of pH 12 STERILE DILUENT for FLOLAN. Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Higher infusion rates, and therefore, more concen¬ trated solutions may be necessary with long-term adminis¬ tration of FLOLAN. Infusion rates may be calculated using the following for¬ mula: [See third table above) 3

10,000 ng/mL 15,000 ng/mLa

* Higher concentrations may be prepared for patients who receive FLOLAN long term.

Table 2. Storage and Administration Limits for Reconstituted FLOLAN

Stability

CONTRAINDICATIONS

FLOLAN is contraindicated in patients with heart failure caused by reduced left ventricular ejection fraction [see Clinical Studies (14.3)].

FLOLAN is contraindicated in patients with a hypersensi¬ tivity to the drug or any of its ingredients. WARNINGS AND PRECAUTIONS Pulmonary Edema

If the patient develops pulmonary edema during initiation wjth FLOLAN. discontinue therapy and do not readminis¬ ter. Consider the possibility of associated pulmonary venoocclusive disease in such patients. 5.2

Rebound Pulmonary Hypertension following Abrupt

Withdrawal

Avoid abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of FLOLAN because symptoms associated with rebound pulmonary hy¬ pertension (e.g.. dyspnea, dizziness, and asthenia) may oc¬ cur. In clinical trials, one Class III patient's death was judged attributable to the interruption of FLOLAN. 5.3

Vasodilation

FLOLAN is a potent pulmonary and systemic vasodilator and can cause hypotension and other reactions such as flushing, nausea, vomiting, dizziness, and headache. Moni¬ tor blood pressure and symptoms regularly during initiation and after dose change [see Dosage and Administration (2.2)]. 5.4

for FLOLAN

for FLOLAN

When used at room temperature, (15°C to 25°C; 59°F to 77°F) reconstituted solutions: • are stable for up to 8 hours following reconstitution or removal from refrigerated storage • may be stored for up to 40 hours refrigerated at 2°C to 8°C (36°F to 46°F) before use. When used with a cold pack, reconstituted solutions: • are stable for up to 24 hours use • may be stored refrigerated at 2°C to 8°C (36°F to 46°F) before use as long as the total time of refrigerated storage and infusion does not exceed 48 hours • Change cold packs every 12 hours.

Freshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2°C to 8°C (36°F to 46°F) for no longer than 8 davs can be administered up to: • 72 hours at up to 25°C (77°F). • 48 hours at up to 30°C (86°F). • 24 hours at up to 35°C (95'F). • 12 hours at up to 40°C (104°F).

• Reconstituted solutions can be used immediately. Refrigerate at 2°C to 8°C (36°F to 46°F) if not used immediately. • Protect from light. • Do not freeze reconstituted solutions.

Infusion Rate (mL/h)

= [Dose (ng/kg/min) x Weight Ikg) x 60 min/h] Final Concentration (ng/mL)

Example calculations for infusion rates are as follows: Example 1: for a 60-kg person at the recommended initial dose of 2 ng/kg/min using a 3,000-ng/mL concnetration, the infusion rate would be as follows: Infusion Rate (mL/h) = [2 (ng/kg/min) x 60 (kg) x 60 (min/h'1 = (2.4 (mL/hi 3,000 ng/mL

2: for a 70-kg person at a dose of 16 ng/kg/min using a 15,000-ng/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [16 (ng/kg/min) x 70 (kg) x 60 (min/h)] = (4.48 (mL/h) Example

15,000 ng/mL

6 6.1

5 5.1

When Using pH 12 STERILE DILUENT

DOSAGE FORMS AND STRENGTHS

For injection: 0.5 mg or 1.5 mg of epoprostenol, freeze-dried powder in a single-dose vial for reconstitution with the sup¬ plied diluent. 4

When Using STERILE DILUENT

Increased Risk for Bleeding

FLOLAN is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic compli¬ cations, particularly for patients with other risk factors for bleeding [set Clinical Pharmacology (12.3)].

ADVERSE REACTIONS Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions are shown in Table 3 and are generally related to vasodilatory effects. [See table 3 at top of next page! Adverse Events Attributable to the Drug Delivery System Chronic infusions of FLOLAN are delivered using a small, portable infusion pump through an indwelling central ve¬ nous catheter. During controlled PAH trials of up to 12 weeks’ duration, the local infection rate was about 18'T, and the rate for pain was about 11(1. During long-term follow¬ up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with FLOLAN. 6.2

Postmarketing Experience

8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B. There are no adequate and wellcontrolled studies in pregnant women. Because animal re¬ production studies are not always predictive of human re¬ sponse, FLOLAN should be used during pregnancy only if clearly needed. Animal Data Reproductive studies have been performed in pFegnant rats and rabbits at doses up to 100 mcg/kg/day 1600 mcg/mVday in rats, 2.5 times the recommended human dose, and 1,180 mcg/m^/day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to FLOLAN. 8.3

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FLOLAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The following events have been identified during postap¬ proval use of FLOLAN. Because these reactions are re¬ 8.4 Pediatric Use ported voluntarily from a population of uncertain size, it is Safety and effectiveness in pediatric patients have not been not always possible to estimate reliably their frequency or ! established. establish a causal relationship to drug exposure. 8.5 Geriatric Use Blood and Lymphatic Clinical trials of FLOLAN in pulmonary hypertension did Anemia, hypersplenism, pancytopenia, splenomegaly, not include sufficient numbers of subjects aged 65 and over thrombocytopenia. to determine whether they respond differently from younger Endocrine and Metabolic subjects. Other reported clinical experience has not identi¬ fied differences in responses between the elderly and Hyperthyroidism. younger patients. In general, dose selection for an elderly Gastrointestinal patient should be cautious, usually starting at the low end Hepatic failure. of the dosing range, reflecting the greater frequency of de¬ Respiratory, Thoracic, and Mediastinal creased hepatic, renal, or cardiac function and of concomi¬ Pulmonary embolism. tant disease or other drug therapy

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936/GLAXOSMITHKLINE • FLOLAN

Table 3. Adverse Reactions Occurring in Patients with idiopathic or Heritable PAH and with PAH Associated with

PAH/SSD

Idiopathic or Heritable PAH Conventional

FLOLAN

FLOLAN

Adverse Reaction

(n = 52)

(n = 54)

(n = 56)

(n = 55)

54% 35% 83% 25%

0% 15% 33% 11%

75% 84% 46% 13%

0% 65% 5%

42% 27% 35%

2% 31% 24%

23% 13% 43%

0% 42%

25% 67% 37%

30% 48% 6%

66% 41% 50%

47% 16% 5%

10%

13%

39% 25%

24% 4%

44%

31%

21%

9%

7%

5%

12%

2%

5%

Body as a whole

Jaw pain Nonspecific musculoskeletal pain Headache Chills/fever/sepsis/flu-like symptoms Cardiovascular system

Flushing Hypotension Tachycardia Digestive system

Anorexia Nausea/Vomiting Diarrhea Skin and Appendages

Skin ulcer Eczema/rash/urticaria

Conventional Therapy

Therapy

11%

0%

Musculoskeletal System

Myalgia Nervous system

Anxiety/hyperkinesias/nervousness/ tremor Hyperesthesia/hypesthesia/ paresthesia Dizziness 10

OVERDOSAGE

Signs and Symptoms Hypoxemia, hypotension, and respiratory arrest leading to death have been reported in clinical practice following over¬ dosage of FLOLAN. Excessive doses of FLOLAN were associated with flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea during clinical trials. One patient with PAH/SSD accidentally received 50 mL of an unspecified concentration of FLOLAN. The patient vom¬ ited and became unconscious with an initially unrecordable blood pressure. FLOLAN was discontinued and the patient regained consciousness within seconds. Single intravenous doses of FLOLAN at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase hu¬ man dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breath¬ ing, and hypothermia. Treatment Discontinue or reduce dose of FLOLAN. 11

DESCRIPTION

FLOLAN (epoprostenol sodium) for injection is sterile sodium salt that is a white or off-white powder formulated for intravenous (IV) administration. Each vial of FLOLAN contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 50 mg mannitol, and 2.93 mg sodium chloride. Sodium hydroxide may have been added to adjust pH. Epoprostenol (PG12, PCX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of plate¬ let aggregation. The chemical name of epoprostenol is (5Z.9o,llu,13E,15S >-6,9-epoxy-11,15-dihydroxyprosta-5,13dien-l-oic acid. Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C.j„H:l,NaOs. The structural formula is:

13 13.1

76%

70%

83%

• pH 12 STERILE DILUENT for FLOLAN has sodium hy¬ droxide added to adjust the pH to 11.7 to 12.3. 12 CLINICAL PHARMACOLOGY 12.1

Mechanism of Action

Epoprostenol has 2 major pharmacological actions: (1) di¬ rect vasodilation of pulmonary and systemic arterial vascu¬ lar beds, and (2) inhibition of platelet aggregation. 12.2

Pharmacodynamics

Acute Hemodynamic Effects Acute intravenous infusions of FLOLAN for up to 15 min¬ utes in patients with idiopathic or heritable PAH or PAH/ SSD produce dose-related increases in cardiac index (Cl) and stroke volume (SV) and dose-related decreases in pul¬ monary vascular resistance (PVR), total pulmonary resis¬ tance (TPR), and mean systemic arterial pressure (SAPm). The effects of FLOLAN on mean pulmonary artery pressure (PAPm) were variable and minor. In humans, hemodynamic changes due to epoprostenol (e.g., increased heart rate, facial flushing) returned to baseline within 10 minutes of termination of 60-minute infusions of 1 to 16 ng/kg/min. This pharmacodynamic behavior is con¬ sistent with a short in vivo half-life and rapid clearance in man, as suggested by the results of animal and in vitro studies. In animals, the vasodilatory effects reduce right- and leftventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagallymediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. Drug Interactions Additional reductions in blood pressure may occur when FLOLAN is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is a potential for FLOLAN to increase the risk of bleeding. However, patients receiving infusions of FLOLAN in clinical trials were maintained on anticoagu¬ lants without evidence of increased bleeding. 12.3

epoprostenol. Epoprostenol is metabolized to 2 primary me¬ tabolites: 6-keto-PGF(formed by spontaneous degrada¬ tion) and 6,15-diketo-13,14-dihydro-PGF,„ (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82%. and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is ex¬ tensively metabolized in humans. Elimination The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. Drug Interactions In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide in whom therapy with FLOLAN was initiated, apparent oral clearance values for furosemide (n = 23) were decreased by 13% on the second day of therapy and returned to baseline values by Day 87. The change in furosemide clearance value is not likely to be clinically significant. In a pharmacokinetic substudy in patients with congestive heart failure receiving digoxin in whom therapy with FLOLAN was initiated, apparent oral clearance values for digoxin (n = 30) were decreased by 15% on the second day of therapy and returned to baseline values by Day 87. Clinical significance of this interaction is not known.

Pharmacokinetics

Absorption/Distribution Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. No available FLOLAN must be reconstituted with either STERILE DIL¬ chemical assay is sufficiently sensitive and specific to assess UENT for FLOLAN or pH 12 STERILE DILUENT for the in vivo human pharmacokinetics of epoprostenol. Ani¬ FLOLAN. mal studies using tritium-labeled epoprostenol have indi¬ STERILE DILUENT for FLOLAN is supplied in glass vials cated a high clearance (93 mLAg/min), small volume of disand pH 12 STERILE DILUENT for FLOLAN is supplied in plastic vials each containing 50 mL of 94 mg glycine, I tribution (357 mL/kg), and a short half-life (2.7 minutes). 73.3 mg sodium chloride, sodium hydroxide ladded to adjust | During infusions in animals, steady-state plasma concen¬ trations of tritium-labeled epoprostenol were reached pH), and Water for Injection. The stability of reconstituted within 15 minutes and were proportional to infusion rates. solutions of FLOLAN is pH-dependent. and is greater at Metabolism higher pH. Tritium-labeled epoprostenol has been administered to hu• STERILE DILUENT for FLOLAN has sodium hydroxide I mans in order to identify the metabolic products of added to adjust the pH to 10.2 to 10.8.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instabil¬ ity of epoprostenol makes the significance of these tests un¬ certain. Fertility was not impaired in rats given FLOLAN by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m'Vday, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m2/day, IV] based on body sur¬ face area). 14 14.1

CLINICAL STUDIES Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects 1 Chronic continuous infusions of FLOLAN in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration com¬ paring FLOLAN plus conventional therapy with conventional therapy alone. Dosage of FLOLAN was determined as described in Dosage and Administration (2) and averaged 9.2 ng/kg/min at trials’ end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one-half to two-thirds of patients; and supplemental oxygen in about half the patients. Except for 2 NYHA Functional Class 11 patients, all patients were either functional Class III or Class IV. As results were sim¬ ilar in the 2 trials, the pooled results are described. Chronic hemodynamic effects were generally similar to acute effects. Increases in Cl, SV, and arterial oxygen satu¬ ration and decreases in PAPm. mean right atrial pressure (RAPm), TPR, and systemic vascular resistance tSVRi were observed in patients who received FLOLAN chronically compared with those who did not. Table 4 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment. [See table 4 at top of next page) These hemodynamic improvements appeared to persist when FLOLAN was administered for at least 36 months in an open, nonrandomized trial. The acute hemodynamic response to FLOLAN did not cor¬ relate well with improvement in exercise tolerance or sur¬ vival during chronic use of FLOLAN. Clinical Effects A statistically significant improvement was observed in ex¬ ercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous FLOLAN plus conventional therapy (n = 52) for 8 or 12 weeks compared with those receiving conventional therapy alone In = 54>. Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fa¬ tigue, as measured by the Chronic Heart Failure Question¬ naire and the Dyspnea Fatigue Index, respectively. Survival was improved in NYHA Functional Class III and Class IV patients with idiopathic or heritable PAH treated with FLOLAN for 12 weeks in a multicenter, open, random¬ ized, parallel trial. At the end of the treatment period, 8 of 40 (20% ) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving FLOLAN died (P = 0.003).

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FLOLAN • GLAXOSMITHKLINE/937

Table 4. Hemodynamics during Chronic Administration of FLOLAN in Patients with Idiopathic or Heritable PAH Baseline Hemodynamic Parameter

Mean Change from Baseline at End of Treatment Period*

FLOLAN In = 52)

Standard Therapy (n = 54)

FLOLAN In = 48)

Standard Therapy (n = 41)

Cl (IVmin/m2)

2.0

2.0

0.3"

-0.1

PAPm (mm Hg)

60

60

-5b

1

PVR (Wood U)

16

17

-4b

1

SAPm (mm Hg)

89

91

-4

-3

SV (mL/beat)

44

43

6b

-1

TPR (Wood U)

20

21

-5b

1

pared with those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiv¬ ing FLOLAN died, whereas 5 of 55 (9% i patients receiving conventional therapy alone died.

14.3 Increased Mortality in Patients with Heart Failure Caused by Severe Left Ventricular Systolic Dysfunction A large trial evaluating the effect of FLOLAN on survival in NYHA Class III and IV patients with congestive heart fail¬ ure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients re¬ vealed a higher mortality in patients receiving FLOLAN plus conventional therapy than in those receiving conven¬ tional therapy alone. The chronic use of FLOLAN in pa¬ tients with heart failure due to severe left ventricular sys¬ tolic dysfunction is therefore contraindicated. 16

16.1

“At 8 weeks: FLOLAN’ n = 10, conventional therapy n = 11 (n is the number of patients with hemodynamic data). At 12 weeks: FLOLAN n = 38, conventional therapy n = 30 (n is the number of patients with hemodynamic data). '’Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy. Cl = Cardiac index, PAPm = Mean pulmonary arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure, SV = Stroke volume, TPR = Total pulmonary resistance.

Baseline Hemodynamic Parameter

Mean Change from Baseline at 12 Weeks

FLOLAN (n = 56)

Conventional Therapy (n = 55)

FLOLAN In = 50)

Conventional Therapy (n = 48)

1.9

2.2

0.5“

-0.1

PAPm (nun Hg) RAPm (mm Hg)

51

49

-5“

1

13

11

-1*

1

PVR (Wood U)

14

11

-5’

1

SAPm (mm Hg)

93

89

-8“

-1

Cl (L/min/m2)

y

FLOLAN for injection

0.5-mg (500,000 ng) per vial, carton of 1

NDC 0173-0517-00

1.5-mg (1,500,000 ng) per vial, carton of 1

NDC 0173-0519-00

STERILE DILUENT for FLOLAN

50 mL per vial, carton of 2

NDC 0173-0518-01

pH 12 STERILE DILUENT for FLOLAN

50 mL per vial, carton of 2

NDC 0173-0857-02

14.2

Chronic infusion in PAH/SSD

Hemodynamic Effects Chronic continuous infusions of FLOLAN in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing FLOLAN plus con¬ ventional therapy (n = 56) with conventional therapy alone in = 55). Except for 5 NYHA Functional Class II patients, all patients were either functional Class III or Class IV.In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. Dur¬ ing the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on Day 7 of treatment. At the end of Week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks. Conventional therapy varied among patients and included some or all of the following anticoagulants in essentially all patients, supplemental oxygen and diuretics in two-thirds of the patients, oral vasodilators in 40% of the patients, and diguxin in a third of the patients. A statistically significant increase in Cl, and statistically significant decreases in PAPm. RAPm. PVR. and SAPm after 12 weeks of treatment were observed in patients who received FLOLAN chroni¬

Free

cally compared with those who did not. Table 5 illustrates the treatment-related hemodynamic changes in these pa¬ tients after 12 weeks of treatment. [See table 5 above) Clinical Effects Statistically significant improvement was observed in exer¬ cise* capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous FLOLAN plus conven¬ tional therapy for 12 weeks compared with those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. In¬ creases in exercise capacity were accompanied by statisti¬ cally significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At Week 12. NYHA functional class improved in 21 of 51 (41%) patients treated with FLOLAN compared with none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%) with FLOLAN and 35/48 [73%) with conven¬ tional therapy alone) showed no change in functional class, and 2/51 (4%i with FLOLAN and 13/48 (27%) with conven¬ tional therapy alone worsened. No statistical difference in survival over 12 weeks was ob¬ served in PAH/SSD patients treated with FLOLAN as com¬

mobilePDR

Storage and Handling

Proper storage and handling are essential to maintain the potency of FLOLAN for injection. Unopened vials of FLOLAN powder are stable until the date indicated on the package when stored at room temperature, 15°C to 25°C (59°F to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for FLOLAN and pH 12 STERILE DILUENT for FLOLAN are stable until the date indicated on the package when stored at room tem¬ perature, 15°C to 25“C (59°F to 77“F). DO NOT FREEZE. 17

“Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy (n is the number of patients with hemodynamic data). Cl = Cardiac index, PAPm = Mean pulmonary arterial pressure, RAPm = Mean right arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure.

How Supplied

FLOLAN for injection is supplied as a sterile freeze-dried powder in 17-mL flint glass vials with gray butyl rubber clo¬ sures. STERILE DILUENT for FLOLAN is supplied in flint glass vials containing 50-mL diluent with fluororesin-faced butyl rubber closures with aluminum overseal and yellow plastic flip-off cap. pH 12 STERILE DILUENT for FLOLAN is supplied in plas¬ tic vials containing 50-mL diluent with fluororesin-faced bu¬ tyl rubber closures with aluminum overseal and lavender plastic flip-off cap. [See third table above)

16.2 Table 5. Hemodynamics during Chronic Administration of FLOLAN in Patients with PAH/SSD

HOW SUPPLIED/STORAGE AND HANDLING

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient Information). Advise patients: • FLOLAN must be reconstituted only with STERILE DIL¬ UENT for FLOLAN or pH 12 STERILE DILUENT for FLOLAN. • Reconstituted solution prepared with STERILE DILU¬ ENT for FLOLAN must be used with a cold pouch if not administered within 8 hours. • Reconstituted solutions prepared with pH 12 STERILE DILUENT for FLOLAN do NOT require use with a cold pouch. • FLOLAN is infused continuously through a permanent in¬ dwelling central venous catheter via a small, portable in¬ fusion pump. Thus, therapy with FLOLAN requires com¬ mitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in pre¬ paring the drug and in the care of the catheter, and even brief interruptions in the delivery of FLOLAN may result in rapid symptomatic deterioration. A patient’s decision to receive FLOLAN should be based upon the understanding that there is a high likelihood that therapy with FLOLAN will be needed for prolonged periods, possibly years. Con¬ sider the patient's ability to accept and car* for a perma¬ nent intravenous catheter and infusion pump. • Tb adjust infusion rates of FLOLAN only under the direc¬ tion of a physician. • Tb avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. • To contact their healthcare providers if any unusual bruis¬ ing or bleeding develops. FLOLAN is a registered trademark of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 02015, the GSK group of companies. All rights reserved. FLU4PI PATIENT INFORMATION

FLOLAN* (flow-lan) lepoprostenol sodium) for injection Read this Patient Information before you start taking FLOLAN and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical con¬ dition or treatment. What is FLOLAN? FLOLAN is a prescription medicine used to treat people with certain types of pulmonary arterial hypertension

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938/GLAXOSMITHKLINE • FLOLAN (PAH), which is high blood pressure in the arteries of the lungs. FLOLAN can improve your ability to be physically active. It is not known if FLOLAN is safe and effective in children. Who should not use FLOLAN? Do not use FLOLAN if you:

• have certain types of heart failure: Talk to your healthcare provider before using FLOLAN if you have heart failure. • are allergic to FLOLAN or any of the ingredients in FLOLAN. See the end of this leaflet for a complete list of ingredients in FLOLAN. What should I tell my healthcare provider before using FLOLAN? Before you use FLOLAN, tell your healthcare provider if you:

• are allergic to any medicine. • are pregnant or plan to become pregnant. It is not known if FLOLAN will harm your unborn baby. You and your healthcare provider should decide if you will use FLOLAN. • are breastfeeding or plan to breastfeed. It is not known if FLOLAN passes into your breast milk. You and your healthcare provider should decide if you will take FLOLAN or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medi¬

cines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: • a “water pill” (diuretic) • a medicine for high blood pressure (hypertension) • a blood thinner medicine (antiplatelet or anticoagulant medicine) Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine. How should I use FLOLAN?

• FLOLAN should only be given by infusion through a cath¬ eter placed in a vein (intravenous infusion) using an infu¬ sion pump. • Your first treatment will be given to you by your health¬ care provider or nurse. This is so your healthcare provider can monitor you and find the best dose for you. • If your healthcare provider decides that you or your care¬ giver can give infusions of FLOLAN at home, you or your caregiver will receive training on the right way to mix and infuse FLOLAN. Do not try to infuse FLOLAN until you have been shown the right way to infuse FLOLAN by your healthcare provider. • Treatment will be needed for a long period of time, possi¬ bly years. You must be able to accept and care for a cath¬ eter and infusion pump in order to be treated with FLOLAN. • Use FL01AN exactly as your healthcare provider tells you to. • Do not change your dose or stop your infusion without talking to your healthcare provider. Stopping FLOLAN suddenly can cause serious side effects. • You should have a backup infusion pump and extra supplies needed for your infusion of FLOLAN. • Follow your healthcare provider’s instructions for taking blood thinner medicines, if prescribed for you. • Before you use FLOLAN, you must mix (reconstitute) FLOLAN powder with a diluent. There are 2 different types of diluents: . STERILE DILUENT for FLOLAN (comes in a glass bottle) • pH 12 STERILE DILUENT for FLOLAN (comes in a plastic bottle)

Do not mix FLOLAN with any other diluent. You must use STERILE DrLUENT for FLOLAN or pH 12 STER¬ ILE DILUENT for FLOLAN. See "How should I store and use FLOLAN?" for more in¬ formation about how to use and store FLOLAN the right way. • A mixed solution of FLOLAN is clear and colorless. Do not use FLOLAN if the mixed solution looks discolored or cloudy, or if the solution has flakes or particles in it. LIsing more than the prescribed dose of FLOLAN can lead to death If you use more than the prescribed dose of FLOIAN, call your healthcare provider or go to the nearest emergency room right away.

velop worsening symptoms of your PAH, including short¬ ness of breath, dizziness, weakness, or loss of strength. • Widening of your blood vessels (vasodilation). Vasodila¬ tion reactions can happen after you start FLOLAN. These reactions are common and may cause low blood pressure (hypotension), flushing, nausea, vomiting, dizziness, and headache. Your healthcare provider should check your blood pressure regularly during treatment with FLOLAN, especially when you start FLOLAN and after your dose is changed. • Increased risk for bleeding.FLOLAN affects how well your blood clots, so your risk for bleeding is increased. This is especially true if you have other risk factors for bleeding. Tell your healthcare provider if you develop any unusual bruising or bleeding. The most common side effects of FLOLAN include: • dizziness • jaw pain • headache • muscle or bone pain • nausea or vomiting Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of FLOLAN. For more information, ask your healthcare provider or pharma¬ cist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This leaflet summarizes the most important information about FLOIAN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about FLOLAN that is written for health professionals. For more information, go to www.FLOLAN.com or call 1-888-825-5249. What are the ingredients in FLOLAN? Active ingredient: epoprostenol sodium. Inactive ingredients: glycine, mannitol, sodium chloride.

Sodium hydroxide may have been added. The STERILE DILUENT for FLOLAN and the pH 12 STERILE DILUENT for FLOLAN contain: glycine, sodium chloride, sodium hydroxide, and Water for Injection. This Patient Information has been approved by the U.S. Food and Drug Administration. GlaxoSmithKline Research Triangle Park, NC 27709 FLOLAN is a registered trademark of the GSK group of companies. ©2015, the GSK group of companies. All rights reserved. Revised: April/2015 FLL:1PIL

FLOVENT DISKUS 50 meg [flo'vent]

How should I store and use FLOLAN?

(fluticasone propionate inhalation

• Store FLOLAN powder at room temperature between 59°F to 77°F (15°C to 25°C). • Protect FLOLAN powder from light. Keep unopened vial of FLOLAN in the carton until you are ready to mix. • Store the STERILE DILUENT for FLOIAN and the pH 12 STERILE DILUENT for FLOLAN at room tempera¬ ture, 59"F to 77°F (15°C to 25°C). Do not freeze.

powder, 50 meg)

• Vials of STERILE DILUENT for FLOLAN. and pH 12 STER¬ ILE DILUENT for FLOLAN are for one-time use only.

(fluticasone propionate inhalation

Throw away any unused diluent. • Throw away any vials of FLOLAN powder, STERILE DIL¬ UENT for FLOLAN, and pH 12 STERILE DILUENT for FLOLAN that are out of date or that you no longer need. How to store mixed solutions of FLOLAN:

• Once FLOIAN and the diluent are mixed together, you may use right away or store in the refrigerator. Refriger¬ ate at 36°F to 46°F (2°C to 8°C). • Protect the mixed solution of FLOLAN from light until you are ready to use it. • Do not freeze mixed solutions. Throw away any mixed solution that has been frozen. If you are using STERILE DILUENT for FLOLAN (comes in a glass bottle) for mixing: • If the mixed solution will be used at room temperature: • Use the mixed solution over a period of no longer than 8 hours after mixing if not stored in the refrigerator

• If the mixed solution has been stored in the refrigerator, infuse it over a period of no longer than 8 hours after re¬ moving it from the refrigerator. • You may store the mixed solution for up to 40 hours in the

refrigerator. • Throw away any mixed solution if it has been refrigerated for more than 40 hours. • If the mixed solution will be used with a cold pouch: • You may store the mixed solution in the refrigerator for up to 24 hours.

• Take the mixed solution out of the refrigerator and use it with the cold pouch over a period of no longer than 24 hours. Change the cold pouch every 12 hours. The mixed solution may be kept either in the refrigerator

FLOVENT DISKUS 100 meg

I*

(fluticasone propionate inhalation powder, 100 meg)

FLOVENT DISKUS 250 meg

R

powder, 250 meg) FOR ORAL INHALATION HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLOVENT DISKUS safely and effectively See full pre¬ scribing information for FLOVENT DISKUS. FLOVENT DISKUS 50 meg (fluticasone propionate inhalation powder, 50 meg) FLOVENT DISKUS 100 meg (fluticasone propionate inhalation powder, 100 meg) FLOVENT DISKUS 250 meg (fluticasone propionate inhalation powder, 250 meg) FOR ORAL INHALATION USE Initial U.S. Approval: 1994

-INDICATIONS AND USAGEFLOVENT DISKUS is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. (1) • Treatment of asthma in patients requiring oral cortico¬ steroid therapy. (1 > Important limitation: • Not indicated for the relief of acute bronchospasm. (11 -DOSAGE AND ADMINISTRATIONFor oral inhalation only. Dosing is based on prior asthma therapy. (2)

Previous

Recommended

Therapy

Starting Dosage

or in the cold pouch, or a combination of the two, for no

Highest Recommended Dosage

more than 48 hours. After 48 hours, throw away any mixed solution. If you are using pH 12 STERILE DILUENT for FLOLAN

Patients aged 12

(comes in a plastic bottle) for mixing:

Bronchodilators alone Inhaled corticosteroids Oral corticosteroids

• Freshly prepared mixed solutions may be stored in the re¬ frigerator for up to 8 days • Mixed solutions (freshly prepared or taken out of the re¬ frigerator) are stable for up to 3 days at 77°F 125“C), up to 2 days at 86°F (30°C), up to 1 day at 95°F 135*0 or up to 12 hours at 104°F (40*0. • FLOLAN mixed with pH 12 STERILE DILUENT for FLOLAN does not require use with a cold pouch.

years and older

Patients aged 4-11 years

100 meg twice daily 100-250 meg twice daily 500-1.000 meg twice daily 50 meg twice daily

500 meg twice daily 500 meg twice daily 1,000 meg twice daily 100 meg twice daily

• Throw away any mixed solution if it has been refrigerated for more than 8 days.

What are the possible side effects of FLOLAN? FLOLAN can cause serious side effects, including:

• Fluid in your lungs (pulmonary edema) If you develop pulmonary edema after starting FLOIAN, your health¬ care provider will stop your treatment and you should not receive FLOIAN again.

Keep FLOLAN and all medicines out of the reach of chil¬

-DOSAGE FORMS AND STRENGTHS-

dren.

Inhalation Powder. Inhaler containing fluticasone propionate (50, 100, or 250 meg) as a powder formulation for oral inhalation. (3)

• Worsening symptoms of pulmonary arterial hypertension

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use FLOIAN for a condition for which it was not prescribed. Do not give FLOLAN to other people, even if they have the same symptoms you have. It may harm them.

(PAH) with a sudden decrease in the dose of FLOLAN Do

not change your dose of FLOLAN or stop your infusion without talking to your healthcare provider. If you sud¬ denly stop or decrease your dose of FLOLAN you may de¬

General information about the safe and effective use of FLOLAN

-CONTRAINDICATIONS• Primary' treatment of status asthmaticus or acute epi¬ sodes of asthma requiring intensive measures. i4> • Severe hypersensitivity to milk proteins.

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Look for PDR drug information and services in your EHR -WARNINGS AND PRECAUTIONS• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.1) • Potential worsening of infections (e.g.. existing tuberculo¬ sis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections.More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.3) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from sys¬ temic corticosteroids if transferring to FLOVENT DISKUS. (5.4) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue FLOVENT DISKUS slowly. (5.5) • Assess for decrease in bone mineral density initially and periodically thereafter. (5.7) • Monitor growth of pediatric patients. (5.8) • Close monitoring for glaucoma and cataracts is warranted. (5.9)

-ADVERSE REACTIONSMost common adverse reactions (incidence >3%) include up¬ per respiratory tract infection or inflammation, throat irri¬ tation, sinusitis, rhinitis, oral candidiasis, nausea and vom¬ iting, gastrointestinal discomfort, fever, cough, bronchitis, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch.

-DRUG INTERACTIONSStrong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects (7.1)

FLOVENT DISKUS • GLAXOSMITHKLINE/939 FULL PRESCRIBING INFORMATION

1

2

Table 1. Recommended Dosages of FLOVENT DISKUS NOTE:

Revised: 5/2014

In all patients, it is desirable to titrate to the

lowest effective dosage once asthma stability is achieved.

Hepatic impairment: Monitor patients for signs of in¬ creased drug exposure. (8.6)

17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

DOSAGE AND ADMINISTRATION

Flovent DISKUS should be administered by the orally in¬ haled route only in patients aged 4 years and older. After inhalation, the patient should rinse his/her mouth with wa¬ ter without swallowing to help reduce the risk of oropharyn¬ geal candidiasis. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. After asthma stability has been achieved, it is always desir¬ able to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of FLOVENT DISKUS when adminis¬ tered in excess of recommended dosages have not been es¬ tablished. The recommended starting dosage and the highest recom¬ mended dosage of FLOVENT DISKUS, based on prior asthma therapy, are listed in Table 1.

-USE IN SPECIFIC POPULATIONS-

See

INDICATIONS AND USAGE

FLOVENT® DISKUS® is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. It is also indicated for patients re¬ quiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their re¬ quirement for oral corticosteroids over time. Important Limitation of Use: FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

Previous

Recommended

Therapy

Starting Dosage

Highest Recommended Dosage

Adult and adolescent patients (aged 12 years and older)

FULL PRESCRIBING INFORMATION: CONTENTS*

1 2 3 4 5

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Local Effects of Inhaled Corticosteroids 5.2 Acute Asthma Episodes 5.3 Immunosuppression 5.4 Transferring Patients From Systemic Cortico¬ steroid Therapy 5.5 Hypercorticism and Adrenal Suppression 5.6 Immediate Hypersensitivity Reactions 5.7 Reduction in Bone Mineral Density 5.8 Effect on Growth 5.9 Glaucoma and Cataracts 5.10 Paradoxical Bronchospasm 5.11 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors 5.12 Eosinophilic Conditions and Churg-Strauss Syndrome

6

ADVERSE REACTIONS 6.1 6.2

Clinical Trials Experience Postmarketing Experience

7

DRUG INTERACTIONS

8

USE IN SPECIFIC POPULATIONS

7.1 8.1 8.3 8.4 8.5 8.6 8.7

10 11 12

Pregnancy Nursing Mothers Pediatric Use Geriatric Lise Hepatic Impairment Renal Impairment

OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 12.2 12.3

13

Inhibitors of Cytochrome P450 3A4

Mechanism of Action Pharmacodynamics Pharmacokinetics

NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14

16 17

Bronchodilators 100 meg twice alone daily Inhaled 100-250 meg twice corticosteroids daily* Oral 500-1,000 meg corticosteroids'* 1 11 twice daily*

500 meg daily 500 meg daily 1,000 meg daily

Pediatric patients (aged

50 meg twice daily*

100 meg twice daily

4-11 yearsr

“Starting dosages above 100 meg twice daily for adult and adolescent patients and 50 meg twice daily for pediatric patients aged 4 to 11 years may be considered for patientB with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for the specific agent. bFor patients currently receiving chronic oral corticosteroid therapy, prednisone should be reduced no faster than 2.5 to 5 mg/day on a weekly basis beginning after at least 1 week of therapy with FLOVENT DISKUS. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency [see Warnings and Precautions (5.4)|. Once prednisone reduction is complete, the dosage of FLOVENT DISKUS should be reduced to the lowest effective dosage. The choice of starting dosage should be made on the basis of individual patient assessment. A controlled clinical trial of 111 oral corticosteroid-dependent subjects with asthma showed few significant differences between the 2 doses of FLOVENT DISKUS on safety and efficacy endpoints. However, inability to decrease the dose of oral corticosteroids further during corticosteroid reduction may be indicative of the need to increase the dose of fluticasone propionate up to the maximum of 1,000 meg twice daily. “Because individual responses may vary, pediatric patients previously maintained on other inhaled corticosteroids may require dosage adjustments upon transfer to FLOVENT DISKUS.

3

14.1 Adult and Adolescent Subjects Aged 12 Years and Older 14.2 Pediatric Subjects Aged 4 to 11 Years

Inhalation Powder. Inhaler containing a foil blister strip of powfler formulation for oral inhalation. The strip contains fluticasone propionate 50, 100, or 250 meg per blister.

* Sections or subsections omitted from the full prescribing information are not listed

func¬ tion. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most suscep¬ tible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although FLOVENT DISKUS may control asthma symptoms during these epi¬ sodes, in recommended doses it supplies leBS than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is nec¬ essary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for fur¬ ther instruction These patients should also be instructed to carry a warning card indicating that they may need supple¬ mentary systemic corticosteroids during periods of stress or a severe asthma attack Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS. Prednisone reduction can be accom¬ plished by reducing the daily prednisone dose by 2 5 mg on a weekly basis during therapy with FLOVENT DISKUS Lung function (mean forced expiratory volume in 1 second (FEV,) or morning peak expiratory flow (AM PEF)>, betaagonist use. and asthma symptoms should be carefully mon¬ itored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adre¬ nal insufficiency, such as fatigue, lassitude, weakness, nau¬ sea and vomiting, and hypotension

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940/GLAXOSMITHKLINE • FLOVENT DISKUS

Table 2 Adverse Reactions With FLOVENT DISKUS With >3% Incidence and More Common Than Placebo in Subjects With Asthma

Adverse Event

FLOVENT

FLOVENT

FLOVENT

FLOVENT

DISKUS

DISKUS

DISKUS

DISKUS

50 meg Twice

100 meg

250 meg Twice

Daily

Twice Daily

Daily

500 meg Twice Daily (n = 64)

%

In = 305) %

(n = 86)

%

%

20 13 9 5 4 . respectively, after coadministration of ketoconazole with orally inhaled fluticasone propionate. This increase in plasma fluticasone propionate concentra¬ tion resulted in a decrease (45% ) in serum cortisol AUC.

Erythromycin: In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 meg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinet¬ ics. 13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

Fluticasone propionate demonstrated no tumorigenic poten¬ tial in mice at oral doses up to 1,000 meg/kg (approximately 2 and 10 times the MRHDID for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 meg/kg (approximately 0.2 times and approximately equivalent to the MRHDID for adults and children aged 4 to 11 years, respectively, on a mg/m2 basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in pro¬ karyotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lympho¬ cytes in vitro or in the in vivo mouse micronucleus test. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 50 meg/kg ( ap¬ proximately 0.2 times the MRHDID for adults on a mg/m2 basis). Prostate weight was significantly reduced. 14

CLINICAL STUDIES

14.1

Adult and Adolescent Subjects Aged 12 Years and

Older

Four randomized, double-blind, parallel-group, placebocontrolled, US clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma. Fixed dosages of 100, 250, and 500 meg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily inhaled corticoster¬ oids. All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily. Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEY] prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 meg twice daily) and placebo from the four 12-week trials in adolescents and adults. These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV, re¬ sult, including most patients’ lung function data) are also displayed. Pulmonary function, as determined by percent change from baseline in FEV, at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 meg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone

■ FLOVENT DISKUS 100 meg twice daily (Baseline FEV, - 2.60 L)

Figure 2. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 meg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids

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Look for PDR drug information and services in your EHR Figure 3. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 meg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone

Week

Figure 4. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 meg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone

FLOVENTDISKUS • GLAXOSMITHKLINE/943 open-label extension. Data from this open-label extension suggested that lung function improvements could be main¬ tained up to 1 year. 16

17

In all 4 efficacy trials, measures of pulmonary function (FEV',) were statistically significantly improved as com¬ pared with placebo at all twice-daily doses. Subjects on all dosages of FLOVENT DISKUS were also less likely to dis¬ continue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy in¬ cluding lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo. In a clinical trial of 111 subjects with severe asthma requir¬ ing chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 meg twice daily was evaluated. Both doses enabled a statistically signifi¬ cantly larger percentage of subjects to wean from oral pred¬ nisone as compared with placebo (75% of the subjects on 500 meg twice daily and 89% of the subjects on 1,000 meg twice daily as compared with 9% of subjects on placebo). Ac¬ companying the reduction in oral corticosteroid use, sub¬ jects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group. 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS). approximately half of whom were receiving inhaled cortico¬ steroids at baseline. In this trial, doses of fluticasone propionate inhalation powder 50 and 100 meg twice daily significantly improved FEV, (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change). AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 meg twice daily (26% and 27% change from baseline at Endpoint, respec¬ tively) compared with placebo (14% change). In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as de¬ fined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma). Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approxi¬ mately half of whom were receiving inhaled corticosteroids at baseline. In these trials, FLOVENT DISKUS was effica¬ cious at doses of 50 and 100 meg twice daily when compared with placebo on major endpoints including lung function and symptom scores. Pulmonary function improved signifi¬ cantly compared with placebo by the first week of treat¬ ment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue tnal participation due to asthma deterioration. One hundred ninety-two (192) sub¬ jects received FLOVENT DISKUS for up to 1 year during an

HOW SUPPLIED/STORAGE AND HANDLING

FLOVENT DISKUS 50 meg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch iNDC 0173-0600-02). FLOVENT DISKUS 100 meg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02). FLOVENT DISKLTS 100 meg is also supplied in an institu¬ tional pack containing 28 blisters (NDC 0173-0602-00). FLOVENT DISKUS 250 meg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02). FLOVENT DISKUS 250 meg is also supplied in an institu¬ tional pack containing 28 blisters (NDC 0173-0601-00). Store at room temperature between 68°F and 77“F (20°C and 25°C); excursions permitted from 59°F to 86“F (15°C to 30°C) (See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children. FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard FLOVENT DISKUS 6 weeks (50-meg strength' or 2 months (100- and 250-mcg strengths) after opening the foil pouch or when the counter reads “0” (after all blisters have been used), which¬ ever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart. PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient Information and Instructions for Use). Local Effects: Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) anti¬ fungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water without swallowing after inhalation is advised to help re¬ duce the risk of thrush. Status Asthmaticus and Acute Asthma Symptoms: Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2agonist such as albuterol. Instruct patients to contact their physicians immediately if there is deterioration of their asthma. Immunosuppression: Warn patients who are on immuno¬ suppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their phy¬ sicians without delay. Inform patients of potential worsen¬ ing of existing tuberculosis; fungal, bacterial, viral, or par¬ asitic infections; or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Addition¬ ally, inform patients that deaths due to adrenal insuffi¬ ciency have occurred during and after transfer from sys¬ temic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS. Immediate Hypersensitivity Reactions: Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS. Patients should discontinue FLOVENT DISKUS if such reactions occur. There have been reports of anaphy¬ lactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take FLOVENT DISKUS. Reduction in Bone Mineral Density: Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity: Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS. may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route. Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. Use Daily for Best Effect: Patients should use Flovent DISKUS at regular intervals as directed Individual pa¬

tients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved un¬ til treatment has been administereef for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not im¬ prove or if the condition worsens. Instruct patients not to stop use of FLOVENT DISKUS abruptly. Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS. DISKHALER, DISKUS, FLOVENT. and ROTADISK are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. FLD:8PI Patient Information FLOVENT® DISKUS®/f/6‘ vent disk' us) 50 meg (fluticasone propionate inhalation powder, 50 meg) FLOVENT® DISKUS® 100 meg (fluticasone propionate inhalation powder, 100 meg) FLOVENT® DISKUS® 250 meg (fluticasone propionate inhalation powder, 250 meg)

Read the Patient Information that comes with FLOVENT DISKUS before you start using it and each time you get a refill. There may be new information. This Patient Informa¬ tion does not take the place of talking to your healthcare provider about your medical condition or treatment. What is FLOVENT DISKUS?

FLOVENT DISKUS is a prescription inhaled corticosteroid (ICS) medicine for the long-term treatment of asthma in people aged 4 years and older. • ICS medicines such as fluticasone propionate help to de¬ crease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. • FLOVENT DISKLTS is not used to relieve sudden breath¬ ing problems. • It is not know n if FLOVENT DISKUS is safe and effective in children younger than 4 years of age. Who should not use FLOVENT DISKUS?

Do not use FLOVENT DISKUS if you: • have a severe allergy to milk proteins. Ask your health¬ care provider if you are not sure. • are allergic to fluticasone propionate or any of the ingre¬ dients in FLOVENT DISKUS. See “What are the ingredi¬ ents in FLOVENT DISKUS?” below for a complete list of ingredients. What should I tell my healthcare provider before using FLOVENT DISKUS? Tell your healthcare provider about all of your health con¬ ditions, including if you:

• • • • •

• • • •

•

have liver problems. have weak bones (osteoporosis). have an immune system problem. have eye problems such as glaucoma or cataracts are allergic to any of the ingredients in FLOVENT DISKUS, any other medicines, or food products See “What are the ingredients in FLOVENT DISKUS?" below for a complete list of ingredients. have any type of viral, bacterial, or fungal infection are exposed to chickenpox or measles. have any other medical conditions. are pregnant or planning to become pregnant It is not known if FLOVENT DISKUS may harm your unborn baby. are breastfeeding It is not know n if the medicine in FLOVENT DISKUS passes into your milk and if it can harm your baby.

Tell your healthcare provider about all the medicines you

take.induding prescription and over-the-counter medicines, vitamins, and herbal supplements. FLOVENT DISKUS and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your health¬ care provider if you take antifungal or anti-HIV7 medicines. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use FLOVENT DISKUS? Read the step-by-step instructions for using FLOVENT DISKUS at the end of this Patient Information.

• Do not use FLOVENT DISKUS unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. • Children should use FLOVENT DISKUS with an adult* help, as instructed by the child’s healthcare provider • Flovent DISKUS comes in 3 different strength* Your healthcare provider prescribed the strength that is best for you. • Use FLOVENT DISKUS exactly as your healthcare pro¬ vider tells you to use it Do not use FLOVENT DISKUS more often than prescribed. • It may take 1 to 2 weeks or longer after you start FLOVENT DISKUS for your asthma symptoms to get bet ter. You must use FLOVENT DLSKUS regularly

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944/GLAXOSMITHKLINE • FLOVENT DISKUS • Do not stop using FLOVENT DISKUS, even if you are feeling better, unless your healthcare provider tells you to. • If you miss a dose of FLOVENT DISKUS, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at 1 time. • FLOVENT DISKUS does not relieve sudden symptoms.

Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you. • Call your healthcare provider or get medical care right away ifi • your breathing problems get worse.' • you need to use your rescue inhaler more often than usual. • your rescue inhaler does not work as well to relieve your symptoms. • you need to use 4 or more inhalations of your rescue in¬ haler in 24 hours for 2 or more days in a row. • you use 1 whole canister of your rescue inhaler in 8 weeks. • your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.

scribed. Do not give your FLOVENT DISKUS to other peo¬ ple, even if they have the same condition that you have. It may harm them. This Patient Information leaflet summarizes the most im¬ portant information about FLOVENT DISKUS. If you would like more information, talk with your healthcare pro¬ vider or pharmacist. You can ask your healthcare provider or pharmacist for information about FLOVENT DISKUS that was written for healthcare professionals. For more information about FLOVENT DISKUS, call 1-888825-5249 or visit our website at www.floventdiskus.com. What are the ingredients in FLOVENT DISKUS?

Active ingredient; fluticasone propionate Inactive ingredient: lactose monohydrate (contains milk proteins) Instructions for Use For Oral Inhalation Only Your FLOVENT DISKUS inhaler

Figure C DISKUS level and away from your mouth. See Figure D. Do not breathe into the mouthpiece.

Outer Counter

What are the possible side effects with FLOVENT DISKUS? FLOVENT DISKUS can cause serious side effects, including:

• fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using FLOVENT DISKUS to help reduce your chance of getting thrush. Thumbgrlp

• weakened immune system and increased chance of get¬ ting infections (immunosuppression) • reduced adrenal function (adrenal insufficiency). Adrenal

insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an inhaled steroid (such as FLOVENT DISKUS). When your body is under stress such as from fever, trauma (such as a car accident), infection, or surgery, adrenal insufficiency can get worse and may cause death. Symptoms of adrenal insufficiency include: • feeling tired • lack of energy • weakness • nausea and vomiting • low blood pressure • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction: • rash • hives • swelling of your face, mouth, and tongue • breathing problems

Lever

Figure A Read

this

information

before

you

start

using

your

• Take FLOVENT DISKUS out of the foil pouch just before you use it for the first time. .Safely throw away the pouch. The DISKUS will be in the closed position. • Write the date you opened the foil pouch in the first blank line on the label. See Figure A. • Write the “use by” date in the second blank line on the label. See Figure A. If you are using FLOVENT DISKUS 50 meg, that date is 6 weeks after the date you wrote in the first line. If you are using FLOVENT DISKUS 100 meg or 250 meg, that date is 2 months after the date you wrote in the first line. • The counter should read 60. If you have a sample (with “Sample” on the back label) or institutional (with “INSTI¬ TUTIONAL PACK” on the foil pouch) pack, the counter should read 28.

• bone thinning or weakness (osteoporosis) • slowed growth in children. A child’s growth should be

How to use your FLOVENT DISKUS inhaler Follow these steps every time you use FLOVENT DISKUS.

checked often. • eye problems including glaucoma and cataracts. You should have regular eye exams while using FLOVENT DISKUS. • increased wheezing (bronchospasm). Increased wheezing can happen right away after using FLOVENT DISKUS. Always have a rescue inhaler with you to treat sudden wheezing.

Step 1. Open your FLOVENT DISKUS.

• Hold the DISKUS in your left hand and place the thumb of your right hand in the thumb grip. Push the thumb grip away from you as far as it will go until the mouthpiece shows and snaps into place. See Figure B.

• Keep FLOVENT DISKUS and all medicines out of the reach of children General information about FLOVENT DISKUS

Medicines are sometimes prescribed for purposes not men¬ tioned in a Patient Information leaflet Do not use FLOVENT DISKUS for a condition for which it was not pre-

Figure E • Remove the DISKUS from your mouth and hold your breath for about 10 seconds, or for as long as is comfort¬ able for you. • If your healthcare provider has told you to take more than 1 inhalation of FLOVENT DISKUS, repeat Steps 2 and 3. • The DISKLTS delivers your dose of medicine as a very fine powder that you may or may not taste or feel. Do not take an extra dose from the DISKUS even if you do not taste or feel the medicine.

• upper respiratory tract infection • throat irritation • nausea and vomiting • fever • headache Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the side effects with FLOVENT DISKUS. Ask your healthcare provider or pharmacist for more infor¬ mation. Call your doctor for medical advice about side effects. You mav report side effects to FDA at 1-800-FDA-1088. How should I store FLOVENT DISKUS?

Put the mouthpiece to your lips. See Figure E. Breathe in quickly and deeply through the DISKUS. Do not breathe in through your nose.

• Breathe out slowly as long as you can. See Figure D.

Common side effects of FLOVENT DISKUS Include:

• Store FLOVENT DISKUS at room temperature between 68'F and 77°F (20°C and 25°CT. Keep in a dry place away from heat and sunlight. • Store FLOVENT DISKUS in the unopened foil pouch and only open when ready for use. • Safely throw away FLOVENT DISKUS 50 meg in the trash 6 weeks after you open the foil pouch or when the counter reads 0. whichever comes first. • Safely throw away FLOVENT DISKL'S 100 meg and FLOVENT DISKUS 250 meg in the trash 2 months after you open the foil pouch or when the counter reads 0, whichever comes first.

Figure D

FLOVENT DISKUS inhaler:

Step 4. Close the DISKUS.

• Place your thumb in the thumb grip and slide it back to¬ wards you as far as it will go. See Figure F. Make sure the DISKUS clicks shut and you cannot see the mouthpiece.

Figure B Step 2. Slide the lever until you hear it click. • Hold the Diskus in a level, flat position with the mouth¬

piece towards you. Slide the lever away from the mouth¬ piece as far as it will go until it clicks See Figure C. (See figure C at top of next column) • The number on the counter will count down by 1. The DISKL’S is now' ready to use. Follow the instructions below so you will not accidentally waste a dose: Do not close the DISKUS • Do not close the DISKUS. • Do not tilt the DISKUS • Do not move the lever on the DISKL'S. Step 3. Inhale your medicine. • Before you breathe in your dose from the DISKUS, breathe out (exhale' as long as you can while you hold the

Figure F • The DISKUS is now ready for you to take your next sched¬ uled dose in about 12 hours. When you are ready to take your next dose, repeat Steps 1 through 4.

Step 5. Rinse your mouth. • Rinse your mouth with water after breathing in the med¬ icine. Spit out the water. Do not swallow it. See Figure G

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Figure G When should you get a refill?

The counter on top of the DISKUS shows you how man}’ doses are left. After you have taken 55 doses 123 doses from the sample or institutional pack), the numbers 5 to 0 will show in red. See Figure H. These numbers warn you there are only a few doses left and are a reminder to get a refill.

Figure H For correct use of the DISKUS, remember:

• Always use the DISKUS in a level, flat position. • Make sure the lever firmly clicks into place. • Hold your breath for about 10 seconds after inhaling. Then breathe out fully. • After each dose, rinse your mouth with water and spit it out. Do not swallow the water. • Do not take an extra dose, even if you did not taste or feel the powder. • Do not take the DISKUS apart. • Do not wash the DISKUS. • Always keep the DISKUS in a dry place. • Do not use the DISKUS with a spacer device. If you have questions about FLOVENT DISKUS or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-8255249 or visit www.floventdiskus.com. This Patient Information and Instructions for Use have been approved by the U S. Food and Drug Administration.

FLOVENT and DISKUS are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. April 2014 FLD:6PIL Patient Information FLOVENT* DISKUS*fWo' vent disk' us) 50 meg (fluticasone propionate inhalation powder, 50 meg) FLOVENT* DISKUS* 100 meg (fluticasone propionate inhalation powder, 100 meg) FLOVENT* DISKUS* 250 meg (fluticasone propionate inhalation powder, 250 meg)

Read the Patient Information that comes with FLOVENT DISKUS before you start using it and each time you get a refill. There may be new information. This Patient Informa¬ tion does not take the place of talking to your healthcare provider about your medical condition or treatment. What is FLOVENT DISKUS?

FLOVENT DISKLTS is a prescription inhaled corticosteroid (ICSI medicine for the long-term treatment of asthma in people aged 4 years and older. • ICS medicines such as fluticasone propionate help to de¬ crease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. • FLOVENT DISKUS is not used to relieve sudden breath¬ ing problems. • It is not known if FLOVENT DISKUS is safe and effective in children younger than 4 years of age. Who should not use FLOVENT DISKUS?

Do not use FLOVENT DISKUS if you: • have a severe allergy to milk proteins. Ask your health¬ care provider if you are not sure. • are allergic to fluticasone propionute or any of the ingre¬ dients in FLOVENT DISKUS. See "What are the ingredi¬ ents in FLOVENT DISKUS?" below for a complete list of ingredients.

FLOVENTDISKUS • GLAXOSMITHKLINE/945 What should I tell my healthcare provider before using FLOVENT DISKUS? Tell your healthcare provider about all of your health con¬ ditions, including if you: • have liver problems. • have weak bones (osteoporosis). • have an immune system problem. • have eye problems such as glaucoma or cataracts. • are allergic to any of the ingredients in FLOVENT DISKUS, any other medicines, or food products. See “What are the ingredients in FLOVENT DISKUS?” below for a complete list of ingredients. • have any type of viral, bacterial, or fungal infection. • are exposed to chickenpox or measles. • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if FLOVENT DISKUS may harm your unborn baby. • are breastfeeding. It is not known if the medicine in FLOVENT DISKUS passes into your milk and if it can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medi¬ cines, vitamins, and herbal supplements. FLOVENT DISKUS and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or antiHIV medicines. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use FLOVENT DISKUS? Read the step-by-step instructions for using FLOVENT DISKUS at the end of this Patient Information. • Do not use FLOVENT DISKUS unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. • Children should use FLOVENT DISKUS with an adult’s help, as instructed by the child’s healthcare provider. • Flovent DISKUS comes in 3 different strengths. Your healthcare provider prescribed the strength that is best for you. • Use FLOVENT DISKUS exactly as your healthcare pro¬ vider tells you to use it. Do not use FLOVENT DISKUS more often than prescribed. • It may take 1 to 2 weeks or longer after you start FLOVENT DISKUS for your asthma symptoms to get bet¬ ter. You must use FLOVENT DISKUS regularly. • Do not stop using FLOVENT DISKUS, even if you are feeling better, unless your healthcare provider tells you to. • If you miss a dose of FLOVENT DISKUS, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at 1 time. • FLOVENT DISKUS does not relieve sudden symptoms. Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you. • Call your healthcare provider or get medical care right away if: • your breathing problems get worse. • you need to use your rescue inhaler more often than usual. • your rescue inhaler does not work as well to relieve your symptoms. • you need to use 4 or more inhalations of your rescue in¬ haler in 24 hours for 2 or more days in a row. • you use 1 whole canister of your rescue inhaler in 8 weeks. • your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you. What are the possible side effects with FLOVENT DISKUS? FLOVENT DISKUS can cause serious side effects, including: • fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using FLOVENT DISKUS to help reduce your chance of getting thrush. • weakened immune system and increased chance of get¬ ting infections (immunosuppression) • reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an inhaled steroid (such as FLOVENT DISKUS). When your body is under stress such as from fever, trauma (such as a car accident i, infection, or surgery, adrenal insufficiency can get worse and may cause death. Symptoms of adrenal insufficiency include: • feeling tired • lack of energy • weakness • nausea and vomiting • low blood pressure • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction:

• • • •

rash hives swelling of your face, mouth, and longue breathing problems

• bone thinning or weakness (osteoporosis) • slowed growth in children. A child's growth should be

checked often. • eye problems including glaucoma and cataracts. You

should have regular eye exams while using FLOVENT DISKUS. • increased wheezing (bronchospasm). Increased wheezing can happen right away after using FLOVENT DISKUS. Always have a rescue inhaler with you to treat sudden wheezing. Common side effects of FLOVENT DISKUS include:

upper respiratory tract infection • upper respiratory tract infection • throat irritation • nausea and vomiting • fever • headache Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the side effects with FLOVENT DISKUS. Ask your healthcare provider or pharmacist for more infor¬ mation. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store FLOVENT DISKUS?

• Store FLOVENT DISKUS at room temperature between 68°F and 77°F (20°C and 25°C). Keep in a dry place away from heat and sunlight. • Store FLOVENT DISKUS in the unopened foil pouch and only open when ready for use. • Safely throw away FLOVENT DISKUS 50 meg in the trash 6 weeks after you open the foil pouch or when the counter reads 0, whichever comes first. • Safely throw away FLOVENT DISKUS 100 meg and FLOVENT DISKUS 250 meg in the trash 2 months after you open the foil pouch or when the counter reads 0. whichever comes first. • Keep FLOVENT DISKUS and all medicines out of the reach of children. General information about FLOVENT DISKUS

Medicines are sometimes prescribed for purposes not men¬ tioned in a Patient Information leaflet. Do not use FLOVENT DISKUS for a condition for which it was not pre¬ scribed. Do not give your FLOVENT DISKUS to other peo¬ ple, even if they have the same condition that you have. It may harm them. This Patient Information leaflet summarizes the most im¬ portant information about FLOVENT DISKUS. If you would like more information, talk with your healthcare pro¬ vider or pharmacist. You can ask your healthcare provider or pharmacist for information about FLOVENT DISKUS that was written for healthcare professionals. For more information about FLOVENT DISKUS, call 1-888825-5249 or visit our website at www.floventdiskus.com. What are the ingredients in FLOVENT DISKUS?

Active ingredient, fluticasone propionate Inactive ingredient: lactose monohydrate (contains milk proteins) Instructions for Use For Oral Inhalation Only Your FLOVENT DISKUS inhaler

Lever

Figure

A

Read this information before FLOVENT DISKUS inhaler:

you

start

using

your

• Take FLOVENT DISKUS out of the foil pouch just before you use it for the first time. Safely throw away the pouch. The DISKUS will be in the closed position • Write the date you opened the foil pouch in the first blank line on the label See Figure A • Write the "use by" date in the second blank line on the label See Figure A If you are using FLOVENT DISKUS 50 meg. that date is 6 weeks after the date you wrote on the first line. If you are using FLOVENT DISKUS 100 meg or 250 meg. that date is 2 months after the dale you wrote on the first line.

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946/GLAXOSMITHKLINE • FLOVENT DISKUS • The counter should read 60. If you have a sample (with “Sample” on the back label) or institutional (with “INSTI¬ TUTIONAL PACK” on the foil pouch) pack, the counter should read 28. How to use your FLOVENT DISKUS inhaler Follow these steps every time you use FLOVENT DISKUS. Step 1. Open your FLOVENT DISKUS. • Hold the DISKUS in your left hand and place the thumb of your right hand in the thumb grip. Push the thumb grip away from you as far as it will go until the mouthpiece shows and snaps into place. See Figure B.

• Remove the DISKUS from your mouth and hold your breath for about 10 seconds, or for as long as is comfort¬ able for you. • Breathe out slowly as long as you can. See Figure D. • If your healthcare provider has told you to take more than 1 inhalation of FLOVENT DISKUS, repeat steps 2 and 3. • The DISKUS delivers your dose of medicine as a very fine powder that you may or may not taste or feel. Do not take an extra dose from the DISKUS even if you do not taste or feel the medicine. Step 4. Close the DISKUS. • Place your thumb in the thumb grip and slide it back to¬ wards you as far as it will go. See Figure F. Make sure the DISKUS clicks shut and you cannot see the mouthpiece.

©2014, the GSK group of companies. All rights reserved. April 2014 FLD:6PIL

FLOVENT HFA 44 meg

5

[/Zb' vent] (fluticasone propionate 44 meg) Inhalation Aerosol

FLOVENT HFA 110 meg

5

(fluticasone propionate 110 meg) Inhalation Aerosol

FLOVENT HFA 220 meg

$

(fluticasone propionate 220 meg) Inhalation Aerosol For Oral Inhalation Only HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FLOVENT HFA safely and effectively. See full pre¬ scribing information for FLOVENT HFA. FLOVENT HFA 44 meg (fluticasone propionate 44 meg)

Figure B

Figure F Step 2. Slide the lever until you hear it click. • Hold the Diskus in a level, flat position with the mouth¬ piece towards you. Slide the lever away from the mouth¬ piece as far as it will go until it clicks. See Figure C.

• The DISKUS is now ready for you to take your next sched¬ uled dose in about 12 hours. When you are ready to take your next dose, repeat steps 1 through 4. Step 5. Rinse your mouth. • Rinse your mouth with water after breathing In the med¬ icine. Spit out the water. Do not swallow it. See Figure G.

Inhalation Aerosol FLOVENT HFA 110 meg (fluticasone propionate 110 meg) Inhalation Aerosol FLOVENT HFA 220 meg (fluticasone propionate 220 meg) Inhalation Aerosol FOR ORAL INHALATION Initial U S. Approval: 1994

-INDICATIONS AND USAGEFLOVENT HFA is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. (1) • Treatment of asthma in patients requiring oral cortico¬ steroid therapy. (1) Important limitation: • Not indicated for the relief of acute bronchospasm. 11) -DOSAGE AND ADMINISTRATIONFor oral inhalation only. Dosing is based on prior asthma therapy. (2) [See first table at top of next page] *

Figure C • The number on the counter will count down by 1. The DISKUS is now ready to use. Follow the instructions below so you will not accidentally waste a dose: Do not close the DISKUS. • Do not close the DISKUS. • Do not tilt the DISKUS. • Do not move the lever on the DISKUS. Step 3. Inhale your medicine. • Before you breathe in your dose from the DISKUS, breathe out (exhale) as long as you can while you hold the DISKUS level and away from your mouth. See Figure D. Do not breathe into the mouthpiece.

-DOSAGE FORMS AND STRENGTHSInhalation Aerosol. Inhaler containing fluticasone propionate (44, 110, or 220 meg) as an aerosol formulation for oral inhalation. (3) -CONTRAINDICATIONSWhen should you get a refill? The counter on top of the DISKUS shows you how many doses are left. After you have taken 55 doses (23 doses from the sample or institutional pack), the numbers 5 to 0 will show in red. See Figure H. These numbers warn you there are only a few doses left and are a reminder to get a refill.

Figure H For correct use of the DISKUS, remember:

Figure D • Put the mouthpiece to your lips. See Figure E. Breathe in quickly and deeply through the DISKUS. Do not breathe in through your nose.

Figure E

Siqn

• Always use the DISKUS in a level, flat position. • Make sure the lever firmly clicks into place. • Hold your breath for about 10 seconds after inhaling. Then breathe out fully. • After each dose, rinse your mouth with water and spit it out Do not swallow the water. • Do not take an extra dose, even if you did not taste or feel the powder. • Do not take the DISKL’S apart. • Do not wash the DISKUS. • Always keep the DISKUS in a dry place. • Do not use the DISKUS with a spacer device. If you have questions about FLOVENT DISKUS or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825i 5249 or visit www.floventdiskus.com. This Patient Information and Instructions for Use have been approved by the U S. Food and Drug Administration. FLOVENT and DISKUS are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park. NC 27709 ud

• Primary treatment of status asthmaticus or acute epi¬ sodes of asthma requiring intensive measures. (4) • Hypersensitivity to any ingredient. (4) -WARNINGS AND PRECAUTIONS• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.1) • Potential worsening of infections (e.g., existing tuberculo¬ sis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fata! course of chickenpox or measles can occur in susceptible patients. (5.3) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from sys¬ temic corticosteroids if transferring to FLOVENT HFA (5.4) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue FLOVENT HFA slowly. (5.5) • Assess for decrease in bone mineral density initially and periodically thereafter. (5.7) • Monitor growth of pediatric patients. (5.8) • Close monitoring for glaucoma and cataracts is warranted. (5.9) -ADVERSE REACTIONSMost common adverse reactions (incidence greater than 3%) are upper respiratory tract infection or inflammation, throat irritation, sinusitis, dysphonia, candidiasis, cough, bronchitis, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or 1-800-FDA-1088 or www.fda.gov/medwatch

FDA

at

-DRUG INTERACTIONSStrong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Uae not recommended. May increase risk of systemic corticosteroid effects. (7.1)

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FLOVENT HFA • GLAXOSMITHKLINE/947

-USE IN SPECIFIC POPULATIONSHepatic impairment: Monitor patients for signs of in¬ creased drug exposure. (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2014

Previous Therapy

1 2 3 4 5

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Local Effects of Inhaled Corticosteroids 5.2 Acute Asthma Episodes 5.3 Immunosuppression 5.4 Transferring Patients from Systemic Cortico¬ steroid Therapy 5.5 Hypercorticism and Adrenal Suppression 5.6 Immediate Hypersensitivity Reactions 5.7 Reduction in Bone Mineral Density 5.8 Effect on Growth 5.9 Glaucoma and Cataracts 5.10 Paradoxical Bronchospasm 5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors 5.12 Eosinophilic Conditions and Churg-Strauss Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Tbxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Adult and Adolescent Subjects Aged 12 Years and Older 14.2 Pediatric Subjects Aged 4 to 11 Years 16 IIOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

88 meg twice daily 88-220 meg twice daily 440 meg twice daily

440 meg twice daily 440 meg twice daily 880 meg twice daily

88 meg twice daily

88 meg twice daily

Patients aged 12 years and older

Bronchodilators alone Inhaled corticosteroids Oral corticosteroids

Table 1. Recommended Dosages of FLOVENT HFA Inhalation Aerosol NOTE:

FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGE

FLOVENT® HFA Inhalation Aerosol is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of these patients may be able to reduce or eliminate their requirement for oral corticosteroids over time. Important Limitation of Use: Flovent HFA is not indicated for the relief of acute bronchospasm.

FLOVENT HFA should be administered by the orally in¬ haled route only in patients aged 4 years and older, Alter inhalation, the patient should rinse his/her mouth with wa¬ ter without swallowing to help reduce the risk of oropharyn¬ geal candidiasis. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. After asthma stability has been achieved, it is always desir¬ able to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control. The safety and efficacy of FLOVENT HFA when administered in excess of recommended dosages have not been established. The recommended starting dosage and the highest recom¬ mended dosage of FLOVENT HFA, based on prior asthma therapy, are listed in Table 1. (See table 1 abovel Prime FLOVENT HFA before using for the first time by re¬ leasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the in¬

Recommended Starting Dosage

Highest Recommended Dosage

88 meg twice dailv 88-220 meg twice daily" 440 meg twice daily

440 meg twice dailv 440 meg twice daily 880 meg tw ice daily

88 meg twice daily

88 meg twice daily

Adult and adolescent patients (aged 12 years and older)

Bronchodilators alone Inhaled corticosteroids Oral corticosteroids1’ Pediatric patients (aged 4-11 years)’'

* Starting dosages above 88 meg twice daily may be considered for patients with poorer asthma control or those who have previously required doses of inhaled corticosteroids that are in the higher range for the specific agent. b For patients currently receiving chronic oral corticosteroid therapy, prednisone should be reduced no faster than 2.5 to 5 mg/day on a weekly basis beginning after at least 1 week of therapy with FLOVENT HFA. Patients should be carefully monitored for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency Isee Warnings and Precautions (5.4)]. Once prednisone reduction is complete, the dosage of FLOVENT HFA should be reduced to the lowest effective dosage. c Recommended pediatric dosage is 88 meg twice daily regardless of prior therapy. A valved holding chamber and mask may be used to deliver FLOVENT HFA to young patients.

haler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds and releasing 1 spray into the air away from the face. 3

DOSAGE FORMS AND STRENGTHS

Inhalation Aerosol. Dark orange plastic inhaler with a peach strapeap containing a pressurized mete red-dose aer¬ osol canister containing 120 metered inhalations and fitted with a counter. Each actuation delivers 44, 110, or 220 meg of fluticasone propionate from the mouthpiece. 4

CONTRAINDICATIONS

The use of FLOVENT HFA is contraindicated in the follow¬ ing conditions: • Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required Isee Warnings and Precautions (5.2)1. • Hypersensitivity to any of the ingredients /see Warnings and Precautions (5.6), Adverse Reactions (6.2). Description

(11)]. 5

WARNINGS AND PRECAUTIONS Local Effects of Inhaled Corticosteroids

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT HFA. When such an infection develops, it should be treated with appro¬ priate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT HFA continues, but at times therapy with FLOVENT HFA may need to be interrupted. Advise the patient to rinse his/her mouth with water with¬ out swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.2

DOSAGE .AND ADMINISTRATION

In all patients, it is desirable to titrate to the lowest effective dosage once asthma stability is achieved.

Previous Therapy

5.1

2

Highest Recommended Dosage

Patients aged 4-11 years

FULL PRESCRIBING INFORMATION: CONTENTS*

1

Recommended Starting Dosage

Acute Asthma Episodes

FLOVENT HFA is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Pa¬ tients should be instructed to contact their physicians im¬ mediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT HFA. During such episodes, patients may require therapy with oral corticosteroids. 5.3

Immunosuppression

Persons who are using drugs that suppress the immune sys¬ tem are more susceptible to infections than healthy indi¬ viduals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpux. prophylaxis with var¬ icella zoster immune globulin may be indicated. If a patient is exposed to measles, prophylaxis with pooled in¬ tramuscular immunoglobulin ilG) may be indicated. "See

the respective package inserts for complete VZIG and 1G prescribing information.! If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should lx- used with caution, if at all. in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.4 Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who have been trans¬ ferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hvpothalamic-pituitary-adrenal (HPAi func¬ tion. Patients who have been previously maintained on 20 mg or more of prednisone lor its equivalent) may be most suscep¬ tible. particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection lparticularly gastroenteritis) or other conditions associated with severe electrolyte loss Although FLOVENT HFA may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physio¬ logical amounts of glucocorticoid systemically and does NOT provide the mineralocortieoid activity that is neces¬ sary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians lor fur¬ ther instruction. These patients should also be instructi-d to carry a warning card indicating that they may need supple¬ mentary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring oral corticosteroids should Is- weaned slowly from systemic corticosteroid use after transferring to FLOVENT HFA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT HFA. Lung function (mean forced expiratory volume in 1 second |FEV,I or morn¬ ing peak expiratory flow |AM PEEL, beta-agonist use. and asthma symptoms should he cnrefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal in¬ sufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to FLOVENT HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e g., rhi¬ nitis, conjunctivitis, eczema, arthritis, eosinophilic condi¬ tions ). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticoster-

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948/GLAXOSMITHKLINE • FLOVENT HFA

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812 adult and adolescent subjects (457 females and 355 males) previously treated with as-needed bronchodilators and/or inhaled corticosteroids were treated twice daily for up to 12 weeks with 2 inhalations of FLOVENT HFA 44 meg FLOVENT HFA FLOVENT HFA FLOVENT HFA Inhalation Aerosol, FLOVENT HFA 110 meg Inhalation 440 meg 220 meg 88 meg Aerosol, FLOVENT HFA 220 meg Inhalation Aerosol (dos¬ Placebo Twice Daily Twice Daily Twice Daily ages of 88, 220, or 440 meg twice daily), or placebo. In = 203) (n = 202) (n = 204) (n = 203 [See table 2 above] % % % % Adverse Event Table 2 includes all events (whether considered drugrelated or nondrug-related by the investigator) that Ear, nose, and throat occurred at a rate of over 3% in any of the groups treated 14 16 16 18 Upper respiratory tract infection with FLOVENT HFA and were more common than in the 5 10 8 8 Throat irritation placebo group. Less than 2% of subjects discontinued from 1 5 5 2 Upper respiratory inflammation the trials because of adverse reactions. The average dura¬ 3 4 7 6 Sinusitis/sinus infection tion of exposure was 73 to 76 days in the active treatment 3% Incidence and More Common than Placebo in Subjects Aged 12 Years and Older with Asthma _

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FLOVENT HFA • GLAXOSMITHKLINE/949

marketing us*?, there have been reports of clinically signifi¬ cant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticoster¬ oid effects including Cushing’s syndrome and adrenal sup¬ pression. Ketoconazole: Coadministration of orally inhaled fluticasone propionate (1,000 meg) and ketoconazole • 200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no ef¬ fect on urinary excretion of cortisol. 8 8.1

Table 3. In Vitro Medication Delivery through AeroChamber Plus® Valved Holding Chamber with a Mask Mean Medication Delivery through Flow Rate

Holding Time

AeroChamber Plus VHC

(L/min)

(seconds)

(mcg/actuation)

(kg)*

6 to 12 Months

Small

4.9

0 2 5 10

8.3 6.7 7.5 7.5

75-9.9

0.8-1.1 0.7-0.9 0.8-1.0 0.8-1.0

2 to 5 Years

Small

8.0

0 2 5 10

7.3 6.8 6.7 7.7

12.3-18.0

0.4-0.6 0.4-0.6 0.4-0.5 0.4-0.6

2 to 5 Years

Medium

8.0

0 2 5 10

7.8 7.7 8.1 9.0

12.3-18.0

0.4-0.6 0.4-0.6 0.5-0.7 0.5-0.7

>5 Years

Medium

12.0

0 2 5 10

12.3 11.8 12.0 10.1

18.0

0.7 0.7 0.7 0.6

Actuation (mcg/kg)b

USE IN SPECIFIC POPULATIONS Pregnancy

8 Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50th percentile weight for boys and girls at the ages indicated. b A single inhalation of FLOVENT HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 44 meg, or 0.6 meg/kg.

Nursing Mothers

It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to iactating rats of tritiated fluticasone propionate at a dose approximately 0.05 times the MRHDID in adults on a mg/m basis resulted in measurable radioactivity in milk. Since there are no data from controll*?d trials on the use of FLOVENT HFA by nursing mothers, caution should he ex¬ ercised when FLOVENT HFA is administered to a nursing woman. 8.4

Medication Delivered per

Mask

Age

Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with FLOVENT HFA in pregnant women. Corticosteroids have been shown to be ter¬ atogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal repro¬ duction studies are not always predictive of human response, FLOVENT HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking FLOVENT HFA. Mice and rats at fluticasone propionate doses approximately 0.1 and 0.5 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) for adults (on a mg/m2 basis at maternal subcutaneous doses of 45 and 100 meg/kg/day, respectively) showed fetal toxicity charac¬ teristic of potent corticosteroid compounds, including em¬ bryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses up to 0.3 times the MRHDID (on a meg/m2 basis at maternal inhaled doses up to 68.7 meg/kg/day). In rabbits, fetal weight reduction and cleft palate were ob¬ served at a fluticasone propionate dose approximately 0.04 times the MRHDID for adults (on a mg/m2 basis at a'ma¬ ternal subcutaneous dose of 4 meg/kg/day). However, no ter¬ atogenic effects were reported at fluticasone propionate doses up to approximately 3 times the MRHDID for adults (on a mg/m2 basis at a maternal oral dose up to 300 meg/kg/ day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavail¬ ability following oral administration /see Clinical Pharma¬ cology (12.3)]. Fluticasone propionate crossed the placenta following sub¬ cutaneous administration to mice and rats and oral admin¬ istration to rabbits. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from cor¬ ticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during preg¬ nancy, most women will require a lower exogenous cortico¬ steroid dose and many will not need corticosteroid treat¬ ment during pregnancy. Nontoratogenic Effects: Hypoadrenalism may occur in in¬ fants born of mothers receiving corticosteroids during preg¬ nancy. Such infants should be carefully monitored. 8.3

» Body Weight 50,h Percentile

Pediatric Use

1

The safety and effectiveness of FLOVENT HFA in children aged 4 years and older have been established /see Aduerse Reactions (ti l), Clinual Pharmacology 112.3), Clinical Studies 114.2d.The safety and efli-ctiveness of FLOVENT UFA in children younger than 4 years have not been estab¬ lished I 'se of FLOVENT HFA in patients aged 4 to 11 years is supported by evidence from adequate and well-controlled trials in adults and adolescents aged 12 years and older, pharmacokinetic trials in patients aged 4 to 11 years, estab¬ lished efficacy of fluticasone propionate formulated as FLOVENT’ DISKUS* (fluticasone propionate inhalation powder i and FLOVENT® ROTADISK* (fluticasone propionate inhalatiun powderi in patients aged 4 to 11 years, and supportive findings with FLOVENT HFA in a trial conducted in subjects aged 4 to 11 years. Effects on Growth: Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pedi¬ atric patients. A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids including inhaled corticoster¬ oids. The effects of long-term treatment of children and ad¬ olescents with inhaled corticosteroids, including fluticasone propionate, on final adult height are not known.

: i ) '

!

i I ,

'
99.5°F (37.5°C)

6

9

WARNINGS AND PRECAUTIONS

If Guillain-Barr6 syndrome (GBS) has occurred within 6 weeks of receipt of a prior influenza vaccine, the decision to give FLUARIX QUADRIVALENT should be based on care¬ ful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is inconclusive. If influenza vaccine does pose a risk, it is probably slightly more than one additional case/one million persons vaccinated. 5.2

Aged 6 through 17 Years

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of FLUARIX QUADRIVALENT could reveal ad¬ verse reactions not observed in clinical trials. In adults who received FLUARIX QUADRIVALENT, the most common (21091* injection 6ite adverse reaction was

.

5 6

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. ° 7 days included day of vaccination and the subsequent 6 days. b Trial 2: NCT01196988. c. Contained the same composition as FLUARIX (trivalent formulation) manufactured for the 2010-2011 season and an additional influenza type B virus of Yamagata lineage. d Contained the same composition as FLUARIX manufactured for the 2010-2011 season (2 influenza A subtype viruses and an influenza type B virus of Victoria lineage). Contained the same 2 influenza A subtype viruses as FLUARIX manufactured for the 2010-2011 season and an i nfluenza type B virus of Yamagata lineage. 1 Percentage of subjects with pain by age subgroup: 39%, 38%, and 37%. for FLUARIX QUADRIVALENT, TIV-1. and TIV-2, respectively, in children aged 3 through 8 years and 52%, 50%, and 46% for FLUARIX QUADRIVALENT, TIV-1, and TIV-2. respectively, in children aged 9 through 17 years. * Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.

pain (36%). The most common (>10%) systemic adverse events were muscle aches (16%), headache (16%), and fa¬ tigue (16%). In children aged 3 through 17 years who received FLUARIX QUADRIVALENT, injection site adverse reactions were pain (44%), redness (23%), and swelling (19%). In children aged 3 through 5 years, the most common (>10%) systemic adverse events were drowsiness (17%), irritability (17%), and loss of appetite (16%); in children aged 6 through 17 years, the most common systemic adverse events were fa¬ tigue (20%), muscle aches (18%), headache (16%), arthralgia (10%), and gastrointestinal symptoms (10%). FLUARIX QUADRIVALENT in .Adults Trial 1 was a randomized, double-blind (2 arms) and openlabel (one arm), active-controlled, safety, and immunogenicity trial. In this trial, subjects received FLUARIX QUADRIVALENT (N = 3,036) or one of two formulations of comparator trivalent influenza vaccine (FLLTARIX. TIV-1, N = 1.010 or TIV-2, N = 610), each containing an influenza type B virus that corresponded to one of the two type B vi¬ ruses in FLUARIX QUADRIVALENT la type B virus of the Victoria lineage or a type B virus of the Yamagata lineage i. The population was aged 18 years and older (mean age: 58 years) and 57% were female; 69% were white, 27% were Asian, and 4% were of other racial/ethnic groups. Solicited events were collected for 7 days (day of vaccination and the next 6 days). The frequencies of solicited adverse events are shown in Table 2. (See table 2 at top of previous page] Unsolicited events occurring within 21 days of vaccination (Day 0 to 20) were reported in 13%, 14%, and 15% of sub¬

jects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. The unsolicited adverse reactions that occurred most frequently (20.1% for FLUARIX QUADRIVALENT) included dizziness, injection site hema¬ toma, injection site pruritus, and rash. Serious adverse events occurring within 21 days of vaccination were re¬ ported in 0.5%, 0.6%, and 0.2% of subjects who received FLUARIX QUADRIVALENT, TIV-1. or TIV-2, respi-etivelv FLUARIX QUADRIVALENT in Children Trial 2 was a randomized, double-blind, active-controlled, safety, and immunogenicity trial. In this trial, subjects re¬ ceived FLUARIX QUADRIVALENT (N = 915) or one of two formulations of comparator trivalent influenza vaccine i FLUARIX, TIV-1, N = 912 or TIV-2, N = 911), each contain¬ ing an influenza type B virus that corresponded to one of the two type B viruses in FLUARIX QUADRIVALENT (a type B virus of the Victoria lineage or a type B virus of the Yama¬ gata lineage). Subjects were aged 3 through 17 years and 52% were male; 56% were white, 29*1 were Asian, 12% were black, and 3% were of other racial/ethnic groups. Children aged 3 through 8 years with no history of influenza vaccinatibn received 2 doses approximately 28 days apart. Children aged 3 through 8 years with a history of influenza vaccina¬ tion and children aged 9 years and older received one dose Solicited local adverse reactions and systemic adverse events were collected using diary cards for 7 days iday of vaccination and the next 6 days). The frequencies of solic¬ ited adverse events are shown in Table 3. [See table 3 abovel In children who received a second dose of FLUARIX QUADRIVALENT, TIV-1, or TIV-2, the incidence* of ad¬ verse events following the second dose were generally lower than those observed after the first dose.

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956/GLAXOSMITHKLINE • FLUARIX QUADRIVALENT

Table 4. FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 4 Days" of Vaccination in Adults (Total Vaccinated Cohort) Trial 3

b

Trial 4C

Aged 18 through 64 Years

Aged 65 Years and Older

FLUARIX

Placebo

FLUARIX

Comparator

N = 760

N = 192

N = 601-602

N = 596

%

%

%

%

trials. The incidence of solicited adverse events in each age group is shown in Tables 4 and 5. (See table 4 above] [See table 5 above] In children who received a second dose of FLUARIX or the comparator vaccine, the incidences of adverse events follow¬ ing the second dose were similar to those observed after the first dose. Serious Adverse Events: In the 4 clinical trials in adults (N = 10,923), there was a single case of anaphylaxis within one day following administration of FLUARIX (100.4°F (38.0',C)

2

2

-

-

Fever >99.5°F (37.5°C)

-

-

2

1

Systemic

Tbtal vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. “ 4 days included day of vaccination and the subsequent 3 days. •> Trial 3 was a randomized, double-blind, placebo-controlled, safety, and immunogenicity trial (NCT00100399). c Trial 4 was a randomized, single-blind, active-controlled, safety, and immunogenicity trial (NCT00197288). The active control was FLUZONE®, a US-licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur SA).

Table 5. FLUARIX (Trivalent Formulation): Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 4 Days" of First Vaccination in Children Aged 3 through 17 Yearsb (Total Vaccinated Cohort) Aged 3 through 4 Years

Aged 5 through 17 Years

FLUARIX

Comparator

FLUARIX

Comparator

N = 350

N = 1,348

N = 451

%

N = 341 %

%

%

Pain

35

38

56

56

Redness

23

20

18

16

Swelling

14

13

14

13

Irritability

21

22

-

-

Loss of appetite

13

15

-

-

Drowsiness

13

20

-

-

Fever >99.5°F (37.5°C)

7

8

4

3

Muscle aches

-

-

29

29

Local

Systemic

7 7.1

-

-

20

19

Headache

-

-

15

16

Arthralgia

-

-

6

6

-

3

4

Shivering -

Tbtal vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. “4 days included day of vaccination and the subsequent 3 days. ’Trial 6 was a single-blind, active-controlled, safety, and immunogenicity US trial (NCT00383123). The active control was FLUZONE, a US-licensed trivalent, inactivated influenza vaccine (Sanofi Pasteur SA).

Unsolicited adverse events occurring within 28 days of any vaccination were reported in 31%, 33%, and 34% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. The unsolicited adverse reactions that occurred most frequently (20.1% for FLUARIX QUADRIVALENT' included injection site pruritus and rash Serious adverse events occurring within 28 days of

any vaccination were reported in 0.1%, 0.1%, and 0.1% of subjects who received FLUARIX QUADRIVALENT, TIV-1, or TIV-2, respectively. FLUARIX iTYivalent Formulation) FLUARIX has been administered to 10,317 adults aged 18 through 64 years, 606 subjects aged 65 years and older, and 2,115 children aged 6 months through 17 years in clinical

DRUG INTERACTIONS Concomitant Vaccine Administration

FLUARIX QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial. There are insufficient data to assess the concurrent admin¬ istration of FLUARIX QUADRIVALENT with other vac¬ cines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites. 7.2

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, anti¬ metabolites, alkylating agents, cytotoxic drugs, and cortico¬ steroids (used in greater than physiologic doses ', may re¬ duce the immune response to FLUARIX QUADRIVALENT. 8

Fatigue

Postmarketing Experience

Beyond those events reported above in the clinical trials for FLUARIX QUADRIVALENT or FLUARIX, the following adverse events have been spontaneously reported during postapproval use of FLUARIX (trivalent influenza vaccine'. This list includes serious events or events which have cau¬ sal connection to FLUARIX. Because these events are re¬ ported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Blood and Lymphatic System Disorders Lymphadenopathy. Cardiac Disorders Tachycardia. Ear and Labyrinth Disorders Vertigo. Eye Disorders Conjunctivitis, eye irritation, eye pain, eye redness, eye swelling, eyelid swelling. Gastrointestinal Disorders Abdominal pain or discomfort, swelling of the mouth, throat, and/or tongue. General Disorders and Administration Site Conditions Asthenia, chest pain, feeling hot, injection site mass, injec¬ tion site reaction, injection site warmth, body aches. Immune System Disorders Anaphylactic reaction including shock, anaphylactoid reac¬ tion, hypersensitivity, serum sickness. Infections and Infestations Injection site abscess, injection site Cellulitis, pharyngitis, rhinitis, tonsillitis. Nervous System Disorders Convulsion, encephalomyelitis, facial palsy, facial paresis, Guillain-Barre syndrome, hypoesthesia, myelitis, neuritis, neuropathy, paresthesia, syncope. Respiratory, Thoracic, and Mediastinal Disorders Asthma, bronchospasm, dyspnea, respiratory distress, stri¬ dor. Skin and Subcutaneous Tissue Disorders Angioedema, erythema, erythema multiforme, facial swell¬ ing, pruritus, Stevens-Johnson syndrome, sweating, urti¬ caria. Vascular Disorders Henoch-Schonlein purpura, vasculitis.

8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B. A reproductive and developmental toxicity study has been performed in female rats at doses approximately 80 times the human dose ' on a mg/kg basis and revealed no evidence of impaired female fertility or harm to the fetus due to FLUARIX QUADRIVALENT. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, FLUARIX QUADRIVALENT should be given to a pregnant woman only if clearly needed. In a reproductive and developmental toxicity study, the ef¬ fect of FLUARIX QUADRIVALENT on embryo-fetal and pre-weaning development was evaluated in rats. Animals were administered FLUARIX QUADRIVALENT by intra¬ muscular injection twice prior to gestation, during the pe¬ riod of organogenesis (gestation Days 3, 8, 11, and 15', and during lactation (Day 7), 0.2 mL/rat/occasion (approxi¬ mately 80-fold excess relative to the projected human dose on a body weight basis'. No adverse effects on mating, fe¬ male fertility, pregnancy, parturition, lactation parameters, and embryo-fetal or pre-weaning development were ob¬ served. There were no vaccine-related fetal malformations or other evidence of teratogenesis.

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FLUARIX QUADRIVALENT • GLAXOSMITHKLINE/957

Pregnancy Registry GlaxoSmithKline maintains a surveillance registry to col¬ lect data on pregnancy outcomes and newborn health status outcomes following vaccination with FLUARIX QUADRIVALENT during pregnancy. Women who receive FLUARIX QUADRIVALENT during pregnancy should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622. 8.3

Nursing Mothers

It is not known whether FLUARIX QUADRIVALENT is ex¬ creted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLUARIX QUADRIVALENT is administered to a nursing woman. 8.4

Attack Rates (n/N) N

Geriatric Use

In a randomized, double-blind (2 arms) and open-label (one arm), active-controlled trial, immunogenicity and safety were evaluated in a cohort of subjects aged 65 years and older who received FLUARIX QUADRIVALENT (N = 1,517); 469 of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 through 64 years) and the frequencies of solicited and unsolicited ad¬ verse events were generally lower than in younger subjects.

%

%

nr-

UL

Antigenically Matched Strains*

FLUARIX

5,103

49

1.0

66.9*’

51.9

77.4

Placebo

2,549

74

2.9

-

-

—

All Culture-confirme 1 Influenza (Matched, Unmatched, and Untyped)'

FLUARIX

5,103

63

1.2

61.6b

46.0

72.8

Placebo

2,549

82

3.2

-

-

-

0 There were no vaccine matched culture-confirmed cases of A/New with FLUARIX or placebo.

c*J*doll«l/2100.4°F (38.0°C)

4

4

Table 4. FLULAVAL QUADRIVALENT: Incidence of Solicited Local Adverse Reactions and Systemic Adverse Events within 7 Days* of First Vaccination in Children Aged 3 through 8 Years'1 (Total Vaccinated Cohort) FLULAVAL QUADRIVALENT

HAVRIX*

%

%

Aged 3 through 8 Years Local Adverse

N = 2,546

N = 2,551

39

28

Swelling

1

0.3

Redness

0.4

0.2

Reactions

Pain

Aged 3 through 4 Years Systemic Adverse Events

7

Aged 5 through 8 Years Systemic Adverse

N = 1,648

N = 1,654

Muscle aches

12

10

Headache

11

11

Fatigue

8

7

Arthralgia

6

5

Gastrointestinal symptoms'*

6

6

Shivering

3

3

Fever >100.4°F (38.0°C)

3

3

Events

DRUG INTERACTIONS Concomitant Administration with Other Vaccines

FLULAVAL QUADRIVALENT should not be mixed with any other vaccine in the same syringe or vial. There are insufficient data to assess the concomitant admin¬ istration of FLULAVAL QUADRIVALENT with other vac¬ cines. When concomitant administration of other vaccines is required, the vaccines should be administered at different injection sites. 7.2

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, anti¬ metabolites, alkylating agents, cytotoxic drugs, and cortico¬ steroids (used in greater than physiologic doses), may re¬ duce the immune response to FLULAVAL QUADRIVALENT. 8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

In children who received a second dose of FLULAVAL QUADRIVALENT or HAVRIX. the incidences of adverse events following the second dose were generally lower than those observed after the first dose. The frequency of unsolicited adverse events occurring within 28 days of vaccination was similar in both groups (3391 for both FLULAVAL QUADRIVALENT and HAVRIX). The unsolicited adverse events that occurred most fre¬ quently (>1* for FLULAVAL QUADRIVALENT) included diarrhea, pyrexia, gastroenteritis, nasopharyngitis, upper respiratory tract infection, varicella, cough, and rhinorrhea. Serious adverse events occurring within 28 days of any vac¬ cination were reported in 0.741 of subjects who received FLULAVAL QUADRIVALENT and in 0.2* of subjects who received HAVRIX.

Pregnancy Category B. A reproductive and developmental toxicity study has been performed in female rats at a dose 80-fold the human dose (on a mg/kg basis) and showed no evidence of impaired female fertility or harm to the fetus due to FLULAVAL QUADRIVALENT. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not al¬ ways predictive of human response, FLULAVAL QUADRIVALENT should be given to a pregnant woman only if clearly needed. In a reproductive and developmental toxicity study, the ef¬ fect of FLULAVAL QUADRIVALENT on embryo-fetal and pre-weaning development was evaluated in rats. Animals were administered FLULAVAL QUADRIVALENT by intra¬ muscular injection twice prior to gestation, during the pe¬ riod of organogenesis (gestation Days 3, 8, 11, and 15), and during lactation (Day 7), 0.2 mL/dose/rat (80-fold higher than the projected human dose on a body weight basis). No adverse effects on mating, female fertility, pregnancy, par¬ turition, lactation parameters, and embryo-fetal or preweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis. Pregnancy Registry GlaxoSmithKline maintains a surveillance registry to col¬ lect data on pregnancy outcomes and newborn health status outcomes following vaccination with FLULAVAL QUADRIVALENT during pregnancy. Women who receive FLULAVAL QUADRIVALENT during pregnancy should be encouraged to contact GlaxoSmithKline directly or their healthcare provider should contact GlaxoSmithKline by calling 1-888-452-9622.

6.2

8.3

Total vaccinated cohort for safety included all vaccinated subjects for whom safety data were available. * 7 days included day of vaccination and the subsequent 6 davs. b Trial 3: NCT01218308. r Hepatitis A Vaccine used as a control vaccine. d Gastrointestinal symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.

Postmarketing Experience

There are no postmarketing data available for FLlTLAVAL QUADRIVALENT. The following adverse events have been spontaneously reported during postapproval use of FLULAVAL (trivalent influenza vaccine). Because these events are reported voluntarily from a population of uncer¬ tain size, it is not always possible to reliably estimate their incidence rate or establish a causal relationship to the vaccine. Adverse events described here are included be¬ cause- a) they represent reactions which are known to occur following immunizations generally or influenza immuniza¬ tions specifically; b) they are potentially serious; or c) the frequency of reporting.

Nursing Mothers

It is not known whether FLULAVAL QUADRIVALENT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLULAVAL QUADRIVALENT is administered to a nursing woman. 8.4

Pediatric Use

Safety and effectiveness of FLULAVAL QUADRIVALENT in children younger than 3 years have not been established. Safety and immunogenicity of FLULAVAL QUADRIVALENT in children aged 3 through 17 years have been evaluated /see Adverse Reactions (6.1), Clinical Studies

(14 2)1

8.5 Geriatric Use

In a randomized, double-blind, active-controlled trial, im¬ munogenicity and safety were evaluated in a cohort of sub¬ jects aged 65 years and older who received FLULAVAL QUADRIVALENT i N = 397); approximately one-third of these subjects were aged 75 years and older. In subjects aged 65 years and older, the geometric mean antibody titers (GMTs) post-vaccination and seroconversion rates were lower than in younger subjects (aged 18 to 64 years) and the frequencies of solicited and unsolicited adverse events were generally lower than in younger subjects [see Adverse Reac¬ tions (6.1), Clinical Studies (14.2)].

11 DESCRIPTION FLULAVAL QUADRIVALENT, influenza Vaccine, for intra¬ muscular injection, is a quadrivalent, split-virion, inactivated influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens' eggs. Each of the influenza viruses is produced and purified separately. The virus is inactivated with ultraviolet light treatment followed by formaldehyde treatment, purified by centrifugation, and disrupted with sodium deoxycbolate. FLULAVAL QUADRIVALENT is a sterile, opalescent, translucent to off-white suspension in a phosphate-buffered saline solution that may sediment slightly. The sediment re¬ suspends upon shaking to form a homogeneous suspension. FLULAVAL QUADRIVALENT has been standardized ac¬ cording to USPHS requirements for the 2015-2016 influenza season and is formulated to contain 60 micro¬ grams (meg) hemagglutinin U1A) per 0.5-mL dose in the rec¬ ommended ratio of 15 meg HA of each of the following 4 vi¬ ruses (two A strains and two B strains): A/Califomia/7/2009 NYMC X-179A (H1N1), A/Switzerland/9715293/2013 NIB-88 (H3N2), B/Phuket/3073/2013, and B/Brisbane/60/ 2008. The prefilled syringe is formulated without preservatives and does not contain thimerosal. Each 0.5-mL dose from the multi-dose vial contains 50 meg thimerosal (102.2F/39.0°C, physician-verified shortness of breath, least once post-vaccination, and complied with the protocol-specified efficacy criteria. pneumonia, wheezing, bronchitis, bronchiolitis, pulmonary c Number of influenza cases. congestion, croup and/or acute otitis media, and/or d Vaccine efficacy for FLULAVAL QUADRIVALENT met the pre-defined criterion of >30% for the lower limit of the physician-diagnosed serious extra-pulmonary complica¬ tions, including myositis, encephalitis, seizure and/or myo¬ 2-sided 95% CL* * Hepatitis A Vaccine used as a control vaccine. carditis). f Of 162 culture-confirmed influenza cases, 108 (67%) were antigenically typed (87 matched; 21 unmatched); 54 (33%) The risk reduction of fever >102.2°F/39.0°C associated with could not be antigenically typed [but were typed by RT-PCR and nucleic acid sequence analysis: 5 cases A (H1N1) (5 with RT-PCR-positive influenza was 71.0% (95% Cl: 44.8, 84.8) HAVRIX), 47 cases A (H3N2) (10 with FLULAVAL QUADRIVALENT, 37 with HAVRDO, and 2 cases B Victoria (2 with based on the ATP cohort for efficacy [FLULAVAL HAVRDO). QUADRIVALENT (n = 12/2,379); HAVRIX (n = 41/2,398)]. B Since only 67% of cases could be typed, the clinical significance of this result is unknown. The other pre-specified adverse outcomes had too few cases to calculate a risk reduction. The incidence of these adverse outcomes is presented in Table 6. [See table 6 above] Table 6. FLULAVAL QUADRIVALENT: Incidence of Adverse Outcomes Associated with RT-PCR-positive Influenza in 14.2 Immunological Evaluation Children Aged 3 through 8 Years* (Total Vaccinated Cohort)b Adults Trial 1 was a randomized, double-blind, 'active-controlled, FLULAVAL safety and immunogenicity trial conducted in subjects aged HAVRIX* QUADRIVALENT 18 years and older. In this trial, subjects received N = 2,584 N = 2,584 FLULAVAL QUADRIVALENT (N = 1,246), or one of two for¬ mulations of a comparator trivalent influenza vaccine Number of Number of (FLULAVAL, TIV-1, N = 204 or TIV-2, N = 211), each con¬ % Subjects* Number of Events % Subjects* Number of Events Adverse Outcomed taining an influenza type B virus that corresponded to one of the two B viruses in FLULAVAL QUADRIVALENT (a 50 1.9 51f 0.6 15 16f Fever >102.2°F/ type B virus of the Victoria lineage or a type B virus of the 39.0°C Yamagata lineage)/see Adverse Reactions (6.1)]. Immune responses, specifically hemagglutination inhibition 0.2 5 5 0 0 0 Shortness of breath (HI) antibody titers to each virus strain in the vaccine, were evaluated in sera obtained 21 days after administration of 0.1 0 3 3 0 0 Pneumonia FLULAVAL QUADRIVALENT or the comparators. The im¬ munogenicity endpoint was GMTs adjusted for baseline, 1 1 0 1 0 1 Wheezing performed on the According-to-Protocol (ATPl cohort for whom immunogenicity assay results were available after 0 1 1 1 0 1 Bronchitis vaccination. FLIT-AVAI. QUADRIVALENT was non¬ inferior to both TIVs based on adjusted GMTs (Table 7). The 0 1 1 0 0 0 Pulmonary antibody response to influenza B strains contained in congestion FLULAVAL QUADRIVALENT was higher than the anti¬ body response after vaccination with a TIV containing an 0 0 0 1 1 0 Acute otitis media influenza B strain from a different lineage. There was no 0 0 0 0 0 evidence that the addition of the second B strain resulted in 0 Bronchiolitis immune interference to other strains included in the 0 0 0 0 0 0 Croup vaccine (Table 7). ISee table 7 at top of next page] 0 0 0 0 0 Encephalitis 0 Children Trial 2 was a randomized, double-blind, active-controlled 0 0 0 0 0 Myocarditis 0 trial conducted in children aged 3 through 17 years. In this trial, subjects received FLULAVAL QUADRIVALENT 0 0 0 Myositis 0 0 0 (N = 878), or one of two formulations of a comparator triva¬ lent influenza vaccine (FLUARIX, TIV-1, N = 871 or TIV-2 0 0 Seizure 0 0 0 0 N = 878), each containing an influenza type B virus that corresponded to one of the two B viruses in FLULAVAL * Trial 3: NCT01218308. QUADRIVALENT (a type B virus of the Victoria lineage or b Total vaccinated cohort included all vaccinated subjects for whom data were available. a type B virus of the Yamagata lineage) /see Adverse Reac¬ c Hepatitis A Vaccine used as a control vaccine. tions (6.1)]. d In subjects who presented with more than one adverse outcome, each outcome was counted in the respective category. Immune responses, specifically HI antibody titers to each * Number of subjects presenting with at least one event in each group. virus strain in the vaccine, were evaluated in sera obtained 1 One subject in each group had sequential influenza due to influenza type A and type B viruses. 28 days following one or 2 doses of FLULAVAL QUADRIVALENT or the comparators. The immunogenicity endpoints were GMTs adjusted for baseline, and the per¬ 14 CLINICAL STUDIES through 8 years were randomized 11:1) to receive centage of subjects who achieved seroconversion, defined as 14.1 Efficacy against Influenza FLULAVAL QUADRIVALENT (N = 2,5841, containing at least a 4-fold increase in serum HI titer over baseline to The efficacy of FLIT-AVAL QUADRIVALENT was evaluated A/California/7/2009 (H1N11, A/Victoria/210/2009 (H3N2I, >1:40. following vaccination, performed on the ATP cohort. in Trial 3, a randomized, observer-blind, non-influenza B/Bnsbane/60/2008 (Victoria lineagei, and B/Florida/ FLULAVAL QUADRIVALENT was non-inferior to both vaccine-controlled trial conducted in 3 countries in Asia, 3 4/2006 (Yamagata lineage) influenza strains, or HAVRIX TIVs based on adjusted GMTs and seroconversion rates in Latin America, and 2 in the Middle East/Europe during (N = 2.584), as a control vaccine Children with no history of influenza vaccination received 2 doses of FLULAVAL I i Table 8). The antibody response to influenza B strains con¬ the 2010-2011 influenza season. Healthy subjects aged 3 Table 5. FLULAVAL QUADRIVALENT: Influenza Attack Rates and Vaccine Efficacy against Influenza A and/or B in Children Aged 3 through 8 Years* (According-to-Protocol Cohort for Efficacyl

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HAVRIX • GLAXOSMITHKLINE/963

Table 7. Non-inferiority of FLULAVAL QUADRIVALENT Relative to Trivalent Influenza Vaccine (TIV) 21 Days Post-vaccination in Adults Aged 18 Years and Older* (According-to-Protocol Cohort for lmmunogenicity)b

FLULAVAL QUADRIVALENT

Geometric Mean Titers Against

N = 1,245-1,246 (95% Cl)

TIV-1

TIV-2

(B Victoria)1*

(B Yamagata)*

N = 204 (95% Cl)

N = 210-211 (95% Cl)

A/Califomia/7/2009 (H1N1)

204.6f (190.4, 219.9)

176.0 (149.1, 207.7)

149.0 (122.9, 180.7)

A/Victoria/210/2009 (H3N2)

125.4f (117.4, 133.9)

147.5 (124.1, 175.2)

141.0 (118.1, 168.3)

B/Brisbane/60/2008 (Victoria lineage)

177.7f (167.8, 188.1)

135.9 (118.1, 156.5)

71.9 (61.3, 84.2)

B/Florida/4/2006 (Yamagata lineage)

399.7f (378.1, 422.6)

176.9 (153.8, 203.5)

306.6 (266.2, 353.3)

Cl = Confidence Interval. “ Trial 1: NCT01196975. b According-to-protocol cohort for immunogenicity included all evaluable subjects for whom assay results were available after vaccination for at least one trial vaccine antigen. c Containing A/Califomia/07/2009 (HIND A/Victori a/210/2009 (H3N2), B/Florida/04/2006 (Yamagata lineage), and B/ Brisbane/60/2008 (Victoria lineage) t Containing A/Califomia/07/2009 (HIND, A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 (’Victoria lineage' f Containing A/Califomia/07/2009 (HIND, A/Victoria/210/2009 (H3N2), and B/Florida/04/2006 (Yamagata lineage), r-, 10 1)0111 TIVs based on adJust1:10, or an increase in titer from 0.1 mlU/mL to each antigen), pertussis an¬ These highlights do not include all the information needed tigens (percentage of subjects with seroresponse, antibody to use IMITREX safely and effectively. See full prescribing concentrations >5 EL.U./mL in seronegative subjects or information for IMITREX. post-vaccination antibody concentration >2 times the pre¬ IMITREX (sumatriptan succinate) injection, for subcutane¬ vaccination antibody concentration in seropositive subjects, ous use and GMTs), or Hib (percentage of subjects with antibody Initial U.S. Approval: 1992 levels >1 mcg/mL to polyribosyl-ribitol phosphate, PRP) -INDICATIONS AND USAGEwhen HAVRIX was administered concomitantly with INFANRIX and Hib conjugate vaccine (Group 11 relative to IMITREX Injection is a serotonin (5-HT1B/1D) receptor ago¬ INFANRIX and Hib conjugate vaccine administered to¬ nist (triptan) indicated for: • Acute treatment of migraine with or without aura in gether (Group 2). Concomitant Administration With Pneumococcal 7-Valent adulte (1) • Acute treatment of cluster headache in adults (1) Conjugate Vaccine (Study HAV 220): In this US multi¬ center study, 433 children 15 months of age were random¬ Limitations of Use: • Use only if a clear diagnosis of migraine or cluster head¬ ized to receive: Group 11 HAVRIX coadministered with ache has been established (1) PCV-7 vaccine (n = 137); Group 2) HAVRIX administered • Not indicated for the prophylactic therapy of migraine or alone In = 147); or Group 3) PCV-7 vaccine administered alone (n = 149) followed by a first dose of HAVRIX one cluster headache attacks (11 month later All subjects received a second dose of HAVRIX -DOSAGE AND ADMINISTRATION6 to 9 months after the first dose. Among subjects in all • For subcutaneous use only (2.1) groups combined, 53% were female; 61% of subjects were • Acute treatment of migraine: single dose of 1 to 6 mg l white, 16%' were Hispanic, 15% were black, and 8% were (2.1) j other racial/ethnic groups. • Acute treatment of cluster headache: single dose of 6 mg There was no evidence for reduced antibody response to (2.1) PCV-7 (GMC to each serotype' when HAVRIX was adminis¬ • Maximum dose in a 24-hour period: 12 mg. separate tered concomitantly with PCV-7 vaccine (Group 1) relative doses by at least 1 hour i2.1> to PCV-7 administered alone (Group 3).

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Look for PDR drug information and services in your EHR • Patients receiving doses other than 4 or 6 mg: 6-mg single-dose vial (2.3)

IMITREX INJECTION • GLAXOSMITHKLINE/967

Use the

7.4 Selective Serotonin Reuptake Inhibitors/ Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Tbxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Migraine 14.2 Cluster Headache 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed.

-DOSAGE FORMS AND STRENGTHS• Injection: 4- and 6-mg single-dose prefilled syringe car¬ tridges for use with IMITREX STATdose Pen (3) • Injection: 6-mg single-dose vial (3) -CONTRAINDICATIONS• History of coronary artery disease or coronary artery vasospasm (4) • WolfT-Parkinson-White syndrome or other cardiac acces¬ sory conduction pathway disorders (4) • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4) • Peripheral vascular disease (4) • Ischemic bowel disease (4) • Uncontrolled hypertension (4) • Recent (within 24 hours) use of another 5-HT, agonist (e.g., another triptan) or of an ergotamine-containing med¬ ication (4) • Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor (4) • Hypersensitivity to IMITREX (angioedema and anaphy¬ laxis seen)(4) • Severe hepatic impairment (4) -WARNINGS AND PRECAUTIONS• Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1) • Arrhythmias: Discontinue IMITREX if occurs (5.2) • Chest/throat/neck/jaw pain, tightness, pressure, or heavi¬ ness: Generally not associated with myocardial ische¬ mia; evaluate for coronary artery disease in patients at high risk (5.3) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs (5.4) • Gastrointestinal ischemic reactions and peripheral vaso¬ spastic reactions: Discontinue IMITREX if occurs (5.5) • Medication overuse headache: Detoxification may be necessary (5.6) • Serotonin syndrome: Discontinue IMITREX if occurs (5.7) • Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold (5.10) -ADVERSE REACTIONSMost common adverse reactions (>5% and >placebo) were injection site reactions, tingling, dizziness/vertigo, warm/ hot sensation, burning sensation, feeling of heaviness, pres¬ sure sensation, flushing, feeling of tightness, and numbness (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-USE IN SPECIFIC POPULATIONSPregnancy:

Based on animal data, may cause fetal harm

(8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 6/2015 FULL PRESCRIBING INFORMATION: CONTENTS*

1 2

3 4 5

6

7

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Administration Using the IMITREX STATdose Pen* 2.3 Administration of Doses of IMITREX Other than 4 or 6 mg DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions 5.6 Medication Overuse Headache 5.7 Serotonin Syndrome 6.8 Increase in Blood Pressure 5.9 Anaphylactic/Anaphylactoid Reactions 5.10 Seizures ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience DRUG INTERACTIONS 7.1 Ergot-containing Drugs 7.2 Monoamine Oxidase-A Inhibitors 7.3 Other 5-HT, Agonists Free

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE IMITREX® Injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Limitations of Use: • Use only if a clear diagnosis of migraine or cluster head¬ ache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX Injection, reconsider the diagnosis before IMITREX Injection is administered to treat any subse¬ quent attacks. • IMITREX Injection is not indicated for the prevention of migraine or cluster headache attacks. 2

DOSAGE AND ADMINISTRATION

2.1

Dosing Information

The maximum single recommended adult dose of IMITREX Injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treat¬ ment of migraine, if side effects are dose limiting, lower doses (1 mg to 5 mg) may be used [see Clinical Studies and IMITREX Nasal Spray within 24 hours of each other is con¬ traindicated. 7.2

Monoamine Oxidase-A Inhibitors

MAO-A inhibitors increase systemic exposure by up to 7-fold. Therefore, the use of IMITREX Nasal Spray in pa¬ tients receiving MAO-A inhibitors is contraindicated /see Clinical Pharmacology (12.3)]. 7.3 Other 5-HT, Agonists

Because their vasospastic effects may be additive, co¬ administration of IMITREX Nasal Spray and other 5-HT, agonists (e.g., triptans) within 24 hours of each other is con¬ traindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syn¬ drome

Cases of serotonin syndrome have been reported during co¬ administration of triptans and SSRIs, SNRIs. TCAs, and MAO inhibitors /see Warnings and Precautions (5.7)1. 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category C: There are no adequate and wellcontrolled trials in pregnant women. In developmental tox¬ icity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal. Developmental toxicity studies of sumatriptan by the intranasal route have not been conducted. IMITREX Nasal Spray should be used dur¬ 5.5 Other Vasospasm Reactions Seizures have been reported following administration of ing pregnancy only if the potential benefit justifies the po¬ IMITREX Nasal Spray may cause non-coronary vasospastic IMITREX. Some have occurred in patients with either a histential risk to the fetus. reactions, such as peripheral vascular ischemia, gastroin¬ i tory of seizures or concurrent conditions predisposing to sei¬ Oral administration of sumatriptan to pregnant rats during testinal vascular ischemia and infarction i presenting with zures. There are also reports in patients where no such pre¬ the period of organogenesis resulted in an increased inci. abdominal pain and bloody diarrhea), splenic infarction, disposing factors are apparent. IMITREX Nasal Spray dence of fetal blood vessel icervicothoracic and umbilical) and Raynaud's syndrome. In patients who experience symp¬ should be used with caution ih patients with a history of toms or signs suggestive of non-coronary vasospasm reac¬ epilepsy or conditions associated with a lowered seizure ■ abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day. Oral ad¬ tion following the use of any 5-HT, agonist, rule out a vaso¬ threshold. ministration of sumatriptan to pregnant rabbits during the spastic reaction before using additional IMITREX Nasal 6 ADVERSE REACTIONS period of organogenesis resulted in increased incidences of Spray. embryolethality and fetal cervicothoracic vascular and skel¬ Reports of transient and permanent blindness and signifi¬ The billowing adverse reactions are discussed in more detail etal abnormalities. Intravenous administration of cant partial vision loss have been reported with the use of in other sections of the prescribing information:

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Look for PDR drug information and services in your EHR sumatriptan to pregnant rabbits during the period of organ¬ ogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for de¬ velopmental toxicity in rabbits were 15 and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (de¬ creased body weight, decreased ossification, increased inci¬ dence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day. 8.3

Nursing Mothers

Sumatriptan is excreted in human milk following subcuta¬ neous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Nasal Spray. 8.4

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. IMITREX Nasal Spray is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were sim¬ ilar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not es¬ tablish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in adolescents. Adverse reac¬ tions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, w’ith younger patients re¬ porting reactions more commonly than older adolescents. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available. 8.5 Geriatric Use

Clinical trials of IMITREX Nasal Spray did not include suf¬ ficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differ¬ ences in responses between the elderly and younger pa¬ tients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant dis¬ ease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., di¬ abetes, hypertension, smoking, obesity, strong family his¬ tory of CAD) prior to receiving IMITREX Nasal Spray Isee Warnings and Precautions (5.1)].

10

OVERDOSAGE

I n clinical trials, the highest single doses of IMITREX Nasal Spray administered without significant reactions were 40 mg to 12 volunteers and 40 mg to 85 subjects with mi¬ graine. which is twice the highest single recommended dose. In addition, 12 volunteers were administered a total daily dose of 60 mg (20 mg 3 times daily) for 3.5 days without sig¬ nificant adverse reactions. Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, ery¬ thema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2 hours /see Clinical Pharmacology (12.3)], and therefore monitoring of patients after overdose with IMITREX Nasal Spray should continue for at least 10 hours or while symp¬ toms or signs persist. It is unknown what effect hemodialysis or peritoneal dialy¬ sis has on the serum concentrations of sumatriptan

11

DESCRIPTION

IMITREX Nasal Spray contains sumatriptan, a selective 5'HT|B1U receptor agonist. Sumatriptan is chemically des¬

IMITREX NASAL SPRAY

GLAXOSMITHKLINE/975

ignated as 3-l2-(dimethylamino)ethyl]-N-methyl-indole-5methanesulfonamide, and it has the following structure:

, matched fur sex, age and weight with healthy subjects in = 8). Similar changes can be expected following intranasal administration. CHjCHjNICHjIj The pharmacokinetics of sumatriptan in patients with se¬ vere hepatic impairment has not been studied. The use of IMITREX Nasal Spray in patients with severe hepatic im¬ pairment is contraindicated Isee Contraindications (4)]. H Race: The systemic clearance and of subcutaneous sumatriptan were similar in black (n * 341 and Caucasian The empirical formula is ChH^jNjOjjS, representing a mo¬ j (n = 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences. lecular weight of 295.4. Sumatriptan'is a white to off-white 1 Drug Interaction Studies: Monoamine Oxidase A lnhibipowder that is readily soluble in water and in saline. Each IMITREX Nasal Spray contains 5 or 20 mg of | tors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels /see Contraindica sumatriptan in a 100-pL unit dose aqueous buffered solu¬ tions (4) and Drug Interactions (7.2)1. MAO inhibitors inter¬ tion containing monobasic potassium phosphate NF, anhy¬ action studies have not been performed with intranasal drous dibasic sodium phosphate USP, sulfuric acid NF, so¬ sumatriptan. dium hydroxide NF, and purified water USP. The pH of the solution is approximately 5.5. The osmolality of the solution Due to gut and hepatic metabolic first-pass effects, the inis 372 or 742 mOsmol for the 5- and 20-mg IMITREX Nasal | crease of systemic exposure after co-administration of an Spray, respectively. MAO-A inhibitor with oral sumatriptan is greater than af¬ ter co-administration of the MAO inhibitors with subcuta¬ 12 CLINICAL PHARMACOLOGY neous sumatriptan. The effects of an MAO inhibitor on sys¬ 12.1 Mechanism of Action temic exposure after intranasal sumatriptan would be Sumatriptan binds with high affinity to human cloned expected to be greater than the effect after subcutaneous 5-HTIB/1D receptors. Sumatriptan presumably exerts its sumatriptan but smaller than the effect after oral therapeutic effects in the treatment of migraine headache sumatriptan because only swallowed drug would be subject through agonist effects at the 5—HT1B/]D receptors on intra¬ to first-pass effects. cranial blood vessels and sensory nerves of the trigeminal In a trial of 14 healthy females, pretreatment with an system, which result in cranial vessel constriction and inhi¬ MAO-A inhibitor decreased the clearance of subcutaneous bition of pro-inflammatory neuropeptide release.. sumatriptan, resulting in a 2-fold increase in the area under 12.2 Pharmacodynamics the sumatriptan plasma concentration-time curve (ALTC), Blood Pressure: Significant elevation in blood pressure, corresponding to a 40% increase in elimination half-life. including hypertensive crisis, has been reported in patients A small trial evaluating the effect of pretreatment with an with and without a history of hypertension /see Warnings MAO-A inhibitor on the bioavailability from a 25-mg oral and Precautions (5.8)]. sumatriptan tablet resulted in an approximately 7-fold in¬ Peripheral (Small) Arteries: In healthy volunteers crease in systemic exposure. (N = 18), a trial evaluating the effects of sumatriptan on Xylometazoline: An in vivo drug interaction trial indicated peripheral (small vessel) arterial reactivity failed to detect a that 3 drops of xylometazoline (0.1% w/v), a decongestant, clinically significant increase in peripheral resistance. administered 15 minutes prior to a 20-mg nasal dose of Heart Rate: Transient increases in blood pressure ob¬ sumatriptan did not alter the pharmacokinetics of served in some patients in clinical trials carried out during sumatriptan. sumatriptan s development as a treatment for migraine were not accompanied by any clinically significant changes 13 NONCLINICAL TOXICOLOGY in heart rate. 13.1 Carcinogenesis, Mutagenesis. Impairment of Fer¬ 12.3

Pharmacokinetics

Absorption and Bioavailabilitv: In a trial of 20 female vol¬ unteers, the mean maximum concentration following a 5- and 20-mg intranasal dose was 5 and 16 ng/mL, respec¬ tively. The mean Cmax following a 6-mg subcutaneous injec¬ tion is 71 ng/mL (range: 49 to 110 ng/mL). The mean Cmax is 18 ng/mL (range: 7 to 47 ng/mL) following oral dosing with 25 mg and 51 ng/mL ( range: 28 to 100 ng/mL ) following oral dosing with 100 mg of sumatriptan. In a trial of 24 male volunteers, the bioavailability relative to subcutaneous in¬ jection was low, approximately 17%, primarily due to pre¬ systemic metabolism and partly due to incomplete absorp¬ tion. Clinical and pharmacokinetic data indicate that adminis¬ tration of two 5-mg doses, 1 dose in each nostril, is equiva¬ lent to administration of a single 10-mg dose in 1 nostril. Distribution: Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evalu¬ ated. The apparent volume of distribution is 2.7 L/kg. Metabolism: In vitro studies with human microsomes sug¬ gest that sumatriptan is metabolized by MAO, predomi¬ nantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination: The elimination half-life of sumatriptan ad¬ ministered as a nasal spray is approximately 2 hours, sim¬ ilar to the half-life seen after subcutaneous injection. Only 3% of the dose is excreted in the urine as unchanged sumatriptan; 42% of the dose is excreted as the major me¬ tabolite. the indole acetic acid analogue of sumatriptan. The total plasma clearance is approximately 1,200 mL/min. Special Populations: Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Intranasal sumatriptan has not been evaluated for age differences. Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Hepatic Impairment: The effect of mild to moderate he¬ patic disease on the pharmacokinetics of the intranasal for¬ mulation of sumatriptan has not been evaluated. Sumatriptan bioavailability following intranasal adminis¬ tration is 17%, similar to that after oral administration (16%). Following oral administration, an approximately 70% increase in Cmax and AUC was observed in one small trial of patients with moderate liver impairment (n = 8)

tility

Carcinogenesis: In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 and 104 weeks, respectively, there was no evidence in either species of an increase in tumors related to sumatriptan ad¬ ministration. Carcinogenicity studies of sumatriptan using the nasal route have not been conducted.

I

Mutagenesis: Sumatriptan was negative in in vitro(bacterial reverse mutation |Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility: When sumatriptan was adminis¬ tered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no ev¬ idence of impaired fertility at doses up to 60 mg/kg/day. When sumatriptan (5, 50, or 500 mg/kg/day) was adminis¬ tered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or fe¬ males or both. # • Fertility studies of sumatriptan using the intranasal route have not been conducted. 13.2

Animal Toxicology and/or Pharmacology

Corneal Opacities: Dogs receiving oral sumatriptan devel¬ oped corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested. 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established.

14

CLINICAL STUDIES

The efficacy of Imitrex Nasal Spray in the acute treatment of migraine headaches was demonstrated in 8, randomized, double-blind, placebo-controlled trials, of which 5 used the recommended dosing regimen and used the marketed for¬ mulation. Patients enrolled in these 5 trials were predomi¬ nately female (86%) and Caucasian (95%), with a mean age of 41 years (range of 18 to 65 years). Patients were in¬ structed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing Associated symptoms such as nau¬ sea. photophobia, and phonophobia were also assessed Maintenance of response was assessed for up to 24 hours postdose. A second dose of IMITREX Nasal Spray or other medication was allowed 2 to 24 hours after the initial treat-

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976/GLAXOSMITHKLINE • IMITREX NASAL SPRAY Table 2. Percentage of Patients With Headache Response (No or Mild Pain) 2 Hours Following Treatment

Serotonin Syndrome: Caution patients about the risk of serotonin syndrome with the use of IMITREX Nasal Spray or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors I see Warnings

IMITREX Nasal Spray 5 mg

IMITREX Nasal Spray 10 mg

IMITREX Nasal Spray 20 mg

Placebo

49%“ (n = 121)

46%“ (n = 112)

64%nb'c

Trial 1

(n = 118)

25% (n = 63)

Trial 2

Not applicable

44%“ (n = 273)

55%"J> (n = 277)

25% (n = 138)

Not applicable

54%“ (n = 106)

63%“ (n = 202)

35% (n = 100)

Specific Populations (8.1)].

Trial 3

Not applicable

43% (n = 106)

62%“’b (n = 215)

29% (n = 112)

[see Use in Specific Populations (8.3)].

Trial 4

Trial 5d

45%“ (n = 296)

53%“ (n = 291)

60%“c (n = 286)

36% (n ± 198)

and Precautions (5.7) and Drug Interactions placebo) were j after the first dose. The maximum daily dose is 200 mg in a paresthesia, warm/cold sensation, chest pain/tightness/ 24-hour period. pressure and/or heaviness, neck/throat/jaw pain/tightness/ Use after IMITREX Injection: If the migraine returns fol¬ pressure, other sensations of pain/pressure/tightness/heavi¬ lowing an initial treatment with IMITREX (sumatriptan ness, vertigo, and malaise/fatigue. (6.1) succinate) Injection, additional single IMITREX Tablets (up To report SUSPECTED ADVERSE REACTIONS, contact to 100 mg/day) may be given with an interval of at least 2 GlaxoSmithKline at 1-888-825-5249 or FDA at hours between tablet doses. 1-800-FDA-1088 or www.fda.gov/medwatch The safety of treating an average of more than 4 headaches in a 30-day period has not been established. -USE IN SPECIFIC POPULATIONS2.2 Dosing in Patients With Hepatic Impairment Pregnancy: Based on animal data, may cause fetal harm. If treatment is deemed advisable in the presence of mild to (8.1) moderate hepatic impairment, the maximum single dose See 17 for PATIENT COUNSELING INFORMATION should not exceed 50 mg [see Use in Specific Populations and FDA-approved patient labeling.

-ADVERSE REACTIONS-

Revised: 11/2013

(8.6) and Clinical Pharmacology (12.3)]:

3 1 2 3 4 5

DOSAGE FORMS AND STRENGTHS White, triangular-shaped, film-coated, and debossed with “I” on one side and “25” on the other. 50 mg Tablets: White, triangular-shaped, film-coated, and debossed with “IMITREX 50” on one side and a chevron shape U) on the other. 100 mg Ttiblets: Pink, triangular-shaped, film-coated, and debossed with “IMITREX 100" on one side and a chevron shape (A) on the other. 25 mg Tablets:

FULL PRESCRIBING INFORMATION: CONTENTS* *

INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Dosing in Patients With Hepatic Impairment DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina 5.2 Arrhythmias 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.4 Cerebrovascular Events 5.5 Other Vasospasm Reactions

• Wolff-Parkinson-White syndrome or arrhythmias associ¬

ated with other cardiac accessory conduction pathway dis¬ orders [see Warnings and Precautions (5.2)] • History of stroke or transient ischemic attack (TLA) or his¬ tory of hemiplegic or basilar migraine because these pa¬ tients are at a higher risk of stroke /see Warnings and Pre¬ cautions (5.4)] • Peripheral vascular disease [see Warnings and Precau¬ tions (5.5)] • Ischemic bowel disease [see Warnings and Precautions (5.5)] • Uncontrolled hypertension [see Warnings and Precautions (5.8)] • Recent use (i.e., within 24 hours) of ergotamine-containing

medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine, (5-HT!) agonist [see Drug Interactions (7.1, 7.3)1 • Concurrent administration of a monoamine -oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)1

• Hypersensitivity to IMITREX (angioedema and anaphy¬ laxis seen) [see Warnings and Precautions (5.9)] • Severe hepatic impairment [see Use in Specific Popula¬ tions (8.6) and Clinical Pharmacology (12.3)]

5 WARNINGS AND PRECAUTIONS 5.1

Myocardial Ischemia, Myocardial Infarction, and

Prinzmetal's Angina

The use of IMITREX Tablets is contraindicated in patients with ischemic or vasospastic CAD. There have been rare re¬ ports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours follow¬ ing administration of IMITREX Tablets. Some of these re¬ actions occurred in patients without known CAD. IMITREX Tablets may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptari-naive pa¬ tients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Tablets. If there is evidence of CAD or coronary artery vasospasm, IMITREX Tablets are contraindicated. For pa¬ tients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX Tablets in a medically supervised setting and performing an electrocardiogram (ECG) imme¬ diately following administration of IMITREX Tablets. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX Tablets. 5.2

Arrhythmias

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HTt agonists. Discontinue IMITREX Tablets if these disturbances occur. IMITREX Tablets are contraindicated in patients with WolffParkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3

Chest, Throat, Neck, and/or Jaw Pain/Tightness/

Pressure

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX Tablets and are usually non¬ cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX Tablets is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.4

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT, ago¬ nists. and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT, agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, pa¬ tients with migraine may be at increased risk of certain ce¬ rebrovascular events (e.g., stroke, hemorrhage, TLAi. Dis¬ continue IMITREX Tablets if a cerebrovascular event occurs. Before treating headaches in patients not previously diag¬ nosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neuro¬ logical conditions. IMITREX Tablets are contraindicated in patients with a history of stroke or TLA. 5.5

Other Vasospasm Reactions

IMITREX Tablets may cause non-coronary vasospastic re¬ actions, such as peripheral vascular ischemia, gastrointes¬ 4 CONTRAINDICATIONS tinal vascular ischemia and infarction (presenting with ab¬ dominal pain and bloody diarrhea), splenic infarction, and IMITREX Tablets are contraindicated in patients with: Raynaud's syndrome. In patients who experience symptoms • Ischemic coronary artery disease (CAD) (angina pectoris, or signs suggestive of non-coronary vasospasm reaction fol¬ history of myocardial infarction, or documented silent is¬ lowing the use of any 5-HT, agonist, rule out a vasospastic chemia) or coronary artery vasospasm, including Prinz¬ ! reaction before receiving additional IMITREX Tablets. metal’s angina/see Warnings and Precautions (5.1)]

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IMITREX TABLETS • GLAXOSMITHKLINE/979

Reports of transient and permanent blindness and signifi¬ cant partial vision loss have been reported with the use of 5-HT, agonists. Since visual disorders may be part of a mi¬ graine attack, a causal relationship between these events and the use of 5-HT, agonists have not been clearly estab¬ lished. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medica¬ tion overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked in¬ crease in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7

Table 1. Adverse Reactions Reported by at Least 2% of Patients Treated With IMITREX Tablets and at a Greater Frequency Than Placebo Percent of Patients Reporting

Serotonin Syndrome

In = 771)

(n = 437)

Placebo (n = 309)

Atypical sensations Paresthesia (all types) Sensation warm/cold

5 3 3

6 5 2

6 3 3

4 2 2

Pain and other pressure sensations Chest - pain/tightness/ pressure and/or heaviness Neck/throat/jaw - pain/ tightness/pressure Pain - location specified Other - pressure/tightness/ heaviness

6 1

6 2’

8 2

4 1

20 mm

0.3

0.0

1.9

Swelling, any

9.6

20.4

24.8

Swelling, >20 mm

0.6

0.0

1.3

In a US study, the safety of a booster dose of INFANRIX was evaluated in children 15 to 18 months of age whose previous 3 DTaP doses were with INFANRIX 101.3°F) Fever' (>102.2°F)

4.5 0.3

9.7

5.8-

3.1

0.0

0.3

0.3

N

335

323

315

54.0

44.5

48.3

Pain, grade 2 or 3

19.0

18.6

Pain, grade 3

3.6

3.4

Redness, any

48.2

49.9

6.1

6.0

32.8

32.7

3.6

5.2

33.2

26.2

0.0

1.3

2.3

Fever'(>103.1oF)

Drowsiness, any

Pain, any

48.3

38.4 Redness, >20 mm

Drowsiness, grade 2 or 3

17.6

Drowsiness, grade 3

3.6

0.6

1.9

61.5

61.6

56.5

Increase in mid-thigh circumference, any

19.4

Increase in mid-thigh circumference, >40 mm

Irritability/ Fussiness, any

12.4

11.1 Swelling, any

21.1

Swelling, >20 mm

Irritability/ Fussiness, grade 2 or 3

19.4

Irritability/ Fussiness, grade 3

3.9

Loss of appetite, any

27.8

26.6

23.8

Loss of appetite, grade 2 or 3

5.1

3.4

5.4

Drowsiness, any

Loss of appetite, grade 3

0.6

0.0

General

3.4

3.2

Fever* (>99.5“F)

8.9

15.4

Fever* (>100.4°F)

4.5

6.7

Fever* (>101.3°F)

2.0

2.0

35.6

31.3

Drowsiness, grade 2 or 3

9.3

6.7

Drowsiness, grade 3

2.4

1.3

Irritability, any

52.2

53.9

Irritability, grade 2 or 3

18.2

19.7

Irritability, grade 3

3.2

1.4

Loss of appetite, any

24.7

23.3

Loss of appetite, grade 2 or 3

5.3

4.9

Loss of appetite, grade 3

2.4

0.5

«

0.3

Hib conjugate vaccine and PCV7 manufactured by Wyeth Pharmaceuticals Inc. IPV manufactured by Sanofi Pasteur SA. Modified intent to treat cohort = all vaccinated subjects for whom safety data were available. N = number of infants for whom at least one symptom sheet was completed; for fever, numbers exclude missing temperature recordings or tympanic measurements. Grade 2: pain defined as cried/protcsted on touch; drowsiness defined as interfered with normal daily activities; irritability/fussiness defined as crying more than usual/interfered with normal daily activities; loss of appetite defined as eating less than usual/interfered with normal daily activities. Grade 3: pain defined as cried when limb was moved/ spontaneously painful; drowsiness defined as prevented normal daily activities; irritability/fussiness defined as crying that could not be comforted/prevented normal daily activities; loss of appetite defined as no eating at all. “Within 4 days of vaccination defined as day of vaccination and the next 3 days. bLocal reactions at the injection site for INFANRIX.

Local6

Pain, any

53.3

Pain, grade 2 or 3*

12.0

Pain, grade 3'

0.6

Redness, any

36.6

Redness, >50 mm

20.0

Redness, >110 mm

4.1

Arm circumference increase, any

37.8

Arm circumference increase, >20 mm

7.4

Arm circumference increase, >30 mm

3.2

Swelling, any

27.0

Swelling, >50 mm

11.5

Swelling, >110 mm

1.8

General

Drowsiness, any Drowsiness, grade 3d

Total Vaccinated Cohort = all subjects who received a dose of study vaccine. N = number of subjects for whom at least one symptom sheet was completed. Grade 2; pain defined as cried/protested on touch; drowsiness defined as interfered with normal daily activities; irritability defined as crying more than usual/ interfered with normal daily activities; loss of appetite defined as eating less than usual/no effect on normal daily activities.

N = 1,039-1,043

N = 993-1,036

17.5 . 0.8

Fever, >99.5“F

14.8

Fever, >100.4°F

4.4

Fever, >102.2“F

1.1

Fever, >104‘>F

0.0

Loss of appetite, any

16.0

Loss of appetite, grade 3*

0.6

TPV manufactured by Sanofi Pasteur SA. MMR vaccine manufactured by Merck & Co., Inc. Tbtal Vaccinated Cohort = all vaccinated subjects for whom safety data were available. N = number of children with evaluable data for the ev ents listed. * Within 4 days of vaccination defined as day of vaccination and the next 3 days. ‘’Local reactions at the injection site for INFANRIX 'Grade 2 defined as painful when the limb was moved. Grade 3 defined as preventing normal daily activities ‘‘Grade 3 defined as preventing normal daily activities * Grade 3 defined as not eating at all

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990/GLAXOSMITHKLINE • INFANRIX

Table 4. Selected Adverse Events Occurring Within 48 Hours Following Vaccination With INFANRIX or Whole-Cell DTP in Italian Infants at 2, 4, or 6 Months of Age Whole-Cell DTP Vaccine

INFANRIX (N

(N = 13,520 Doses)

13,761 Doses)

Number

Rate/1,000 Doses

Number

Rate/1,000 Doses

Fever(£104°F fb

5

0.36

32

2.4

Hypotonic-hyporesponsive episode'

0

0

9

0.67

Persistent crying >3 hours”

6

0.44

54

4.0

Seizures'1

1'

0.07

3r

0.22

Event

“P 50 mm increase in the mid-thigh circumference compared to the pre-vaccination measurement, and/or any diffuse swelling that interfered with or prevented daily activities. The overall incidence of large swelling reactions occurring within 4 days (Day 0-Day 3) following INFANRIX was 2.3%. In the fifth dose study, a large swelling reaction was defined as swelling that involved >50% of the injected upper arm length and that was associated with a >30 mm increase in mid-upper arm Circumference within 4 days following vac¬ cination. The incidence of large swelling reactions following the fifth consecutive dose of INFANRIX was 1.0%. Less Common and Serious General Adverse Events: Se¬ lected adverse events reported from a double-blind, random¬ ized Italian clinical efficacy trial involving 4,696 children administered INFANRIX or 4,678 children administered whole-cell DTP vaccine (DTwP) (manufactured by Connaught Laboratories, Inc.) as a 3-dose primary series are shown in Table 4. The incidence of rectal temperature >104°F, hypotonic-hyporesponsive episodes and persistent crying >3 hours following administration of INFANRIX was significantly less than that following administration of whole-cell DTP vaccine. [See table 4 above] In a German safety study that enrolled 22,505 infants (66,867 doses of INFANRIX administered as a 3-dose pri¬ mary series at 3, 4, and 5 months of age), all subjects were monitored for unsolicited adverse events that occurred within 28 days following vaccination using report cards. In a subset of subjects (N = 2,457), these cards were standard¬ ized diaries which solicited specific adverse events that occurred within 8 days of each vaccination in addition to un¬ solicited adverse events which occurred from enrollment un¬ til approximately 30 days following the third vaccination. Cards from the whole cohort were returned at subsequent visits and were supplemented by spontaneous reporting by parents and a medical history after the first and second doses of vaccine. In the subset of 2,457, adverse events fol¬ lowing the third dose of vaccine were reported via standard¬ ized diaries and spontaneous reporting at a follow-up visit. Adverse events in the remainder of the cohort were reported via report cards which were returned by mail approximately 28 days after the third dose of vaccine. Adverse events (rates per 1,000 doses) occurring within 7 days following any of the first 3 doses included: unusual crying (0.09), feb¬ rile seizure (0.0), afebrile seizure (0.13), and hypotonichyporesponsive episodes (0.01). 6.2

Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for INFANRIX since mar¬ ket introduction are listed below. This list includes serious events and events which have a plausible causal connection to INFANRIX. These adverse events were reported volun¬ tarily from a population of uncertain size; therefore, it is not always possible to reliably estimate their frequency or es¬ tablish a causal relationship to vaccination. Infections and Infestations: Bronchitis, cellulitis, respira¬ tory tract infection. Blood and Lymphatic System Disorders: Lymphadenopathy, thrombocytopenia. Immune System Disorders: Anaphylactic reaction, hyper¬ sensitivity. Nervous System Disorders: Encephalopathy, headache, hy¬ potonia. syncope.

Ear and Labyrinth Disorders: Ehr pain. Cardiac Disorders: Cyanosis. Respiratory, Thoracic, and Mediastinal Disorders: Apnea, cough. Skin and Subcutaneous Tissue Disorders: Angioedema, ery¬ thema, pruritus, rash, urticaria. General Disorders and Administration Site Conditions: Fatigue, injection site induration, injection site reaction, Sudden Infant Death Syndrome. 7 7.1

DRUG INTERACTIONS Concomitant Vaccine Administration

In clinical trials, INFANRIX was given concomitantly with Hib conjugate vaccine, pneumococcal 7-valent conjugate vaccine, hepatitis B vaccine, IPV, and the second dose of MMR vaccine [see Adverse Reactions (6.1) and Clinical Studies (14.3)]. When INFANRIX is administered concomitantly with other injectable vaccines, they should be given with separate sy¬ ringes. INFANRIX should not be mixed with any other vac¬ cine in the same syringe or vial. 7.2

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, anti¬ metabolites, alkylating agents, cytotoxic drugs, ind cortico¬ steroids (used in greater than physiologic doses), may re¬ duce the immune response to INFANRIX. 8 8.1

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category C Animal reproduction studies have not been conducted with INFANRIX. It is also not known whether INFANRIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 8.4

Pediatric Use

Safety and effectiveness of INFANRIX in infants younger than 6 weeks of age and children 7 to 16 years of age have not been established. INFANRIX is not approved for use in these age groups. 11

DESCRIPTION

INFANRIX (Diphtheria and Tetanus Tixoids and Acellular Pertussis Vaccine Adsorbed) is a noninfectious, sterile vac¬ cine for intramuscular administration. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 meg of inactivated pertussis toxin i PT), 25 meg of filamentous hemagglutinin (FHA), and 8 meg of pertactin (69 kiloDalton outer membrane protein). The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine ex¬ tract. Tetanus toxin is produced by growing Clostridium tetani in a modified I.atham medium derived from bovine casein. The bovine materials used in these extracts are sourced from countries which the United States Depart¬ ment of Agriculture (USDA) has determined neither have nor present an undue risk for bovine spongiform encepha¬ lopathy (BSE). Both toxins are detoxified with formalde¬ hyde. concentrated by ultrafiltration, and purified by precip¬ itation, dialysis, and sterile filtration. The acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in mod¬ ified Stainer-Scholte liquid medium. PT and FHA are iso¬ lated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The anti¬ gens are purified in successive chromatographic and precip¬ itation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formal¬ dehyde. Diphtheria and tetanus toxoids and pertussis antigens (PT, FHA. and pertactin) are individually adsorbed onto alumi¬ num hydroxide.

Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previ¬ ously immunized guinea pigs. The potency of the acellular pertussis components (PT, FHA, and pertactin) is deter¬ mined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Each 0.5-mL dose contains aluminum hydroxide as adju¬ vant (not more than 0.625 mg aluminum by assay) and 4.5 mg of sodium chloride. Each dose also contains 0.01 IU/mL were achieved in 100% of the sera tested. 14.2

Pertussis

Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies. A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy assessed the absolute protective efficacy of INFANRIX when adminis¬ tered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. The mean length of follow-up was 17 months, begin¬ ning 30 days after the third dose of vaccine. After 3 doses, the absolute protective efficacy of INFANRIX against WHOdefined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% Cl: 76, 89). When the definition of pertussis was expanded to include clinically milder disease with respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was calculated to be 71% (95% Cl: 60, 78) against >7 days of any cough and 73% (95% Cl: 63, 80) against £14 days of any cough. Vaccine efficacy after 3 doses and with no booster dose in the second year of life was as¬ sessed in 2 subsequent follow-up periods. A follow-up period from 24 months to a mean age of 33 months was conducted in a partially unblinded cohort (children who received DT were offered pertussis vaccine and those who declined were retained in the study cohort). During this period, the effi¬ cacy of INFANRIX against WHO-defined pertussis was 78% (95% Cl: 62, 87). During the third follow-up period which was conducted in an unblinded manner among children from 3 to 6 years of age, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% Cl: 79, 91). Thus, protection against pertussis in children administered 3 doses of INFANRIX in infancy was sustained to 6 years of age.

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JALYN • GLAXOSMITHKLINE/991

Look for PDR drug information and services in your EHR NDC 58160-810-01 Vial in Package of 10: NDC 58160A prospective efficacy trial was also conducted in Germany employing a household contact study design. In preparation 810-11 for this study, 3 doses of INFANRIX were administered at 3. NDC 58160-810-43 Syringe in Package of 10: NDC 581604, and 5 months of age to more than 22,000 children living 810-52 in 6 areas of Germany in a safety and immunogenicity Store refrigerated between 2° and 8°C (36° and 46°F). Do study. Infants who did not participate in the safety and im¬ not freeze. Discard if the vaccine has been frozen. munogenicity study could have received a DTwP vaccine or 17 PATIENT COUNSELING INFORMATION DT vaccine. Index cases were identified by spontaneous pre¬ sentation to a physician. Households with at least one other The parent or guardian should be: member (i.e., besides index case) aged 6 through 47 months • informed of the potential benefits and risks of immuniza¬ were enrolled. Household contacts of index cases were mon¬ tion with INFANRIX, and of the importance of completing itored for incidence of pertussis by a physician who was the immunization series. blinded to the vaccination status of the household. Calcula¬ • informed about the potential for adverse reactions that tion of vaccine efficacy was based on attack rates of pertus¬ have been temporally associated with administration of sis in household contacts classified by vaccination status. Of INFANRIX or other vaccines containing similar compo¬ the 173 household contacts who had not received a pertussis nents. • instructed to report any adverse events to their health¬ vaccine, 96 developed WHO-defined pertussis, as compared with 7 of 112 contacts vaccinated with INFANRIX. The pro¬ care provider. tective efficacy of INFANRIX was calculated to be 89'; (95% • given the Vaccine Information Statements, which are re¬ Cl: 77, 95), with no indication of waning of protection up quired by the National Childhood Vaccine Injury Act of until the time of the booster vaccination. The average age of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease infants vaccinated with INFANRIX at the end of follow-up in this trial was 13 months (range 6 to 25 months). When Control and Prevention (CDC) website (www.cdc.gov/vaccines). the definition of pertussis was expanded to include clinically ENGERIX-B, INFANRIX, PEDIARIX, and TIP-LOK are milder disease, with infection confirmed by culture and/or registered trademarks of the GlaxoSmithKline group of serologic testing, the efficacy of INFANRIX against >7 days of any cough was 67% (95% Cl: 52, 78) and against >7 days companies. Manufactured by GlaxoSmithKline Biologicals of paroxysmal cough was 81% (95% Cl: 68, 89). The corre¬ Rixensart, Belgium, US License 1617 sponding efficacy of INFANRIX against 214 days of any Novartis Vaccines and Diagnostics GmbH cough or paroxysmal cough were 73% (95% Cl: 59, 82) and j Marburg, Germany, US License 1754 84% (95% Cl: 71, 91), respectively. Distributed by GlaxoSmithKline Pertussis Immune Response to INFANRIX Administered as a 3-Dose Primary Series: The immune responses to each of j Research Triangle Park, NC 27709 the 3 pertussis antigens contained in INFANRIX were eval¬ | ©2013, GlaxoSmithKline group of companies. All rights re¬ uated in sera obtained 1 month after the third dose of vac¬ served. INF:25PI cine in each of 3 studies (schedule of administration: 2, 4, and 6 months of age in the Italian efficacy study and one-US study; 3, 4, and 5 months of age in the German efficacy JALYN IJ study). One month after the third dose of INFANRIX, the [JAY-LIN] response rates to each pertussis antigen were similar in all (dutasteride and tamsulosin hydrochloride) 3 studies. Thus, although a serologic correlate of protection capsules for pertussis has not been established, the antibody re¬ sponses to these 3 pertussis antigens (PT. FHA. and pertacHIGHLIGHTS OF PRESCRIBING INFORMATION tin) in a US population were similar to those achieved in 2 These highlights do not include all the information needed populations in which efficacy of INFANRIX was demon¬ to use JALYN safely and effectively. See full prescribing in¬ strated. 14.3

Immune Response to Concomitantly Administered

Vaccines

formation for JALYN. JALYN (dutasteride

and

tamsulosin

;

j

j

j ,

-ADVERSE REACTIONSThe most common adverse reactions, reported in 21% of subjects treated with coadministered dutasteride and tamsulosin are ejaculation disorders, impotence, decreased libido, dizziness, and breast disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 1/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1

hydrochloride)

capsules In a US study, INFANRIX was given concomitantly, at sep¬ Initial U.S. Approval: 2010 arate sites, with Hib conjugate vaccine (Sanofi Pasteur SA) at 2, 4, and 6 months of age. Subjects also received -INDICATIONS AND USAGEENGERIX-B and oral poliovirus vaccine (OPV). One month | JALYN is a combination of dutasteride. a 5-alpha-reductase after the third dose of Hib conjugate vaccine, 90% of 72 in¬ inhibitor, and tamsulosin, an alpha-adrenergic antagonist, fants had anti-PRP (polyribosyl-ribitol-phosphate) indicated for the treat ment of symptomatic benign prostatic >1.0 mcg/mL. hyperplasia (BPII) in men with an enlarged prostate. (1.1) In a US study, INFANRIX was given concomitantly, at sep¬ Limitations of Use: Dutasteride-containing products, inarate sites, with ENGERIX-B, IPV (Sanofi Pasteur SA), eluding JALYN, are not approved for the prevention of pros¬ pneumococcal 7-valent conjugate (PCV7). and Hib conjugate tate cancer. (1.2) vaccines (Wyeth Pharmaceuticals Inc.) at 2, 4, and 6 months of age. Immune responses were measured in sera obtained -DOSAGE AND ADMINISTRATIONapproximately one month after the third dose of vaccines. • Take one capsule daily approximately 30 minutes after the Among 121 subjects who had not receiver! a birth dose of same meal each day. (2) hepatitis B vaccine. 99.2% had anti-HBsAg (hepatitis B sur¬ • Swallow capsule whole. (2) face antigen) >10 mlU/mL following the third dose of ENGERIX-B. Among 153 subjects. 100% had anti-poliovirus -DOSAGE FORMS AND STRENGTHS1, 2, and 3, 21:8 following the third dose of IPV'. Although 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride. serological correlates for protection have not been estab¬ (3) lished for the pneumococcal serotypes, a threshold level of -CONTRAINDICATIONS20.3 mcg/mL was evaluated. Following the third dose of PCV7 vaccine, 91.8% to 99.4% of subjects (N = 146-156) had • Pregnancy and women of childbearing potential < 4, 5.6, anti-pneumococcal polysaccharide 20.3 mcg/mL for sero- i 8 1) types 4, 9V. 14, 18C, 19F. and 23F, and 73.0% had a level ' • Pediatric patients. (4) 20.3 mcg/mL for serotype 6B. • Patients with previously demonstrated, clinically signifi¬ cant hypersensitivity (e.g.. serious skin reactions, angio15 REFERENCES edema. urticaria, pruritus, respiratory symptoms) to 1. Vitek GR and Wharton M. Diphtheria Toxoid. In: Plotkin dutasteride, other 5-alpha-reductase inhibitors, SA, Orenstein WA, and Offit PA. eds. Vaccines. 5th ed. tamsulosin. or any component of JALYN. (4) Saunders; 2008:139-156. 2. Wassilak SGF, Roper MH, Kretsinger K, and Orenstein -WARNINGS AND PRECAUTIONSWA. Tbtanus Toxoid. In: Plotkin SA, Orenstein WA, and • Orthostatic hypotension and/or syncope can occur. Advise Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:805-839. patients of symptoms related to postural hypotension and 3. Department of Health and Human Services, Food and to avoid situations where injury could result if syncope ocDrug Administration. Biological products; Bacterial vac¬ curs. (5.1) cines and toxoids; Implementation of efficacy review; Pro • Do not use JALYN with other alpha-adrenergic antago¬ posed rule. Federal Register December 13, nists. as this may increase the risk of hypotension (5.2) 1985;50(240):51002-51117. • JALYN reduces serum prostate-specific antigen (PSA)con4. Centers for Disease Control and Prevention. General Rec¬ centration by approximately 50%. However, any confirmed ommendations on Immunization. Recommendations of increase in PSA while on JALYN may signal the presence the Advisory Committee on Immunization Practices of prostate cancer and should be evaluated, even if those (ACIP). MMWR 2006;55(RR-15): 1 -48. values are still within the normal range for untreated 16 HOW SUPPLIED/STORAGE AND HANDLING men. (5.3) Do not use JALYN with strong inhibitors of cytochrome INFANRIX is available in 0.5-mL single-dose vials and dis¬ P450 (CYP) 3A4 (e.g., ketoconazole). Use caution in com¬ posable prefilled TIP-LOK syringes (packaged without bination with moderate CYP3A4 inhibitors (e.g., erythro¬ needles):

J •

mycin) or strong (e.g., paroxetine) or moderate CYP2D6 inhibitors, or known poor metabolizers of CYP2D6. Con¬ comitant use with known inhibitors can cause a marked increase in drug exposure. (5.2, 7 1, 12.3) • Exercise caution with concomitant use of phosphodiesterase-5- (PDE-51 inhibitors, as this may in¬ crease the risk of hypotension. (5.2) • Drugs that contain dutasteride, including JALYN, may in¬ crease the risk of high-grade prostate cancer. (5.4, 6.1) • Prior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. (5.5) • Women who are pregnant or could become pregnant should not handle JALYN capsules due to potential risk to a male fetus. (5.6, 8.1) • Advise patients about the possibility and seriousness of priapism. (5.7) • Patients should not donate blood until 6 months after their last dose of JALYN. (5.8) • Intraoperative Floppy Iris Syndrome has been observed during cataract surgery after alpha-adrenergic antagonist exposure. Advise patients considering cataract surgery to tell their ophthalmologist that they take or have taken JALYN capsules. (5.9) • Exercise caution with concomitant use of warfarin. (5.2, 7.2. 12.3)

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INDICATIONS AND USAGE 1.1 Benign Prostatic Hyperplasia (BPH) Treat¬ ment Limitations of Use 1.2 DOSAGE AND ADMINISTRATION 2 DOSAGE FORMS AND STRENGTHS 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 Orthostatic Hypotension 5.1 Drug-drug Interactions 5.2 Effects on Prostate-specific Antigen (PSA) 5.3 and the Use of PSA in Prostate Cancer Detection Increased Risk of High-grade Prostate Can5.4 cer Evaluation for Other Urological Diseases 5.5 Exposure of Women—Risk to Male Fetus 5.6 Priapism 5.7 Blood Donation 5.8 Intraoperative Floppy Iris Syndrome 5.9 Sulfa Allergy 5.10 Effect on Semen Characteristics 5.11 ADVERSE REACTIONS 6 Clinical Trials Experience 6.1 Postmarketing Experience 6.2 DRUG INTERACTIONS 7 Cytochrome P450 3A Inhibitors 7.1 Warfarin 7.2 Nifedipine, Atenolol, Enalapril , 7.3 Digoxin and Theophylline 7.4 F urosemide 7.5 Calcium Channel Antagonists 7.6 Cholestyramine 7.7 USE IN SPECIFIC POPULATIONS 8 Pregnancy 8.1 Nursing Mothers 8.3 Pediatric Use 8.4 Geriatric Use 8.5 Renal Impairment 8.6 Hepatic Impairment 8.7 OVERDOSAGE 10 DESCRIPTION 11 CLINICAL PHARMACOLOGY 12 Mechanism of Action 12.1 Pharmacodynamics 12.2 Pharmacokinetics 12.3 NONCLINICAL TOXICOLOGY 13 Carcinogenesis, Mutagenesis, Impairment of 13.1 Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed.

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992/GLAXOSMITHKLINE • JALYN 5.3 FULL PRESCRIBING INFORMATION

1 1.1

INDICATIONS AND USAGE Benign Prostatic Hyperplasia (BPH) Treatment

JALYN® (dutasteride and tamsulosin hydrochloride) capsules are indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.2

Limitations of Use

Dutasteride-containing products, including JALYN, are not approved for the prevention of prostate cancer. 2

DOSAGE AND ADMINISTRATION

The recommended dosage of JALYN is 1 capsule (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) taken once daily approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Contact with the contents of the JALYN capsule may result in irritation of the oropharyngeal mucosa. 3

DOSAGE FORMS AND STRENGTHS

JALYN capsules, containing 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride, are oblong, hard-shell capsules with a brown body and an orange cap imprinted with “GS 7CZ” in black ink. 4

CONTRAINDICATIONS

JALYN is contraindicated for use in: • Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, JALYN may cause fetal harm when administered to a pregnant woman. If JALYN is used during pregnancy, or if the pa¬ tient becomes pregnant while taking JALYN, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.6), Use in Specific Popula¬ tions (8.1)]. • Women of childbearing potential [see Warnings and Pre¬ cautions (5.6), Use in Specific Populations (8.1)]. • Pediatric patients [see Use in Specific Populations (8.4)]. • Patients with previously demonstrated, clinically signifi¬ cant hypersensitivity (e.g., serious skin reactions, angioedema, urticaria, pruritus, respiratory symptoms) to dutasteride, other 5-alpha-reductase inhibitors, tamsulosin, or any other component of JALYN [see Ad¬ verse Reactions (6.2)]. 5 5.1

Effects on Prostate-specific Antigen (PSA) and the

Use of PSA in Prostate Cancer Detection

WARNINGS AND PRECAUTIONS Orthostatic Hypotension

As with other alpha-adrenergic antagonists, orthostatic hy¬ potension (postural hypotension, dizziness, and vertigo) may occur in patients treated with tamsulosin-containing products, including JALYN, and can result in syncope. Pa¬ tients starting treatment with JALYN should be cautioned to avoid situations where syncope could result in an injury [see Adverse Reactions (6.1)]. 5.2 Drug-drug Interactions Strong Inhibitors of CYP3A4 Tamsulosin-containing products, including JALYN, should not be coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) as this can significantly increase tamsulosin exposure [see Drug Interactions (7.1), Clinical Pharmacol¬ ogy (12.3)1. Inhibitors of CYP2D6 and Moderate Inhibitors of CYP3A4 Tamsulosin-containing products, including JALYN, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g., erythromycin), strong (e.g., par¬ oxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Cimetidine Caution is advised when tamsulosin-containing products, including JALYN, are coadministered with cimetidine [see Drug Interactions (7.1), Clinical Pharmacology (12.3)1. Other Alpha-adrenergic Antagonists Tamsulosin-containing products, including JALYN, should not be coadministered with other alpha-adrenergic antago¬ nists because of the increased risk of symptomatic hypoten¬ sion. Phosphodiesterase-5 tPDE-5) Inhibitors Caution is advised when alpha-adrenergic-antagonistcontaining products, including JALYN, are coadministered with PDE-5 inhibitors. Alpha-adrenergic antagonists and PDE-5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these 2 drug classes can po¬ tentially cause symptomatic hypotension. Warfarin Caution should be exercised with concomitant administration of warfarin and tamsulosin-containing products, in¬ cluding JALYN /see Drug Interactions (7.2). Clinical Pharmacology (12.3)].

Coadministration of dutasteride with tamsulosin resulted in similar changes to serum PSA as with dutasteride mono¬ therapy. In clinical trials, dutasteride reduced serum PSA concentra¬ tion by approximately 50% within 3 to 6 months of treat¬ ment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride-containing treatment, including JALYN, may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men treated with a dutasteride-containing product, in¬ cluding JALYN, a new baseline PSA should be established at least 3 months after starting treatment and PSA moni¬ tored periodically thereafter. Any confirmed increase from the lowest PSA value while on a dutasteride-containing treatment, including JALYN, may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5-alpha-reductase inhibitor. Noncompliance with JALYN may also affect PSA test results. Tb interpret an isolated PSA value in a man treated with JALYN, for 3 months or more, the PSA value should be dou¬ bled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains con¬ stant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving JALYN, no adjustment to its value appears necessary. 5.4

Increased Risk of High-grade Prostate Cancer

In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8 to 10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage (1.2), Adverse Reactions (6.1)]. In a 7-year placebocontrolled clinical trial with another 5-alpha-reductase in¬ hibitor (finasteride 5 mg, PROSCAR®), similar results for Gleason score 8 to 10 prostate cancer were observed (finas¬ teride 1.8% versus placebo 1.1%). 5-alpha-reductase inhibitors may increase the risk of devel¬ opment of high-grade prostate cancer. Whether the effect of 5-alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established. 5.5

Evaluation for Other Urological Diseases

Prior to initiating treatment with JALYN, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist. 5.6

Exposure of Women—Risk to Male Fetus

JALYN capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is ab¬ sorbed through the skin and could result in unintended fe¬ tal exposure. If a woman who is pregnant or could become pregnant comes in contact with a leaking capsule, the con¬ tact area should be washed immediately with soap and wa¬ ter [see Use in Specific Populations (8.1)]. 5.7

Priapism

Priapism (persistent painful penile erection unrelated to sexual activity) has been associated (probably less than 1 in 50,000) with the use of alpha-adrenergic antagonists, in¬ cluding tamsulosin, which is a component of JALYN. Be¬ cause this condition can lead to permanent impotence if not properly treated, patients should be advised about the seri¬ ousness of the condition. 5.8

Blood Donation

Men being treated with a dutasteride-containing product, including JALYN, should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. 5.9

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been ob¬ served during cataract surgery in some patients on or pre¬ viously treated with alpha-adrenergic antagonists, includ¬ ing tamsulosin, which is a component of JALYN. Most reports were in patients taking the alpha-adrenergic antagonist when IFIS occurred, but in some cases, the alpha-adrenergic antagonist had been stopped prior to sur¬ gery. In most of these cases, the alpha-adrenergic antago¬ nist had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the pa¬ tients had been off the alpha-adrenergic antagonist for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and is characterized by the combina¬ tion of a flaccid iris that bdlows in response to intraopera¬ I tive irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic 1 drugs, and potential prolapse of the iris toward the pha¬ coemulsification incisions. The patient's ophthalmologist

should be prepared for possible modifications to their surgi¬ cal technique, such as the utilization of iris hooks, iris dila¬ tor rings, or viscoelastic substances. IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alphaadrenergic antagonist therapy prior to cataract surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract surgery is sched¬ uled is not recommended. 5.10

Sulfa Allergy

In patients with sulfa allergy, allergic reaction to tamsulosin has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is war¬ ranted when administering tamsulosin-containing prod¬ ucts, including JALYN. 5.11

Effect on Semen Characteristics

Dutasteride The effects of dutasteride 0.5 mg/day on semen characteris¬ tics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaf¬ fected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group re¬ mained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual pa¬ tient’s fertility is not known. Tamsulosin The effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated. 6 6.1

ADVERSE REACTIONS Clinical Trials Experience

There have been no clinical trials conducted with JALYN; however, the clinical efficacy and safety of coadministered dutasteride and tamsulosin, which are individual compo¬ nents of JALYN, have been evaluated in a, multicenter, ran¬ domized, double-blind, parallel group tripl (the Combina¬ tion with Alpha-Blocker Therapy, or CombAT, trial). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. • The most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disor¬ ders, and dizziness. Ejaculation disorders occurred signif¬ icantly more in subjects receiving coadministration ther¬ apy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy, • Trial withdrawal due to adverse reactions occurred in 6' > of subjects receiving coadministered dutasteride and tamsulosin, and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse re¬ action in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). In the CombAT trial, over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride. 0.4 mg tamsulosin hydrochloride, or coadministration ther¬ apy (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) administered once daily in a 4-year double¬ blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy w ith tamsulosin; and 1,610 subjects received coadministration therapy. The population was aged 49 to 88 years ( mean age; 66 years) and 88% were white. Table 1 summarizes adverse reactions reported in at least 1% of subjects receiving coad¬ ministration therapy and at a higher incidence than sub¬ jects receiving either dutasteride or tamsulosin as mono¬ therapy. (See table 1 at top of next page) Cardiac Failure In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the coadministration group (12/1,610; 0.7%) was higher than in either mono¬ therapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate can¬ cer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects w ith

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Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the individual components of JALYN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to re¬ liably estimate their frequency or establish a causal rela¬ tionship to drug exposure. These reactions have been chosen for inclusion due to a combination of their serious¬ ness, frequency of reporting, or potential causal connection to drug exposure. Dutasteride: Immune System Disorders: Hypersensitivity reactions, in¬ cluding rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema. Neoplasms: Male breast cancer. Psychiatric Disorders: Depressed mood. Reproductive System and Breast Disorders: Testicular pain and testicular swelling. Tamsulosin: Immune System Disorders: Hypersensitivity reactions, in¬ cluding rash, urticaria, pruritus, angioedema, and respira¬ tory problems have been reported with positive rechallenge in some cases. Cardiac Disorders: Palpitations, dyspnea, atrial fibrilla¬ tion. arrhythmia, and tachycardia. Skin Disorders: Skin desquamation, including StevensJohnson syndrome, erythema multiforme, dermatitis exfoli¬ ative. Gastrointestinal Disorders: Constipation, vomiting, dry mouth. Reproductive System and Breast Disorders: Priapism. Respiratory: Epistaxis

Adverse Reaction Time of Onset Year 1 Adverse Reaction

Coadministration0 Dutasteride Tamsulosin

Months 0-6

Months 7-12

Year 2

Year 3

Year 4

(n = 1,610) (n = 1,623) (n = 1,611)

(n = 1,527) (n = 1,548) (n = 1,545)

(n = 1,428) (n = 1,464) (n = 1,468)

(n = 1,283* (n = 1,325) (n = 1,2811

(n = 1,2001 (n = 1,200)

Ejaculation disorders1*-0 Coadministration Dutasteride Tamsulosin Impotence0-*1 Coadministration Dutasteride Tamsulosin

7.8% 1.0% 2.2%

1.6% 0.5% 0.5%

1.0% 0.5% 0.5%

0.5% 0.2% 0.2%

20 mm Arm circumference increase, >30 mm

36.0

37.8

6.9

7.4

2.4

32

Swelling, any Swelling, >50 mm Swelling, 2110 mm

26.0 10.2 1.4

27.0 11.5 1.8

DRUG INTERACTIONS

7.1

Concomitant Vaccine Administration

In US clinical trials. KINRIX was administered concomi¬ tantly with the second dose of MMR vaccine 'Merck & Co., Inc.); in one of these trials (Study 055), KINRIX was also administered concomitantly with varicella vaccine i Merck & Co., Inc.) Isee Clinical Studies (14.2)1. When KINRIX is administered concomitantly with other in¬ jectable vaccines, they should be given with separate syrin¬ ges. KINRIX should not be mixed with any other vaccine in the same syringe or vial. 7.2

Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, anti¬ metabolites, alkylating agents, cytotoxic drugs, and cortico¬ steroids (used in greater than physiologic doses), may re| duce the immune response to KINRIX. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with I KINRIX. It is also not known whether KINRIX can cause fetal harm when administered to a pregnant woman or can I affect reproduction capacity

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1000/GLAXOSMITHKLINE • KINRIX

Table 2. Pre-Vaccination Antibody Levels and Post-Vaccination3 Antibody Responses Following KINRIX Compared With Separate Concomitant Administration of INFANRIX and IPV in Children 4 to 6 Years of Age When Coadministered With MMR Vaccine (Study 048) (ATP Cohort for Immunogenicity) KINRIX

INFANRIX + IPV

N = 787-851

N = 237-262

The tip caps of the prefilled syringes may contain natural rubber latex; the plungers are not made with natural rub¬ ber latex. The vial stoppers are not made with natural rub¬ ber latex. KINRIX does not contain a preservative. 12 12.1

Anti-Diphtheria Toxoid

Pre-vaccination % >0.1 IU/mL (95% Cl >b Post-vaccination % >0.1 IU/mL (95% CD5 % Booster Response (95% CI)C

87.7 (85.3, 89.9) 100 (99.6, 100) 99.5 (98.8, 99.9)d

85.5 (80.6, 89.5) 100 (98.6, 100) 100 (98.6, 100)

87.8 (85.4, 90.0) 100 (99.6, 100) 96.7 (95.2, 97.8)d

88.2 (83.6, 91.8) 100 (98.6, 100) 93.9 (90.2, 96.5)

92.2 (90.2, 94.0)d

92.6 (88.7, 95.5)

95.4 (93.7, 96.7)d

96.2 (93.1, 98.1)

97.8 (96.5, 98.6)d

96.9 (94.1, 98.7)

88.3 (85.9, 90.4) 99.9 (99.3, 100) ' 2,127 (1,976, 2,290)r

85.1 (80.1, 89.2) 100 (98.5, 100) 1,685 (1,475, 1,925)

91.8 (89.7, 93.6) 100 (99.6, 100) 2,265 (2,114, 2,427/

87.0 (82.3, 90.8) 100 (98.5, 100) 1,818 (1,606, 2,057)

Anti-Tetanus Toxoid

Pre-vaccination % >0.1 IU/mL (95% Cl)1’ Post-vaccination % >0.1 IU/mL (95% CI)b % Booster Response (95% CIF Anti-PT

% Booster Response (95% CI)e Anti-FHA

% Booster Response (95% CI) Anti-Pertactin

% Booster Response (95% CI)e Anti-Poliovirus 1

Pre-vaccination % >1:8 (95% CI)b Post-vaccination % >1:8 (95% CI)b Post-vaccination GMT (95% Cl) Anti-Poliovirus 2

Pre-vaccination % >1:8 (95% CI)b Post-vaccination % >1:8 (95% CI)b Post-vaccination GMT (95% CD

Pre-vaccination % £1:8 (95% CI)b Post-vaccination % >1:8 (95% CI)b Post-vaccination GMT (95% Cl)

84.7(82.0, 87.0) .100 (99.5, 100) 3,588 (3,345, 3,849/

85.0 (80.1, 89.1) . 100 (98.5, 1001 3,365 (2,961, 3,824)

ATP = according-to-protocol; Cl = Confidence Interval; GMT = geometric mean antibody titer; IPV = inactivated poliovirus vaccine (Sanofi Pasteur SA); MMR = measles, mumps, and rubella vaccine (Merck & Co., Inc.). N = Number of subjects with available results. " One month blood sampling, range 31 to 48 days. b Seroprotection defined as anti-diphtheria toxoid and anti-tetanus toxoid antibody concentrations >0.1 IU/mL by ELISA and as anti-poliovirus Type 1, Type 2, and Type 3 antibody titer >1:8 by micro-neutralization assay for poliovirus. c Booster response: In subjects with pre-vaccination unless lamotrigine plasma levels or clinical response support larger increases. Gradual tran¬ sient increases in lamotrigine plasma levels may occur dur¬ ing the week of inactive hormonal preparation (pill-free week i, and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizzi¬ ness, ataxia, and diplopia. If adverse reactions attributable to IAMICTAL consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking LAMICTAL in ad¬ dition to carbamazepine, phenytoin, phenobarbital. primi-

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LAMICTAL • GLAXOSMITHKLINE/1003

done, or other drugs such as rifampin and the protease in¬ Table 2. Escalation Regimen for LAMICTAL in Patients Aged 2 to 12 Years with Epilepsy hibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions In Patients TAKING (7), Clinical Pharmacology (12.3)1, no adjustment to the In Patients NOT TAKING Carbamazepine, Phenytoin. dose of LAMICTAL should be necessary. Carbamazepine. Phenytoin. Phenobarbital, or (3) Stopping Estrogen-Containing Oral Contraceptives: In In Patients TAKING Phenobarbital, Primidone,b Primidoneb and NOT Valproate* women not taking carbamazepine, phenytoin, phenobarbior Valproate* TAKING Valproate* tal, primidone, or other drugs such as rifampin and the pro¬ 0.15 mg/kg/day tease inhibitors lopinavir/ritonavir and atazanavir/ritonavir 0.3 mg/kg/day 0.6 mg/kg/day in 1 or 2 divided doses, that induce lamotrigine glucuronidation [see Drug Interac¬ in 1 or 2 divided doses, in 2 divided doses, rounded Weeks 1 and 2 rounded down to the nearest tions (7), Clinical Pharmacology (12.3IJ, the maintenance rounded down to the nearest down to the nearest whole whole tablet (see Table 3 for dose of LAMICTAL will in most cases need to be decreased whole tablet tablet weight-based dosing guide) by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of 0.3 mg/kg/day 0.6 mg/kg/day 1.2 mg/kg/day LAMICTAL should not exceed 25% of the total daily dose in 1 or 2 divided doses, in 2 divided doses, rounded in 2 divided doses, rounded per week over a 2-week period, unless clinical response or Weeks 3 and 4 rounded down to the nearest down to the nearest whole down to the nearest whole lamotrigine plasma levels indicate otherwise [see Clinical whole tablet (see Table 3 for tablet tablet Pharmacology (12.3)1. In women taking LAMICTAL in ad¬ weight-based dosing guide) dition to carbamazepine, phenytoin, phenobarbital, primi¬ The dose should be The dose should be done, or other drugs such as rifampin and the protease in¬ The dose should be increased every 1 to 2 weeks increased every 1 to 2 weeks increased every 1 to 2 weeks hibitors lopinavir/ritonavir and atazanavir/ritonavir that as follows: calculate as follows: calculate as follows: calculate induce lamotrigine glucuronidation [see Drug Interactions Week 5 onward to 0.3 mg/kg/day, round this 0.6 mg/kg/day. round this 1.2 mg/kg/day, round this (7), Clinical Pharmacology (12.3)1, no adjustment to the maintenance amount down to the nearest amount down to the nearest amount down to the nearest dose of LAMICTAL should be necessary. whole tablet, and add this whole tablet, and add this whole tablet, and add this Women and Other Hormonal Contraceptive Preparations or amount to the previously amount to the previously amount to the previously Hormone Replacement Therapy administered daily dose. administered daily dose. administered daily dose. The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of 1 to 5 mg/kg/day lamotrigine has not been systematically evaluated. It has (maximum 200 mg/day in 1 4.5 to 7.5 mg/kg/day 5 to 15 mg/kg/day been reported that ethinylestradiol, not progestagens, in¬ Usual maintenance dose or 2 divided doses) 1 maximum 300 mg/day in 2 1 maximum 400 mg/day in 2 creased the clearance of lamotrigine up to 2-fold, and the 1 to 3 mg/kg/day divided doses) divided doses) progestin-only pills had no effect on lamotrigine plasma lev¬ with valproate alone els. Therefore, adjustments to the dosage of LAMICTAL in May need to be increased by May need to be increased by May need to be increased by the presence of progestagens alone will likely not be needed. Maintenance dose in as much as 50%, based on as much as 50%, based on as much as 50%, bast'd on Patients Taking Atazanavir/Ritonavir patients less than 30 kg clinical response. clinical response. clinical response. While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended Note: Only whole tablets should be used for dosing. dose-escalation guidelines for LAMICTAL should be neces¬ “ Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug sary solely based on the use of atazanavir/ritonavir. Dose Interactions (7), Clinical Pharmacology (12.3)] . escalation should follow the recommended guidelines for h Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, initiating adjunctive therapy with LAMICTAL based on include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ concomitant AED or other concomitant medications (see Ta¬ ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in bles 1, 2, and 5). In patients already taking maintenance General Dosing Considerations [see Dosage and Administration (2.1)1 . Patients on rifampin and the protease inhibitor doses of LAMICTAL and not taking glucuronidation induc¬ lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that ers, the dose of LAMICTAL may need to be increased if ata¬ induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. zanavir/ritonavir is added, or decreased if atazanavir/rito¬ navir is discontinued [see Clinical Pharmacology (12.3)1. Patients with Hepatic Impairment Experience in patients with hepatic impairment is limited. the clinical development program in adults with bipolar dis¬ Table 3. The Initial Weight-Based Dosing Guide for Based on a clinical pharmacology study in 24 subjects with order. 2 patients experienced seizures shortly after abrupt Patients Aged 2 to 12 Years Taking Valproate mild, moderate, and severe liver impairment /see Use in withdrawal of LAMICTAL. Discontinuation of LAMICTAL (Weeks 1 to 4| with Epilepsy Specific Populations (8.6). Clinical Pharmacology (12.3)1, should involve a step-wise reduction of dose over at least 2 the following general recommendations can be made. No weeks (approximately 50% per week! unless safety concerns Give this daily dose, using the dosage adjustment is needed in patients with mild liver im¬ require a more rapid withdrawal /see Warnings and Precau¬ If the patient's weight most appropriate combination of pairment. Initial, escalation, and maintenance doses should is LAMICTAL 2- and 5-mg tablets tions (5.8)]. generally be reduced by approximately 25% in patients with 2.2 Epilepsy—Adjunctive Therapy moderate and severe liver impairment without ascites and Greater And less Weeks 1 and 2 Weeks 3 and 4 This section provides specific dosing recommendations for than than 50% in patients with severe liver impairment with ascites. patients older than 12 years and patients aged 2 to 12 years. Escalation and maintenance doses may be adjusted accord¬ Within each of these age-groups, specific dosing recommen¬ 6.7 kg 14 kg 2 mg every 2 mg every day ing to clinical response. dations are provided depending upon concomitant AEDs or other day Patients with Renal Impairment other concomitant medications (see Table 1 for patients Initial doses of LAMICTAL should be based on patients' older than 12 years and Table 2 for patients aged 2 to 12 27 kg 2 mg every day 4 mg every day 14.1 kg concomitant medications (see Tables 1-3 and 5); reduced years). A weight-based dosing guide for patients aged 2 to 12 maintenance doses may be effective for patients with signif¬ years on concomitant valproate is provided in Table 3. 4 mg every day 8 mg every day 27.1kg 34 kg icant renal impairment [see Use in Specific Populations Patients Older than 12 Years (8.7), Clinical Pharmacology (12.3)1. Few patients with se¬ 40 kg 5 mg every day 10 mg every 34.1 kg Recommended dosing guidelines are summarized in vere renal impairment have been evaluated during chronic day Table 1. treatment with LAMICTAL. Because there is inadequate (See table 1 at top of previous pagel experience in this population, LAMICTAL should be used Patients Aged 2 to 12 Years with caution in these patients. Usual Adjunctive Maintenance Dose for Epilepsy Recommended dosing guidelines are summarized in Discontinuation Strategy The usual maintenance doses identified in Tables 1 and 2 Table 2. Epilepsy: For patients receiving LAMICTAL in combina¬ are derived from dosing regimens employed in the placeboLower starting doses and slower dose escalations than those tion with other AEDs, a re-evaluation of all AEDs in the reg¬ controlled adjunctive trials in which the efficacy of imen should be considered if a change in seizure control or used in clinical trials are recommended because of the sug¬ LAMICTAL was established. In patients receiving multian appearance or worsening of adverse reactions is ob¬ gestion that the risk of rash may be decreased by lower drug regimens employing carbamazepine, phenytoin, phe¬ served. starting doses and slower dose escalations. Therefore, main¬ nobarbital,. or primidone without valproate, maintenance If a decision is made to discontinue therapy with tenance doses will take longer to reach in clinical practice doses of adjunctive LAMICTAL as high as 700 mg/day have LAMICTAL, a step-wise reduction of dose over at least 2 ! than in clinical trials. It may take several weeks to months been used. In patients receiving valproate alone, mainte¬ weeks (approximately 50% per week I is recommended un¬ to achieve an individualized maintenance dose. Mainte¬ nance doses of adjunctive LAMICTAL as high as 200 mg/ less safety concerns require a more rapid withdrawal /see nance doses in patients weighing less than 30 kg, regardless day have been used. The advantage of using doses above Warnings and Precautions (8.8)1 of age or concomitant AED, may need to be increased as those recommended in Tables 1-4 has not been established Discontinuing carbamazepine, phenytoin, phenobarbital. much as 50%, based on clinical response. in controlled trials. primidone, or other drugs such as rifampin and the protease The smallest available strength of LAMICTAL chewable 2.3 Epilepsy—Conversion from Adjunctive Therapy to inhibitors lopinavir/ritonavir and atazanavir/ritonavir that dispersible tablets is 2 mg. and only whole tablets should be Monotherapy induce lamotrigine glucuronidation should prolong the halfadministered. If the calculated dose cannot be achieved us¬ The goal of the transition regimen is to attempt to maintain life of lamotrigine: discontinuing valproate should shorten ing whole tablets, the dose should be rounded down to the seizure control while mitigating the risk of serious rash as¬ the half-life of lamotrigine nearest whole tablet [see Hou- Supplied I Storage and Han¬ sociated with the rapid titration of LAMICTAL. Bipolar Disorder: In the controlled clinical trials, there dling (16) and Medication Guide]. The recommended maintenance dose of LAMICTAL as was no increase in the incidence, type, or severity of adverse monotherapy is 500 mg/day given in 2 divided daeee. |See table 2 above] reactions following abrupt termination of LAMICTAL. In

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1004/GLAXOSMITHKLINE • LAMICTAL

2.6 Administration of LAMICTAL ODT Orally Disinte¬ Table 4. Conversion from Adjunctive Therapy with Valproate to Monotherapy with LAMICTAL in Patients Aged 16 Years and Older with Epilepsy Valproate

LAMICTAL

Step 1

Achieve a dose of 200 mg/day according to guidelines in Table 1.

Maintain established stable dose.

grating Tablets

LAMICTAL ODT orally disintegrating tablets should he placed onto the tongue and moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food. 3 3.1

Step 2

Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week.

Maintain at 200 mg/day.

Step 3

Increase to 300 mg/day and maintain for 1 week.

Simultaneously decrease to 250 mg/day and maintain for 1 week.

Step 4

Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.

Discontinue.

In Patients NOT TAKING Carbamazepine, Phenytoin,

In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone6 and

Valproate8

Phenobarbital, Primidone,6 or Valproate8

Weeks 1 and 2

25 mg every other day

25 mg daily

50 mg daily

Weeks 3 and 4

25 mg daily

50 mg daily

100 mg daily, in divided doses

Week 5

50 mg daily

100 mg daily

200 mg daily, in divided doses

Week 6

100 mg daily

200 mg daily

300 mg daily, in divided doses

Week 7

100 mg daily

200 mg daily

up to 400 mg daily, in divided doses

In Patients TAKING

NOT TAKING Valproate8

Tb avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for LAMICTAL should not be exceeded [see Boxed Warning], Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with LAMICTAL After achieving a dose of 500 mg/day of LAMICTAL using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the con¬ trolled monotherapy clinical trial. Conversion from Adjunctive Therapy with Valproate to Monotherapy with LAMICTAL The conversion regimen involves the 4 steps outlined in Ta¬ ble 4. [See table 4 above] Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine,_Phenytoin. Phenobarbital. Primidone, or Valproate to Monotherapy with LAMICTAL No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL with AEDs other than car¬ bamazepine, phenytoin, phenobarbital, primidone, or val¬ proate. 2.4 Bipolar Disorder

The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood episodes 'depression, mania, hvpomania. mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (I)]. Patients taking IAMICTAL for more than 16 weeks should be periodically reassessed to determine the need for main¬ tenance treatment. Adults The target dose of LAMICTAL is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine. and 400 mg/day in patients not taking valproate and taking either carbamazepine, pheny¬ toin. phenobarbital, primidone, or other drugs such as rif¬ ampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clin¬ ical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at

with with with with

Chewable Dispersible Tablets

2 mg, white to off-white, round tablets debossed with “LTG” over “2.” 5 mg, white to off-white, caplet-shaped tablets debossed with “GX CL2.” 25 mg, white, super elliptical-shaped tablets debossed with “GX CL5.” 3.3

Orally Disintegrating Tablets

25 mg, white to off-white, round, flat-faced, radius-edge tab¬ lets debossed with “LMT” on one side and “25" on the other side. 50 mg, white to off-white, round, flat-faced, radius-edge tab¬ lets debossed with “LMT” on one side and “50” on the other side. 100 mg, white to off-white, round, flat-faced, radius-edge tablets debossed with “LAMICTAL” on one side and “100” on the other side. 200 mg, white to off-white, round, flat-faced, radius-edge tablets debossed with “LAMICTAL” on one side and “200” on the other side. 4

" Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)] . b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)] . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)] .

Tablets

25 mg, white, scored, shield-shaped tablets debossed “LAMICTAL” and “25." 100 mg, peach, scored, shield-shaped tablets debossed “LAMICTAL” and “100.” 150 mg, cream, scored, shield-shaped tablets debossed “LAMICTAL” and “150.” 200 mg, blue, scored, shield-shaped tablets debossed “LAMICTAL” and “200.” 3.2

Table 5. Escalation Regimen for LAMICTAL in Adults with Bipolar Disorder

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

LAMICTAL is contraindicated in patients who have demon¬ strated hypersensitivity (e.g., rash, angioedema, acute urti¬ caria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precau¬ tions (5.1, 5.2)]. 5 5.1

WARNINGS AND PRECAUTIONS Serious Skin Rashes /see Boxed Warning]

Pediatric Population The incidence of serious rash associated> with hospitaliza¬ tion and discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients faged 2 to 17 years) is 400 mg/day compared with 200 mg/day [see Clinical Studies approximately 0.3% to 0.8%. One rash-related death was re¬ ported in a prospectively followed cohort of 1,983 pediatric (14.2)]. Accordingly, doses above 200 mg/day are not recom¬ patients (aged 2 to 16 years) with epilepsy taking mended. LAMICTAL as adjunctive therapy. Additionally, there have Treatment with LAMICTAL is introduced, based on concur¬ been rare cases of toxic epidermal necrolysis with and with¬ rent medications, according to the regimen outlined in Table out permanent sequelae and/or death in US and foreign 5. If other psychotropic medications are withdrawn follow¬ postmarketing experience. ing stabilization, the dose of LAMICTAL should be ad¬ There is evidence that the inclusion of valproate in a mul¬ justed. In patients discontinuing valproate, the dose of tidrug regimen increases the risk of serious, potentially lifeLAMICTAL should be doubled over a 2-week period in equal threatening rash in pediatric patients. In pediatric patients weekly increments (see Table 6). In patients discontinuing who used valproate concomitantly for epilepsy, 1.2% (6 of carbamazepine, phenytoin, phenobarbital, primidone, or 482) experienced a serious rash compared with 0.6% '6 of other drugs such as rifampin and the protease inhibitors 952) patients not taking valproate. lopinavir/ritonavir and atazanavir/ritonavir that induce Adult Population lamotrigine glucuronidation, the dose of IAMICTAL should Serious rash associated with hospitalization and discon¬ remain constant for the first week and then should be de¬ tinuation of LAMICTAL occurred in 0.3% (11 of 3,348) of creased by half over a 2-week period in equal weekly decre¬ adult patients who received LAMICTAL in premarketing ments (see Table 6). The dose of LAMICTAL may then be clinical trials of epilepsy. In the bipolar and other mood dis¬ orders clinical trials, the rate of serious rash was 0.08% (1 of further adjusted to the target dose (200 mg) as clinically in¬ 1,233) of adult patients who received LAMICTAL as initial dicated. monotherapy and 0.13% (2 of 1,538) of adult patients who If other drugs are subsequently introduced, the dose of received LAMICTAL as adjunctive therapy. No fatalities LAMICTAL may need to be adjusted. In particular, the in¬ occurred among these individuals. However, in worldwide troduction of valproate requires reduction in the dose of postmarketing experience, rare cases of rash-related death LAMICTAL /see Drug Interactions (7), Clinical Pharmacol¬ have been reported, but their numbers are too few to permit ogy (12.3)]. a precise estimate of the rate. To avoid an increased risk of rash, the recommended initial Among the rashes leading to hospitalization were Stevensdose and subsequent dose escalations of LAMICTAL should Johnson syndrome, toxic epidermal necrolysis, angioedema, not be exceeded [see Boxed Warning I. and those associated with multiorgan hypersensitivity Isee [See table 5 above] Warnings and Precautions (5.2)]. [See table 6 at top of next page! There is evidence that the inclusion of valproate in a mul¬ 2.5 Administration of LAMICTAL Chewable Dispersible tidrug regimen increases the risk of serious, potentially lifeTablets threatening rash in adults. Specifically, of 584 patients ad¬ LAMICTAL chewable dispersible tablets may be swallowed ministered LAMICTAL with valproate in epilepsy clinical whole, chewed, or dispersed in water or diluted fruit juice. If trials, 6(1%) were hospitalized in association with rash; in the tablets are chewed, consume a small amount of water or contrast, 4 (0.16%) of 2,398 clinical trial patients and volun¬ diluted fruit juice to aid in swallowing. teers administered LAMICTAL in the absence of valproate To disperse LAMICTAL chewable dispersible tablets, add ■ were hospitalized. the tablets to a small amount of liquid (1 teaspoon, or j Patients with History of Allergy or Rash to Other Antiepi¬ enough to cover the medication). Approximately 1 minute j leptic Drugs later, when the tablets are completely dispersed, swirl the j The risk of nonserious rash may be increased when the rec¬ solution and consume the entire quantity immediately. So j ommended initial dose and/or the rate of dose escalation for attempt should be made to administer partial quantities of \ LAMICTAL is exceeded and in patients with a history of al¬ lergy or rash to other AEDs, the dispersed tablets.

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Look for PDR drug information and services in your EHR 5.2 Multiorgan Hypersensitivity Reactions and Organ Failure

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with LAMICTAL. Some have been fatal or life threatening. DRESS typically, although not ex¬ clusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute vi¬ ral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and var¬ ious degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received LAMICTAL in epilepsy clinical trials. Rare fatali¬ ties from multiorgan failure have also been reported in post¬ marketing use. Isolated liver failure without rash or involvement of other organs has also been reported with LAMICTAL. It is important to note that early manifestations of hyper¬ sensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiol¬ ogy for the signs or symptoms cannot be established. Prior to initiation of treatment with LAMICTAL, the pa¬ tient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopa¬ thy) may herald a serious medical event and that the pa¬ tient should report any such occurrence to a healthcare pro¬ vider immediately. 5.3

Table 6. Dosage Adjustments to LAMICTAL in Adults with Bipolar Disorder Following Discontinuation of Psychotropic Medications After Discontinuation of After Discontinuation of Valproate'

Carbamazepine, Phenytoin, Phenobarbital, or Primidone6

Drugs (excluding Valproate,'

Current Dose of LAMICTAL

Current Dose of LAMICTAL

Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb)

(mg/day) 100

(mg/day) 400

Week 1

Maintain current dose of LAMICTAL

150

400

Week 2

Maintain current dose of LAMICTAL

200

300

Week 3 onward

Maintain current dose of LAMICTAL

200

200

Discontinuation of Psychotropic

“Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine Isee Drug Interactions (7), Clinical Pharmacology (12.3)]. '’Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations Isee Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance Isee Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Table 7. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have included neutropenia, leukopenia, ane¬ mia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. 5.4

LAMICTAL • GLAXOSMITHKLINE/1005

Relative Risk: Incidence of

Risk Difference:

Placebo Patients with

Drug Patients with

Events in Drug Patients/

Additional Drug

Events per 1,000

Events per 1,000

Incidence in Placebo

Patients with Events

Patients

Patients

Patients

per 1,000 Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

Indication

Suicidal Behavior and Ideation

AEDs, including LAMICTAL, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indica¬ tion should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any un¬ usual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had ap¬ proximately twice the risk (adjusted Relative Risk 1.8, 95% Cl: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated inci¬ dence of suicidal behavior or ideation among 27,863 AEDtreated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for ev¬ ery 530 patients treated. There were 4 suicides in drugtreated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treat¬ ment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally con¬ sistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk ap¬ plies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical tri¬ als analyzed. Table 7 shows absolute and relative risk by indication for all evaluated AEDs. [See table 7 above] The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differ¬ ences were similar for the epilepsy and psychiatric indica¬ tions. Anyone considering prescribing LAMICTAL or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves as¬ sociated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behav¬ ior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of de¬ pression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.5

Aseptic Meningitis

Therapy with LAMICTAL increases the risk of developing aseptic meningitis. Because of the potential for serious out¬ comes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. Postmarketing cases of aseptic meningitis have been re¬ ported in pediatric and adult patients taking LAMICTAL for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal ri¬ gidity. Rash, photophobia, myalgia, chills, altered conscious¬ ness, and somnolence were also noted in some cases. Symp¬ toms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinu¬ ation of LAMICTAL. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re¬ initiation of treatment) that were frequently more severe. Some of the patients treated with LAMICTAL who devel¬ oped aseptic meningitis had underlying diagnoses of sys¬ temic lupus erythematosus or other autoimmune diseases. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a ma¬ jority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of in¬ volvement of other organs < predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction (see Warnings and Precautions (5.2)]. 5.6

Potential Medication Errors

Medication errors involving LAMICTAL have occurred. In particular, the names LAMICTAL or lamotrigine can be confused with the names of other commonly used medica¬

tions. Medication errors may also occur between the differ¬ ent formulations of LAMICTAL. To reduce the potential of medication errors, write and say LAMICTAL clearly. Depic¬ tions of the IAMICTAL tablets, chewable dispersible tab¬ lets, and orally disintegrating tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. Tb avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are IAMICTAL. as well as the correct formulation of IAMICTAL, each time they fill their prescription. 5.7

Concomitant Use with Oral Contraceptives

Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine Isee Clinical Pharmacology (12.3)1. Dosage adjustments will be necessary in most patients who start or stop estrogencontaining oral contraceptives while taking LAMICTAL (see Dosage and Administration (2.1)J. During the week of inac¬ tive hormone preparation i pill-free week) of oral contracep¬ tive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reac¬ tions consistent with elevated levels of lamotrigine. such as dizziness, ataxia, and diplopia, could occur. 5.8

Withdrawal Seizures

As with other AEDs, LAMICTAL should not be abruptly dis¬ continued In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder. 2 patients experienced seizures shortly af¬ ter abrupt withdrawal of IAMICTAL. Unless safety con¬ cerns require a more rapid withdrawal, the dose of IAMICTAL should be tapered over a period of at least 2 weeks (approximately 50% reduction per week l (see Dosage and Administration (2.1)1. 5.9

Status Epiiapticus

Valid estimates of the incidence of treatment-emergent sta¬ tus epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum. 7 of 2.343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g.. seizure clusters, seizure flumes) were made

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1006/GLAXOSMITHKLINE • LAMICTAL 5.10

Sudden Unexplained Death in Epilepsy (SUDEP)

During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a co¬ hort of .4,700 patients with epilepsy 15,747 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This rep¬ resents an incidence of 0.0035 deaths per patient-year. Al¬ though this rate exceeds that expected in a healthy popula¬ tion matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development pro¬ gram for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassur¬ ing or suggest concern depends on the comparability of the populations reported upon with the cohort receiving LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Im¬ portantly, that drug is chemically unrelated to LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect. 5.11

Addition of LAMICTAL to a Multidrug Regimen

that Includes Valproate

Because valproate reduces the clearance of lamotrigine, the dosage of LAMICTAL in the presence of valproate is less than half of that required in its absence [see Dosage and Administration (2.2, 2.3, 2.4), Drug Interactions (7)]. 5.12

Binding in the Eye and Other Melanin-Containing

Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was per¬ formed in I controlled clinical trial, the testing was inade¬ quate to exclude subtle effects or injury occurring after long¬ term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine’s binding to melanin is unknown /see Clinical Pharmacology (12.2)]. Accordingly, although there are no specific recommenda¬ tions for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmo¬ logic effects. 5.13 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine tPCPl. A more specific analytical method should be used to confirm a positive result. Plasma Concentrations of Lamotrigine The value of monitoring plasma concentrations of lamotrigine in patients treated with LAMICTAL has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 13), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, par¬ ticularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary. 6

ADVERSE REACTIONS

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label • Serious skin rashes I see Warnings and Precautions (5.1)1 • Multiorgan hypersensitivity reactions and organ failure I see Warnings and Precautions (5.2)1 • Blood dyscrasias /see Warnings and Precautions (5.3)] • Suicidal behavior and ideation /see Warnings and Precau¬ tions 5% for LAMICTAL and more common on drug than placebo i adverse reactions seen in as- !

sociation with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somno¬ lence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nau¬ sea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in pa¬ tients receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precau¬ tions (5.1)]. Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reac¬ tion. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%). In a dose-response trial in adults, the rate of discontinua¬ tion of LAMICTAL for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (>5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, in¬ fection, pain, weight decrease, chest pain, and dysmenor¬ rhea. The most commonly observed (>5% for LAMICTAL and more common on drug than placebo) adverse reactions associated with the use of LAMICTAL during the conver¬ sion to monotherapy (add-on) period, not seen at an equiv¬ alent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystag¬ mus, diarrhea, lymphadenopathy, pruritus, and sinusitis. Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discon¬ tinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%). Adjunctive Therapy in Pediatric Patients with Epi¬ lepsy: The most commonly observed (>5% for LAMICTAL and more common on drug than placebo) adverse reactions seen in association with the use of LAMICTAL as adjunctive treatment in pediatric patients aged 2 to 16 years and not seen at an equivalent rate in the control group were infec¬ tion, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia. In 339 patients aged 2 to 16 years with partial-onset sei¬ zures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on LAMICTAL and 2.9% of patients on pla¬ cebo discontinued due to adverse reactions. The most com¬ monly reported adverse reaction that led to discontinuation of LAMICTAL was rash. Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received LAMICTAL as adjunctive therapyin premarketing clinical trials discontinued treatment be¬ cause of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%). Controlled Adjunctive Clinical Trials in Adults with Epi¬ lepsy: Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with LAMICTAL in placebo-controlled trials. In these trials, either LAMICTAL or placebo was added to the patient’s current AED therapy. Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy"1* Percent of Patients Receiving Body System/Adverse Reaction

Body as a whole Headache Flu syndrome Fever Abdominal pain Neck pain Reaction aggravated (seizure exacerbation) Digestive Nausea Vomiting

Percent of Patients Receiving

Adjunctive

Adjunctive

LAMICTAL (n = 711)

Placebo In = 419)

29 7 6 5 2 2

19 6 4 4 1 1

19 9

10

4

6 5 4 2

4 2 3 1

2

0

38 22 14 6 6 4 4 4 3 3 3 2

13 6 7 2 2 1 3 3 1 2 0 1

Respiratory Rhinitis Pharyngitis Cough increased

14 10 8

9 9 6

Skin and appendages Rash Pruritus

10 3

5 2

Special senses Diplopia Blurred vision Vision abnormality

28 16 3

7 5 1

(n = 365) 7 4 2

(n = 207) 6 1 1

Diarrhea Dyspepsia Constipation Anorexia Musculoskeletal Arthralgia Nervous Dizziness Ataxia Somnolence Incoordination Insomnia Tremor Depression Anxiety Convulsion Irritability Speech disorder Concentration disturbance

Urogenital Female patients only Dysmenorrhea Vaginitis Amenorrhea

a Adverse reactions that occurred in at least 2% of patients treated with LAMICTAL and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine. phenytoin, phenobarbital, or primidone in addition to LAMICTAL or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category. In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of LAMICTAL, some of the more com¬ mon drug-related adverse reactions were dose related (see Table 9). Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled Adjunctive Trial in Adults with Epilepsy Percent of Patients Experiencing Adverse Reactions LAMICTAL Adverse Reaction

Ataxia Blurred vision Diplopia Dizziness Nausea Vomiting

LAMICTAL

Placebo

300 mg

500 mg

In = 73)

(n = 71)

In = 72)

10 10 8 27 11 4

10 11 24* 31 18 11

28«.b 25*-b 49*J> 54*b 25* 18*

“ Significantly greater than placebo group (P e similar to that seen with the ethinylestradiol/levonorgestrel combinations. d Modest decrease in levonorgestrel. e Slight decrease, not expected to be clinically meaningful. r Compared with historical controls. * Not administered, but an active metabolite of carbamazepine. h Not administered, but an active metabolite of oxcarbazepine. active metabolite of 1 Not administered. but an risperidone. ‘ Slight increase, not expected to be clinically meaningful. = No significant effect. ? = Conflicting data. Estrogen-Containing Oral Contraceptives In 16 female volunteers, an oral contraceptive preparation containing 30 meg ethinylestradiol and 150 meg levonorges¬ trel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in ALJC of 52% and in CmM of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the ac¬ tive hormone cycle. Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, pri¬ midone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7)1. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions. In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and C^,, of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of

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Look for PDR drug information and services in your EHR serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitaryovarian axis. The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials. The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern te.g., break-through bleeding i. Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations /see Dosage and Administration (2.1)1. Other Hormonal Contraceptives or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, in¬ creased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma lev¬ els. Therefore, adjustments to the dosage of LAMICTAL in the presence of progestogens alone will likely not be needed. Aripiprazole In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the lamotrigine AUC and Cmax were reduced by approximately 10% in patients who received aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in lamotrigine exposure is not considered clinically meaning¬ ful. Atazanavir/Ritonavir In a study in healthy volunteers, daily doses of atazanavir/ ritonavir (300 mg/100 mg) reduced the plasma AUC and Cm„ of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of atazanavir/rito¬ navir were similar in the presence of concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine. Bupropion The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formu¬ lation 1150 mg twice daily) starting 11 days before lamotrigine. Carbamazepine Lamotrigine has no appreciable effect on steady-state car¬ bamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamaze¬ pine with lamotrigine than in patients receiving other AEDs with lamotrigine /see Adverse Reactions (6.1)1. The mecha¬ nism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is un¬ clear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study in = 9), carbamazepine-epoxide levels increased. The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%. Felbamato In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically rele¬ vant effects on the pharmacokinetics of lamotrigine. Folate Inhibitors Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism. Gabapentin Based on a retrospective analysis of plasma levels in 34 sub¬ jects who received lamotrigine both with and without gaba¬ pentin, gabapentin does not appear to change the apparent clearance of lamotrigine. Levetiracetam Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentra¬ tions of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine. lithium The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.

LAMICTAL • GLAXOSMITHKUNE/1011 Lopinavir/Ritonavir The addition of lopinavir (400 mg twice daily Vritonavir (100 mg twice daily) decreased the AUC, CMI^ and elimina¬ tion half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ ritonavir were similar with concomitant lamotrigine, com¬ pared with that in historical controls. Olanzapine The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) com¬ pared with the AUC and Cmaj[ in healthy male volunteers receiving olanzapine alone (n = 16). In the same trial, the AUC and C^, of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically meaningful. Oxcarbazepine The AUC and Cmas of oxcarbazepine and its active 10monohydroxy oxcarbazepine metabolite were not signifi¬ cantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13). In the same trial, the AUC and Cmal of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers com¬ pared with those receiving lamotrigine alone. Limited clin¬ ical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone. Phenobarbital, Primidone The addition of phenobarbital or primidone decreases lamotrigine steadv-state concentrations bv approximately 40%. Phenytoin Lamotrigine has no appreciable effect on steady-state phen¬ ytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%. Pregabalin Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacoki¬ netic interactions between lamotrigine and pregabalin. Rifampin In 10 male volunteers, rifampin (600 mg/day for 5 days) sig¬ nificantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC de¬ creased by approximately 40%). Risperidone In a 14 healthy volunteers study', multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone. Tbpiramate Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations. Valproate When lamotrigine was administered to healthy volunteers in = 18) receiving valproate, the trough steady-state val¬ proate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials. The addition of valproate increased lamotrigine steadystate concentrations in normal volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased. Zonisamide In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine. Known Inducers or Inhibitors of Glucuronidation Drugs other than those listed above have not been system¬ atically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjust¬ ment based on clinical response.

I Other I In vitro assessment of the inhibitory effect of lamotrigine at : OCT2 demonstrate that lamotrigine. but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at poI tentially clinically relevant concentrations, with ICso value of 53.8 pM Isee Drug Interactions (7)J. Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant admin¬ istration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, sertraline, or tra¬ zodone. Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predomi¬ nantly by CYP2D6. Specific Populations Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance; 13 mL/min, range; 6 to 23) and another 6 individuals undergoing hemodialysis j were each given a single 100-mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 j hours (chronic renal failure), 13.0 hours (during hemodial. ysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approxi¬ mately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during l a 4-hour session Isee Dosage and Administration (2.DJ, Hepatic Disease: The pharmacokinetics of lamotrigine fol¬ lowing a single 100-mg dose of lamotrigine were evaluated \ in 24 subjects with mild, moderate, and severe hepatic im¬ pairment (Child-Pugh classification system) and compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ±0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild, moderate, se¬ vere without ascites, and severe with ascites hepatic im¬ pairment were 46 ± 20, 72 ± 44,67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy con¬ trols /see Dosage and Administration (2.1)1. Age: Pediatric Subjects: The pharmacokinetics of lamotrigine following a single 2-mg/kg dose were evaluated in 2 studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16. Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and con¬ current AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg compared with those weighing greater than 30 kg Accordingly, pa¬ tients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical re¬ sponse, as compared with subjects weighing more than 30 kg being administered the same AEDs Isee Dosage and Administration (2.2)1 These analyses also revealed that, af¬ ter accounting for body weight, lamotrigine clearance was j not significantly influenced by age. Thus, the same weightadjusted doses should be administered to children irrespec¬ tive of differences in age. Concomitant AEDs which influ| ence lamotrigine clearance in adults were found to have | similar effects in children. [ (See table 16 at top of next page) Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of lamotrigine were evaluated in 12 el¬ derly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range: 33 to j 108 mL/min). The mean half-life of lamotrigine in these j subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to i 0.48 mL/min/kg). Gender: The clearance of lamotrigine is not affected by gender However, during dose escalation of lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of | valproate (n = 77), mean trough lamotrigine concentrations : unadjusted for weight were 24% to 45% higher (0.3 to | 1.7 meg/mL > in females than in males. Race: The apparent oral clearance of lamotrigine was 25% i lower in non-Caucasians than Caucasians. 13 13.1

NONCLINICAL TOXICOLOGY Carcinogenesis. Mutagenesis, Impairment ol Fer¬

tility

No evidence of carcinogenicity was seen in mouse or rat fol¬ lowing oral administration of lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in

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1012/GLAXOSMITHKLINE • LAMICTAL Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects with Epilepsy

Pediatric Study Population Ages 10 months-5.3 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone" Subjects taking antiepileptic drugs with no known effect on the apparent clearance of lamotrigine Subjects taking valproate only

Ages 5-11 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone* Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate Subjects taking valproate only11

Ages 13-18 years Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone* Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate Subjects taking valproate only

(h)

t>A lh)

CL/F (mL/min/kg)

3.0 (1.0-5.9) 5.2 (2.9-6.1)

7.7 (5.7-11.4) 19.0 (12.9-27.1)

3.62 (2.44-5.28) 1.2 (0.75-2.42)

8

2.9 (1.0-6.0)

44.9 (29.5-52.5)

0.47 (0.23-0.77)

7

1.6 (1.0-3.0) 3.3 (1.0-6.4) 4.5 (3.0-6.0)

7.0 C3.8-9.8) 19.1 (7.0-31.2) 65.8 (50.7-73.7)

2.54 (1.35-5.58) 0.89 (0.39-1.93) 0.24 (0.21-0.26)

11

-C

1.3

8

-C

0.5

4

—1

Number of Subjects

10 7

8 3

-I

0.3

* Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to increase the apparent clearance of lamotrigine [see Drug In teractions (7)]. b Two subjects were included in the calculation for mean T max. c Parameter not estimated. mouse and rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m2) basis. Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) as¬ says. No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2 basis. 14 CLINICAL STUDIES 14.1 Epilepsy Monotherapy with LAMICTAL in Adults with Partial-Onset Seizures Already Receiving Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug The effectiveness of monotherapy with LAMICTAL was es¬ tablished in a multicenter, double-blind clinical trial enroll¬ ing 156 adult outpatients with partial-onset seizures. The patients experienced at least 4 simple partial-onset, com¬ plex partial-onset, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phen¬ ytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period. Trial endpoints were completion of all weeks of trial treat¬ ment or meeting an escape criterion. Criteria for escape rel¬ ative to baseline were: (1) doubling of average monthly sei¬ zure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (de¬ fined as a seizure that did not occur during the 8-week base¬ line' that is more severe than seizure types that occur dur¬ ing study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The pri¬ mary efficacy variable was the proportion of patients in each treatment group who met escape criteria. The percentages of patients who met escape criteria were 42% (32/76) in the group receiving LAMICTAL and 69% (55/ 80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically signifi¬ cant (P = 0.0012) in favor of LAMICTAL. No differences in efficacy based on age. sex, or race were detected. Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole ob¬ jective of this trial was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be in¬ terpreted to imply the superiority of LAMICTAL to an ade¬ quate dose of valproate. Adjunctive Therapy with LAMICTAL in Adults with Partial-Onset Seizures The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDsI was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials

in 355 adults with refractory partial-onset seizures. The pa¬ tients had a history of at least 4 partial-onset seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their established AED regimen during baselines that varied be¬ tween 8 to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing ther¬ apy. In all 3 trials, change from baseline in seizure fre¬ quency was the primary measure of effectiveness. The re¬ sults given below are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial, unless otherwise indi¬ cated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy trials. One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Pa¬ tients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the frequency of all partial-onset seizures rel¬ ative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group. A second trial (n = 98) was a double-blind, placebocontrolled, randomized, crossover trial consisting of two 14week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Pa¬ tients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in sei¬ zure frequency was a 25% reduction on LAMICTAL com¬ pared with placebo (P to the drug or its ingredients [see Boxed Warning. Warnings and Precautions (5.1, 5.2)].

matologist considered none of the cases to be StevensJohnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent se¬ quelae and/or death in US and foreign postmarketing expe¬ rience. There is evidence that the inclusion of valproate in a mul¬ tidrug regimen increases the risk of serious, potentially lifethreatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experi¬ enced a serious rash compared with 0.6% (6 of 952) patients not taking valproate. LAMICTAL XR is not approved in patients younger than 13 years. Adult Population Serious rash associated with hospitalization and discon¬ tinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediaterelease lamotrigine in premarketing clinical trials of epi¬ lepsy. In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate. Among the rashes leading to hospitalization were StevensJohnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.2)). There is evidence that the inclusion of valproate in a mul¬ tidrug regimen increases the risk of serious, potentially lifethreatening rash in adults. Specifically, of 584 patients ad¬ ministered immediate-release lamotrigine with valproate in epilepsy clinical trials. 6 (1%) were hospitalized in associa¬ tion with rash; in contrast. 4 (0.16%) of 2,398 clinical trial patients and volunteers administered immediate-release lamotrigine in the absence of valproate were hospitalized. Patients with History of Allergy or Rash to Other Antiej>ileptic Drugs The risk of nonserious rash may be increased when the rec¬ ommended initial dose and/or the rate of dose escalation for LAMICTAL XR is exceeded and in patients with a history of allergy or rash to other AEDs. 5.2 Multiorgan Hypersensitivity Reactions and Organ

5 WARNINGS AND PRECAUTIONS

Failure

5.1 Serious Skin Rashes /see Boxed Warning)

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not ex¬ clusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute vi¬ ral infection. Eosinophilia is often present. This disorder is variable in its expression and other organ systems not noted here may be involved Fatalities associated with acute multiorgan failure and var¬ ious degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical Inals. Rare fatali¬ ties from multiorgan failure have also been reported in postmarketing use.

The risk of serious rash caused by treatment with LAMICTAL XR is not expected to differ from that with immediate-release lamotrigine /see Boxed WarningI. How¬ ever, the relatively limited treatment experience with LAMICTAL XR makes it difficult to characterize the fre¬ quency and risk of serious rashes caused by treatment with LAMICTAL XR. Pediatric Population The incidence of serious rash associated with hospitaliza¬ tion and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% < 16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagree¬ ment as to their proper classification Tb illustrate, one der¬

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1018/GLAXOSMITHKLINE • LAMICTAL XR

5.8 Withdrawal Seizures As with other AEDs, LAMICTAL XR should not be abruptly discontinued. In patients with epilepsy there is a possibility Risk Difference: of increasing seizure frequency. Unless safety concerns re¬ Additional Drug quire a more rapid withdrawal, the dose of LAMICTAL XR Patients with Relative Risk: Incidence of Events in Drug Patients with Placebo Patients should be tapered over a period of at least 2 weeks (approx¬ Events per 1,000 Drug Patients/Incidence in Placebo Events per 1,000 with Events per imately 50% reduction per week) [see Dosage and Adminis¬ Patients Patients Patients 1,000 Patients Indication tration (2.1)]. 5.9 Status Epilepticus 2.4 3.5 3.4 1.0 Epilepsy Valid estimates of the incidence of treatment-emergent sta¬ tus epilepticus among patients treated with immediate2.9 1.5 8.5 5.7 Psychiatric release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical 0.9 1.9 1.8 1.0 Other rules for identifying cases. At a minimum, 7 of 2,343 adult 1.9 patients had episodes that could unequivocally be described 1.8 4.3 2.4 Tbtal as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., sei¬ zure clusters, seizure flurries) were made. ior and should be advised of the need to be alert for the Isolated liver failure without rash or involvement of other emergence or worsening of the signs and symptoms of de¬ 5.10 Sudden Unexplained Death in Epilepsy (SUDEP) organs has also been reported with lamotrigine. pression, any unusual changes in mood or behavior, the During the premarketing development of immediate-release It is important to note that early manifestations of hyper¬ emergence of suicidal thoughts or suicidal behavior, or lamotrigine, 20 sudden and unexplained deaths were re¬ sensitivity (e.g., fever, lymphadenopathy) may be present thoughts about self-harm. Behaviors of concern should be corded among a cohort of 4,700 patients with epilepsy (5,747 even though a rash is not evident. If such signs or symptoms reported immediately to healthcare providers. patient-years of exposure). are present, the patient should be evaluated immediately. 5.5 Aseptic Meningitis LAMICTAL XR should be discontinued if an alternative eti¬ Some of these could represent seizure-related deaths in Therapy with lamotrigine increases the risk of developing which the seizure was not observed, e.g., at night. This rep¬ ology for the signs or symptoms cannot be established. aseptic meningitis. Because of the potential for serious out¬ resents an incidence of 0.0035 deaths per patient-year. Al¬ Prior to initiation of treatment with LAMICTAL XR, the pa¬ comes of untreated meningitis due to other causes, patients though this rate exceeds that expected in a healthy popula¬ tient should be instructed that a rash or other signs or should also be evaluated for other causes of meningitis and tion matched for age and sex, it is within the range of symptoms of hypersensitivity (e.g., fever, lymphadenopa¬ treated as appropriate. thy) may herald a serious medical event and that the pa¬ estimates for the incidence of sudden unexplained death in Postmarketing cases of aseptic meningitis have been re¬ ported in pediatric and adult patients taking lamotrigine for epilepsy (SUDEP) in patients not receiving lamotrigine tient should report any such occurrence to a healthcare pro¬ various indications. Symptoms upon presentation have in¬ (ranging from 0.0005 for the general population of patients vider immediately. cluded headache, fever, nausea, vomiting, and nuchal rigid¬ 5.3 Blood Dyscrasias with epilepsy, to 0.004 for a recently studied clinical trial ity. Rash, photophobia, myalgia, chills, altered conscious¬ There have been reports of blood dyscrasias with population similar to that in the clinical development pro¬ ness, and somnolence were also noted in some cases." immediate-release lamotrigine that may or may not be as¬ gram for immediate-release lamotrigine, to 0.005 for pa¬ Symptoms have been reported to occur within 1 day to one sociated with multiorgan hypersensitivity (also known as tients with refractory epilepsy). Consequently, whether and a half months following the initiation of treatment. In DRESS) [see Warnings and Precautions (5.2)]. These have these figures are reassuring or suggest concern depends on most cases, symptoms were reported to resolve after discon¬ included neutropenia, leukopenia, anemia, thrombocytope¬ the comparability of the populations reported upon with the tinuation of lamotrigine. Re-exposure resulted in a rapid re¬ nia, pancytopenia, and, rarely, aplastic anemia and pure red cohort receiving immediate-release lamotrigine and the ac¬ turn of symptoms (from within 30 minutes to 1 day follow¬ cell aplasia. curacy of the estimates provided. Probably most reassuring ing re-initiation of treatment) that were frequently more 5.4 Suicidal Behavior and Ideation is the similarity of estimated SUDEP rates in patients re¬ severe. Some of the patients treated with lamotrigine who AEDs, including LAMICTAL XR, increase the risk of sui¬ ceiving immediate-release lamotrigine and those receiving developed aseptic meningitis had underlying diagnoses of cidal thoughts or behavior in patients taking these drugs for other AEDs, chemically unrelated to each other, that under¬ systemic lupus erythematosus or other autoimmune dis¬ any indication. Patients treated with any AED for any indi¬ went clinical testing in similar populations. Importantly, eases. cation should be monitored for the emergence or worsening that drug is chemically unrelated to lamotrigine. This evi¬ Cerebrospinal fluid (CSF) analyzed at the time of clinical of depression, suicidal thoughts or behavior, and/or any un¬ dence suggests, although it certainly does not prove, that presentation in reported cases was characterized by a mild usual changes in mood or behavior. the high SUDEP rates reflect population, rates, not a drug to moderate pleocytosis, normal glucose levels, and mild to Pooled analyses of 199 placebo-controlled clinical trials effect. moderate increase in protein. CSF white blood cell count (monotherapy and adjunctive therapy) of 11 different AEDs 5.11 Addition of LAMICTAL XR to a Multidrug Regimen differentials showed a predominance of neutrophils in a ma¬ showed that patients randomized to 1 of the AEDs had ap¬ that Includes Valproate jority of the cases, although a predominance of lymphocytes proximately twice the risk (adjusted Relative Risk 1.8, 95% Because valproate reduces the clearance of lamotrigine, the was reported in approximately one third of the cases. Some Cl: 1.2, 2.7) of suicidal thinking or behavior compared with dosage of lamotrigine in the presence of valproate is less patients also had new onset of signs and symptoms of in¬ patients randomized to placebo. In these trials, which had a than half of that required in its absence [see Dosage and volvement of other organs (predominantly hepatic and renal median treatment duration of 12 weeks, the estimated inci¬ Administration (2.1, 2.2), Drug Interactions (7)]. involvement), which may suggest that in these cases the dence of suicidal behavior or ideation among 27,863 AED5.12 Binding in the Eye and Other Melanin-Containing aseptic meningitis observed was part of a hypersensitivity treated patients was 0.43%, compared with 0.24% among Tissues reaction [see Warnings and Precautions (5.2)]. 16,029 placebo-treated patients, representing an increase of Because lamotrigine binds to melanin, it could accumulate 5.6 Potential Medication Errors approximately 1 case of suicidal thinking or behavior for ev¬ in melanin-rich tissues over time. This raises the possibility Medication errors involving LAMICTAL have occurred. In ery 530 patients treated. There were 4 suicides in drugthat lamotrigine may cause toxicity in these tissues after particular, the names LAMICTAL or lamotrigine can be treated patients in the trials and none in placebo-treated extended use. Although ophthalmological testing was per¬ confused with the names of other commonly used medica¬ patients, but the number of events is too small to allow any formed in 1 controlled clinical trial, the testing was inade¬ tions. Medication errors may also occur between the differ¬ conclusion about drug effect on suicide. quate to exclude subtle effects or injury occurring after long¬ ent formulations of LAMICTAL. To reduce the potential of The increased risk of suicidal thoughts or behavipr with term exposure. Moreover, the capacity of available tests to medication errors, write and say LAMICTAL XR clearly. De¬ AEDs was observed as early as 1 week after starting treat¬ detect potentially adverse consequences, if any, of lamopictions of the LAMICTAL XR extended-release tablets can ment with AEDs and persisted for the duration of treatment trigine’s binding to melanin is unknown. be found in the Medication Guide. Each LAMICTAL XR tab¬ assessed. Because most trials included in the analysis did Accordingly, although there are no specific recommenda¬ let has a distinct color and white center, and is printed with not extend beyond 24 weeks, the risk of suicidal thoughts or tions for periodic ophthalmological monitoring, prescribers “LAMICTAL XR” and the tablet strength. These distinctive behavior beyond 24 weeks could not be assessed. should be aware of the possibility of long-term ophthalmo¬ features serve to identify the different presentations of the The risk of suicidal thoughts or behavior was generally con¬ logic effects. drug and thus may help reduce the risk of medication er¬ sistent among drugs in the data analyzed. The finding of 5.13 Laboratory Tests rors. LAMICTAL XR is supplied in round, unit-of-use increased risk with AEDs of varying mechanism of action False-Positive Drug Test Results bottles with orange caps containing 30 tablets. The label on and across a range of indications suggests that the risk ap¬ Lamotrigine has been reported to interfere with the assay the bottle includes a depiction of the tablets that further plies to all AEDs used for any indication. The risk did not used in some rapid urine drug screens, which can result in communicates to patients and pharmacists that the medi¬ vary substantially by age (5 to 100 years) in the clinical tri¬ false-positive readings, particularly for phencyclidine cation is LAMICTAL XR and the specific tablet strength in¬ als analyzed. (PCP). A more specific analytical method should be used to cluded in the bottle. The unit-of-use bottle with a distinctive Table 3 shows absolute and relative risk by indication for all confirm a positive result. orange cap and distinctive bottle label features serves to evaluated AEDs. Plasma Concentrations of Lamotrigine identify the different presentations of the drug and thus [See table 3 above) The value of monitoring plasma concentrations of may help to reduce the risk of medication errors, lb avoid The relative risk for suicidal thoughts or behavior was lamotrigine in patients treated with LAMICTAL XR has not the medication error of using the wrong drug or formula¬ higher in clinical trials for epilepsy than in clinical trials for been established. Because of the possible pharmacokinetic tion, patients should be strongly advised to visually inspect psychiatric or other conditions, but the absolute risk differ¬ interactions between lamotrigine and other drugs, including their tablets to verify that they are LAMICTAL XR each ences were similar for the epilepsy and psychiatric indica¬ AEDs (see Table 6), monitoring of the plasma levels of j time they fill their prescription. tions. lamotrigine and concomitant drugs may be indicated, par¬ 5.7 Concomitant Use with Oral Contraceptives Anyone considering prescribing LAMICTAL XR or any ticularly during dosage adjustments. In general, clinical Some estrogen-containing oral contraceptives have been other AED must balance the risk of suicidal thoughts or be¬ judgment should be exercised regarding monitoring of shown to decrease serum concentrations of lamotrigine [see havior with the risk of untreated illness. Epilepsy and many Clinical Pharmacology 112.3)1. Dosage adjustments will be j plasma levels of lamotrigine and other drugs and whether other illnesses for which AEDs are prescribed are them¬ or not dosage adjustments are necessary. necessary in most patients who start or stop estrogenselves associated with morbidity and mortality and an in¬ Effect on Leukocytes containing oral contraceptives while taking LAMICTAL XR creased risk of suicidal thoughts and behavior. Should sui¬ Treatment with LAMICTAL XR caused an increased inci¬ [see Dosage and Administration 12.1)]. During the week of cidal thoughts and behavior emerge during treatment, the dence of subnormal (below the reference range) values in prescriber needs to consider whether the emergence of these inactive hormone preparation (pill-free week) of oral contra¬ some hematology analytes (e.g., total white blood cells, ceptive therapy, plasma lamotrigine levels are expected to symptoms in any given patient may be related to the illness monocytes). The treatment effect (LAMICTAL XR % - Pla¬ rise, as much as doubling at the end of the week. Adverse being treated. cebo %) incidence of subnormal counts was 3% for total Patients, their caregivers, and families should be informed reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. white blood cells and 4% for monocytes. that AEDs increase the risk of suicidal thoughts and behav¬ Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

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ADVERSE REACTIONS

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: • Serious skin rashes I see Warnings and Precautions to. 1)1 • Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions birth control pills i or other • vomiting female hormonal medicines. Do not start or stop taking • stiff neck birth control pills or other female hormonal medicine until • .rash you have talked with your healthcare provider. Tfell your • unusual sensitivity to light healthcare provider if you have any changes in your men¬ • muscle pains strual pattern such as breakthrough bleeding. Stopping • chills these medicines may cause side effects (such as dizziness, • confusion lack of coordination, or double vision). Starting these • drowsiness medicines may lessen how well LAMICTAL XR works. Meningitis has many causes other than LAMICTAL XR, • are pregnant or plan to become pregnant. It is not known which your doctor would check for if you developed menin¬ if LAMICTAL XR will harm your unborn baby. If you be¬ gitis while taking LAMICTAL XR. come pregnant while taking LAMICTAL XR, talk to your LAMICTAL XR can have other serious side effects. For more healthcare provider about registering with the North information ask your healthcare provider or pharmacist, i American Antiepileptic Drug Pregnancy Registry. You can Tfell your healthcare provider if you have any side effect that enroll in this registry by calling 1-888-233-2334. The pur¬ bothers you. Be sure to read the section below entitled | pose of this registry is to collect information about the "What are the possible side effects of LAMICTAL XR’“ safety of antiepileplic drugs during prugnancy. 5. Patients prescribed LAMICTAL have sometimes been • are breastfeeding. LAMICTAL XR passes into breast milk given the wrong medicine because many medicines have and may cause side effects in a breastfed baby. If you names similar to LAMICTAL. so always check that you re¬ breastfeed while taking LAMICTAL XR. watch your baby ceive LAMICTAL XR closely for trouble breathing, episodes of temporarily stop¬ ping breathing, sleepiness, or poor sucking. Call your ba¬ Taking the wrong medication can cause serious health prob¬ by's healthcare provider right away if you see any of these lems. When your healthcare provider gives you a prescrtp- 1 problems. Talk to your healthcare provider about the best tion for LAMICTAL XR: way to feed your baby if you take LAMICTAL XR. • Make sure you can read it clearly.

Ttell your healthcare provider about all the medicines you take or if you are planning to take a new medicine, includ¬ ing prescription and non-prescription medicines, vitamins, and herbal supplements. If you use LAMICTAL XR with certain other medicines, they can affect each other, causing side effects. How should I take LAMICTAL XR? • Take LAMICTAL XR exactly as prescribed. • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare pro¬ vider. • Do not stop taking LAMICTAL XR without talking to your healthcare provider. Stopping LAMICTAL XR suddenly may cause serious problems. For example, if you have ep¬ ilepsy and you stop taking LAMICTAL XR suddenly, you may have seizures that do not stop. Talk with your health¬ care provider about how to stop LAMICTAL XR slowly. • If you miss a dose of LAMICTAL XR, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time. • If you take too much LAMICTAL XR. call your healthcare provider or your local Poison Control Center or go to the nearest hospital emergency room right away. • You may not feel the full effect of 1-AM1CTAL XR for sev¬ eral weeks. • If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any new types of sei¬ zures. • LAMICTAL XR can be taken with or without food. • Do not chew, crush, or divide LAMICTAL XR. • Swallow LAMICTAL XR tablets whole. • If you have trouble swallowing LAMICTAL XR tablets, tell your healthcare provider because there may be another form of LAMICTAL you can take. • If you receive LAMICTAL XR in a blisterpack. examine the blisterpack before use. Do not use if blisters are tom. broken, or missing. What should I avoid while taking LAMICTAL XR? Do not drive a car or operate complex, hazardous machinery until you know how LAMICTAL XR affects you. What are the possible side effects of LAMICTAL XR? Sec “What is the most important information I should know about LAMICTAL XR?” Common side effects of LAMICTAL XR include: • dizziness • tremor • double vision • nausea • vomiting • trouble with balance and coordination • anxiety Other common side effects that have been reported with an¬ other form of LAMICTAL include headache, sleepiness, blurred vision, runny nose, and rash. Tfell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of I.AMICTAL XR. For more information, ask your healthcare provider or phar¬ macist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store LAMICTAL XR? • Store LAMICTAL XR at room temperature between 59°F and 86°F (15*C and 30“C>. • Keep LAMICTAL XR and all medicines out of the reach of children. General information about LAMICTAL XR Medicines are sometimes proscribed for purposes other than those listed in a Medication Guide. Do not use LAMICTAL XR for a condition for which it was not proscribed. Do not give LAMICTAL XR to other people, even if they have the same symptoms you have. It may harm them. If you take a urine drug screening test, LAMICTAL XR may make the test result positive for another drug. If you require a urine drug screening test, tell the healthcare professional administering the test that you arc taking LAMICTAL XR. This Medication Guide summarizes the most important in¬ formation about LAMJCTAL XR. If you would like more informuUuo. talk with your healthcare provider. You can ask your healthcare provider .or pharmacist for information about LAMICTAL XR that is written for healthcare profes¬ sionals. For more information, go to www.lamictalxr.com or call 1-888-825-5249. What ara the ingredients in LAMICTAL XR? Active ingredient: lamotrigine. Inactive ingredients: glycerol monostearate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer dispersion, polyethylene glycol 400. poiyaorbate 80, silicon dioxide '25- and 50-mg tablets only), titanium di¬ oxide, triethyl citrate, carmine' 250-mg tablet only), iron ox¬ ide black 150-, 250-. and 300-mg tablets onlyl. iron oxide yel¬ low 125-, 50-. and 100-mg tablets only), iron oxide red

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1026/GLAXOSMITHKLINE • LAMICTAL XR (100-mg tablet only), FD&C Blue No. 2 Aluminum Lake 1200- and 250-mg tablets only). Tablets are printed with ed¬ ible black ink. This Medication Guide has been approved by the U S. Food and Drug Administration. IAMICTAL XR is a trademark of the GSK group of compa¬ nies. The other brands listed are trademarks of their respec¬ tive owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products. GlaxoSmithKline Research Triangle Park, NC 27709 • ©2015, the GSK group of companies. All rights reserved. March 2015 LXR:15MG

LOVAZA® \lo-V&' 2(5]

(omega-3-acid ethyl esters) Capsules, for oral use HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LOVAZA safely and effectively. See full prescribing information for LOVAZA. LOVAZA® (omega-3-acid ethyl esters) Capsules, for oral use Initial U.S. Approval: 2004 -RECENT MAJOR CHANGES-

Indications and Usage, Limitations of Use (1)

05/2014

-INDICATIONS AND USAGELOVAZA is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA, indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia (HTG). (1) Limitations of Use: • The effect of LOVAZA on the risk for pancreatitis has not been determined. (1) • The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined. (1) -DOSAGE AND ADMINISTRATION• The daily dose of LOVAZA is 4 grams per day taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily). (2) • Patients should be advised to swallow LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA. (2) -DOSAGE FORMS AND STRENGTHSCapsules:

1-gram (3)

-CONTRAINDICATIONSLOVAZA is contraindicated in patients with known hyper¬ sensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components. (4) -WARNINGS AND PRECAUTIONS• In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy. (5.1) • LOVAZA may increase levels of LDL. Monitor LDL levels periodically during therapy. (5.1) • Use with caution in patients with known hypersensitivity to fish and/or shellfish. (5.2) • There is a possible association between LOVAZA and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fi¬ brillation, particularly within the first months of initiating therapy. (5.3) -ADVERSE REACTIONSThe most common adverse reactions (incidence >371 and greater than placebo) were eructation, dyspepsia, and taste perversion. (6) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch -DRUG INTERACTIONSOmega-3-acids may prolong bleeding time. Patients taking LOVAZA and an anticoagulant or other drug affecting coag¬ ulation ie.g.. anti-platelet agents* * should be monitored pe¬ riodically. (7.1) -USE IN SPECIFIC POPULATIONS• Pregnancy Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2012

FULL 1 2 3 4 5

PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5.1 Monitoring: Laboratory Tests 6.2 Fish Allergy 5.3 Recurrent Atrial Fibrillation (AF) or Flutter 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Anticoagulants or Other Drugs Affecting Co¬ agulation 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Severe Hypertriglyceridemia 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION • Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

LOVAZA® (omega-3-acid ethyl esters) is indicated as an ad¬ junct to diet to reduce triglyceride (TG) levels in adult pa¬ tients with severe (>500 mg/dL) hypertriglyceridemia (HTG). Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA and should continue this diet during treatment with LOVAZA. Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with LOVAZA. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are con¬ tributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy. Limitations of Use: The effect of LOVAZA on the risk for pancreatitis has not been determined. The effect of LOVAZA on cardiovascular mortality and mor¬ bidity has not been determined. 2

DOSAGE AND ADMINISTRATION

• Assess triglyceride levels carefully before initiating ther¬ apy. Identify other causes (e.g., diabetes mellitus. hypo¬ thyroidism. medications) of high triglyceride levels and manage as appropriate /see Indications and Usage tW. • Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA, and should continue this diet during treatment with LOVAZA. In clinical studies, LOVAZA was administered with meals. The daily dose of LOVAZA is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules i or as two 2-gram doses (2 capsules given twice daily). Patients should be advised to swallow LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA. 3

DOSAGE FORMS AND STRENGTHS

LOVAZA (omega-3-acid ethyl esters) capsules are supplied as 1-gram transparent, soft-gelatin capsules filled with light-yellow oil and bearing the designation LOVAZA. 4

CONTRAINDICATIONS

LOVAZA is contraindicated in patients with known hyper¬ sensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components. 5 WARNINGS AND PRECAUTIONS 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotrans! ferase ALT> and aspartate aminotransferase (AST) levels

should be monitored periodically during therapy with LOVAZA. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed. In some patients, LOVAZA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with LOVAZA. Laboratory studies should be performed periodically to mea¬ sure the patient’s TG levels during therapy with LOVAZA. 5.2 Fish Allergy LOVAZA contains ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to LOVAZA. LOVAZA should be used with caution in patients with known hypersensitivity to fish and/or shellfish. 5.3 Recurrent Atrial Fibrillation (AF) or Flutter In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in sub¬ jects randomized to LOVAZA who received 8 grams/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg/dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline. At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on LOVAZA [primary endpoint, HR 1.19; 95% Cl: 0.93, 1.35], In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52% ) events on LOVAZA [HR 1.63; 95% Cl: 0.91, 2.18], For both strata combined, the HR was 1.25; 95% Cl: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between LOVAZA and more fre¬ quent recurrences of symptomatic atrial fibrillation or flut¬ ter in patients with paroxysmal or persistent atrial fibrilla¬ tion, particularly within the first 2 to 3 months of initiating therapy. LOVAZA is not indicated for the treatment of AF or flutter. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in at least 3%' and at a greater rate than placebo for subjects treated with LOVAZA based on pooled data across 23 clinical trials are listed in Table 1. Table 1. Adverse Reactions Occurring at Incidence a3% and Greater than Placebo in Clinical Trials of LOVAZA Adverse Reaction*

Eructation Dyspepsia Taste perversion

LOVAZA (N = 655)

Placebo (N = 370)

n

%

n

%

29 22 27

4 3 4

5 6 1

1 2 15 years of age with body weights from 31 to 110 kg ranged from 1,617 to 2,502 L. In pediatric patients 80 mL/min*. j In patients with moderate renal impairment (creatinine I clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clear¬ ance >80 mL/min, and the oral clearance of atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of MALARONE for long-term prophylaxis (over 2 months* 1 in individuals with moderate renal failure. In patients with se¬ vere renal impairment /creatinine clearance 99%) but does not dis¬ place other highly protein-bound drugs in vitro. Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions between proguanil or cycloguanil and other drugs that are CYP2C19 substrates or inhibitors are unknown. Rifampin I Rifabutin: Concomitant administration of rif¬ ampin or rifabutin is known to reduce atovaquone concen¬ trations by approximately 50% and 34%, respectively The mechanisms of these interactions are unknown. Tetracycline: Concomitant treatment with tetracycline has been associated with approximately a 40% reduction in plasma concentrations of atovaquone. Metoclopramide: Concomitant treatment with metoclopramide has been associated with decreased bioavailability of atovaquone. Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indina¬ vir (23% decrease [90% Cl = 8%, 35%]). 12.4 Microbiology Activity In Vitro and In Vivo: Atovaquone and cycloguanil (an active metabolite of proguanil) are active against the erythrocytic and exoerythrocytic stages of Plasmodium spp. Enhanced efficacy of the combination compared to either atovaquone or proguanil hydrochloride alone was demon¬ strated in clinical trials in both immune and non-immune patients/see Clinical Studies (14.1, 14.2)]. Drug Resistance: Strains of P. falciparum with decreased susceptibility to atovaquone or proguanil/cycloguanil alone can be selected in vitro or in vivo. The combination of atovaquone and proguanil hydrochloride may not be effec¬ tive for treatment of recrudescent malaria that develops af¬ ter prior therapy with the combination. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of MALARONE on male and female reproductive performance are unknown. Atovaquone: A 24-month carcinogenicity study in CD rats was negative for neoplasms at doses up to 500 mg/kg/day corresponding to approximately 64 times the average steady-state plasma concentrations in humans during pro¬ phylaxis of malaria. In CD-I mice, a 24-month study showed treatment-related increases in incidence of hepato¬ cellular adenoma and hepatocellular carcinoma at all doses tested (50, 100, and 200 mg/kg/day) which correlated with at least 15 times the average steady-state plasma concen¬ trations in humans during prophylaxis of malaria. Atovaquone was negative with or without metabolic activa¬ tion in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay Atovaquone did not impair fertility in male and female rats at doses up to 1,000 mg/kg/day corresponding to plasma ex¬ posures of approximately 7.3 times the estimated human exposure during treatment of malaria based on AUC. Proguanil: No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-I mice at doses up to 16 mg/kg/day corresponding to 1.5 times the av¬ erage human plasma exposure during prophylaxis of ma¬ laria based on AUC, and in Wistar Hannover rats at doses up 20 mg/kg/day corresponding to 1.1 times the average hu¬ man plasma exposure during prophylaxis of malaria based on AUC. Proguanil was negative with or without metabolic activa¬ tion in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of geno¬ toxicity was observed in the in vivo Mouse Micronucleus as¬ say. Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These

positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation. A fertility study in Sprague-Dawley rats revealed no ad¬ verse effects at doses up to 16 mg/kg/day of proguanil hydrochloride (up to 0.04-times the average human expo¬ sure during treatment of malaria based on AUC). Fertility studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been con¬ ducted. 13.2 Animal Toxicology and/or Pharmacology Fibrovascular proliferation in the right atrium, pyelone¬ phritis, bone marrow hypocellularity, lymphoid atrophy, and gastritis/enteritis were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 12 mg/kg/day (approximately 3.9 times the recommended daily human dose for malaria prophylaxis on a mg/m2 ba¬ sis). Bile duct hyperplasia, gall bladder mucosal atrophy, and interstitial pneumonia were observed in dogs treated with proguanil hydrochloride for 6 months at a dose of 4 mg/kg/day (approximately 1.3 times the recommended daily human dose for malaria prophylaxis on a mg/m2 ba¬ sis). Mucosal hyperplasia of the cecum and renal tubular basophilia were observed in rats treated with proguanil hydrochloride for 6 months at a dose of 20 mg/kg/day (ap¬ proximately 1.6 times the recommended daily human dose for malaria prophylaxis on a mg/m2 basis). Adverse heart, lung, liver, and gall bladder effects observed in dogs and kidney effects observed in rats were not shown to be revers¬ ible. 14 CLINICAL STUDIES 14.1 Prevention of P. falciparum Malaria MALARONE was evaluated for prophylaxis of P. falciparum malaria in 5 clinical trials in malaria-endemic areas and in 3 active-controlled trials in non-immune travelers to ma¬ laria-endemic areas. Three placebo-controlled trials of 10 to 12 weeks’ duration were conducted among residents of malaria-endemic areas in Kenya, Zambia, and Gabon. The mean age of subjects was 30 (range 17-55), 32 (range 16-64), and 10 (range 5-16) years, respectively. Of a total of 669 randomized patients (including 264 pediatric patients 5 to 16 years of age), 103 were withdrawn for reasons other than falciparum malaria or drug-related adverse events (55% of these were lost to follow-up and 45% were withdrawn for protocol violations). The results are listed in Table 6. Table 6. Prevention of Parasitemia* in Placebo Controlled Clinical Trials of MALARONE for Prophylaxis of P. falciparum Malaria in Residents of Malaria Endemic Areas MALARONE

Placebo

Total number of patients randomized

326

343

Failed to complete study

57

46

Developed parasitemia iP falciparum)

o

92

" Free of parasitemia during the 10 to 12-week period of prophylactic therapy. In another study, 330 Gabonese pediatric patients (weigh¬ ing 13 to 40 kg, and aged 4 to 14 years) who had received successful open-label radical cure treatment with artesunate, were randomized to receive either MALARONE (dos¬ age based on body weight) or placebo in a double-blind fash¬ ion for 12 weeks. Blood smears were obtained weekly and any time malaria was suspected. Nineteen of the 165 chili dren given MALARONE and 18 of 165 patients given plaI cebo withdrew from the study for reasons other than para¬ sitemia (primary reason was lost to follow-up). One out of 150 evaluable patients (11 kg and 2 to 17 years of age) who were at risk of con¬ tracting malaria by traveling to an endemic area. The mean duration of travel was 15 days (range 1 to 30 days). Prophy¬ laxis with MALARONE (n = 110, dosage based on body weight) began 1 or 2 days before entering the endemic area and lasted until 7 days after leaving the area. A control group (n = 111) received prophylaxis with chloroquine/ proguanil dosed according to WHO guidelines. No cases of malaria occurred in either group of children. However, the study was not large enough to allow for statements of com¬ parative efficacy. In addition, the true exposure rate to P. falciparum malaria in this study is unknown. Causal Prophylaxis: In separate trials with small num¬ bers of volunteers, atovaquone and proguanil hydrochloride were independently shown to have causal prophylactic ac¬ tivity directed against liver-stage parasites of P. falcipa¬ rum. Six patients given a single dose of atovaquone 250 mg 24 hours prior to malaria challenge were protected from de¬ veloping malaria, whereas all 4 placebo-treated patients developed malaria. During the 4 weeks following cessation of prophylaxis in clinical trial participants who remained in malaria-en¬ demic areas and were available for evaluation, malaria de¬ veloped in 24 of 211 (11.4%) subjects who took placebo and 9 of 328 (2.7%) who took MALARONE. While new infections could not be distinguished from recrudescent infections, all but 1 of the infections in patients treated with MALARONE occurred more than 15 days after stopping therapy. The sin¬ gle case occurring on day 8 following cessation of therapy with MALARONE probably represents a failure of prophy¬ laxis with MALARONE. The possibility that delayed cases of P. falciparum malaria may occur some time after stopping prophylaxis with MALARONE cannot be ruled out. Hence, returning travel¬ ers developing febrile illnesses should be investigated for malaria. 14.2 Treatment of Acute, Uncomplicated P. falciparum Malaria Infections In 3 phase II clinical trials, atovaquone alone, proguanil hydrochloride alone, and the combination of atovaquone and proguanil hydrochloride were evaluated for the treat¬ ment of acute, uncomplicated malaria caused by P. falcipa¬ rum. Among 156 evaluable patients, the parasitological cure rate (elimination of parasitemia with no recurrent parasite¬ mia during follow-up for 28 days) was 59/89 t66% > with atovaquone alone, 1/17 (6%) with proguanil hydrochloride alone, and 50/50(100%) with the combination of atovaquone and proguanil hydrochloride. MALARONE was evaluated for treatment of acute, uncom¬ plicated malaria caused by P. falciparum in 8 phase III ran¬ domized, open-label, controlled clinical trials (N = 1,030 en¬ rolled in both treatment groups). The mean age of subjects was 27 years and 16% were children 30 mm

14.7 0.5

20.4 0.3

23.8 0.3

25.4 0.6

20.5 1.5

20.8 0.2

28.6 0.4

31.7 0.8

2,008-2,009

1,871

1,723

1,535-1,536

659

609-610

569

493-494

Irritability Irritability, grade 3f

67.5 3.7

70.8 4.8

65.8 3.3

62.1 2.5

76.9 7.4

75.1 5.6

65.4 4.2

66.1 4.3

Drowsiness, any Drowsiness, grade 38

62.8 2.7

57.7 3.2

49.5 1.7

48.7 2.1

66.9 2.7

61.8 2.6

52.4 1.4

48.5 2.0

Loss of appetite, any Loss of appetite, grade 3h

33.8 0.5

32.1 0.7

30.1 0.5

32.1 1.1

37.6 0.3

33.6 0.7

30.2 1.1

32.5 2.2

Fever, £100.4^ Fever, >102.2°F' Fever, >104°F‘

18.9 1.1 0.0

25.9 1.9 0.1

23.0 3.2 0.3

11.0 1.5 0.3

21.4 0.9 0.0

28.2 2.6 0.0

23.7 2.8 0.4

12.6 2.0 0.2

Locald N

Systemic N

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with MENHIBRIX. It is also not known whether MENHIBRIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 8.4 Pediatric Use Safety and effectiveness of MENHIBRIX in children younger than 6 weeks of age and in children 19 months to 16 years of age have not been established.

11

DESCRIPTION

MENHIBRIX i Meningococcal Groups C and Y and Haemophilus b TVtanus Toxoid Conjugate Vaccine), for in¬ tramuscular injection, is supplied as a sterile, lyophilized powder which is reconstituted at the time of use with the accompanying saline diluent. MENHIBRIX contains Neisse¬ ria meningitidis serogroup C and Y capsular polysaccharide antigens and Haemophilus b capsular polysaccharide Ipolyribosyl-ribitol-phosphate 1PRP1). The Neisseria menin¬ gitidis C strain and Y strain are grown in semi-synthetic media and undergo heat inactivation and purification The PRP is a high molecular weight polymer prepared from the Haemophilus influenzae type b strain 20,752 grown in a synthetic medium that undergoes heat inactivation and pu¬ rification. The tetanus toxin, prepared from Clostridium tetani grown in a semi-synthetic medium, is detoxified with formaldehyde and purified Each capsular polysaccharide is individually covalently bound to the inactivated tetanus toxoid After purification, the conjugate is lyophilized in the presence of sucrose as a stabilizer. The diluent for MENHIBRIX is a sterile saline solution (Oft*, sodium chlo¬ ride* supplied in vials. When MENHIBRIX is reconstituted with the accompanying vial of saline diluent, each 0.5-mL dose is formulated to con¬ tain 6 meg of purified Neisseria meningitidis C capsular pol¬

I I ! j

i

MENHIBRIX Post-Dose 4

N = 491

N = 331

% £1:8 95% Cl

98.8 97.4, 99.6

98.5' 96.5, 99.5

GMT 95% Cl

968 864, 1084

2040 1746, 2383

hSBA-MenC

hSBA-MenY

N = 481

200 mlU/mL, anti¬ polysaccharide vaccine , an anti-PRP concentration of mumps >51 EDju, anti-rubella £10 IU/mL, and anti0.15 mcg/mL has been accepted as a minimal protective varicella £1:40) administered at 12 to 15 months of age level. Data from an efficacy study with unconjugated concomitantly with MENHIBRIX and PCV7 relative to Haemophilus b polysaccharide vaccine indicate that an these vaccines administered concomitantly with PRP-OMP anti-PRP concentration of >1.0 mcg/mL predicts protection and PCV7.4-5 The immune responses to MMR and varicella through at least a 1-year period.11^* These antibody levels vaccines were evaluated 6 weeks post-vaccination. Data are have been u4ed to evaluate the effectiveness of H influenzae insufficient to evaluate potential interference when a fourth type b-contaming vaccines, including MENHIBRIX. PCV7 dose is administered concomitantly with MENHIBRIX at 12 to 15 months of age. 13 NONCL1NICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility ; MENHIBRIX has not been evaluated for carcinogenic or j mutagenic potential, or for impairment of fertility. 14 CLINICAL STUDIES 14.1 Immunological Evaluation ! In Study 009/0106 the immune response to MENHIBRIX and control vaccines was evaluated in a subset of LTS parI ticipants. In this clinical study, MENHIBRIX and Hib con-

15

REFERENCES

All NCT numbers are as noted in the National Library of Medicine clinical trial database 'see www.clinicaltriala.gov). 1 NCT00127855 (001). 2. NCT00129116 (003/004) 3. NCT00129129(005/006>. ‘ 4 NCT00134719 (007/008). 5. NCT00289783 (009/010). 6 NCT00345579/NCT00345683 (011/012)

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Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

1036/GLAXOSMITHKLINE • MENHIBRIX

Table 3. Comparison of anti-PRP Responses Following MENHIBRIX or Haemophilus b Conjugate Vaccine* (One Month After Dose 3 and 6 Weeks After Dose 4) in US Children Vaccinated at 2, 4, 6, and 12 to 15 Months of Age (ATP Cohort for Immunogenicity)

• PCP Treatment: The most frequent adverse reactions (£14% that required discontinuation) were rash (including maculopapular), nausea, diarrhea, headache, vomiting, and fever. (6.1)

MENHIBRIX

PRP-T

MENHIBRIX

PRP-OMP

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Anti-PRP

N = 518

N = 171

N = 361

N = 126

-DRUG INTERACTIONS-

% £0.15 mcg/mL

95% Cl

100 99.3, 100

98.2 95.0, 99.6

100 99.0, 100

100 97.1, 100

% £1.0 mcg/mL 95% Cl

96.3b 94.3, 97.8

91.2 85.9, 95.0

99.2b 97.6, 99.8

99.2 95.7, 100

GMC (mcg/mL) 95% Cl

11.0 10.0, 12.1

6.5 5.3, 7.9

34.9 30.7, 39.6

20.2 16.4, 24.9

Post-Dose 4

Post-Dose 3

ATP = according to protocol; anti-PRP = antibody concentrations to H. influenzae capsular polysaccharide; Cl = confidence interval; GMC = geometric mean antibody concentration. N = number of US children eligible for inclusion in the ATP immunogenicity cohort for whom serological results were available for the post-dose 3 and post-dose 4 immunological evaluations. n US-licensed monovalent Haemophilus b Conjugate Vaccine for doses 1, 2, and 3 (PRP-T) and for dose 4 (PRP-OMP). b Non-inferiority was demonstrated (lower limit of 95% Cl on the group difference of MENHIBRIX minus Haemophilus b Conjugate Vaccine £-10%).

• Concomitant administration of rifampin or rifabutin re¬ duces atovaquone concentrations; concomitant use with MEPRON suspension is not recommended. (7.1) • Concomitant administration of tetracycline reduces atovaquone concentrations; use caution when coadminis¬ tering. Monitor patients for potential loss of efficacy of MEPRON if coadministration of tetracycline is necessary. (7.2) • Concomitant administration with metoclopramide reduces atovaquone concentrations; administer concomitantly only if other antiemetics are not available. (7.3) • Concomitant administration of indinavir reduces indina¬ vir trough concentrations; use caution when coadminister¬ ing. Monitor patients for potential loss of efficacy of indi¬ navir if coadministration is necessary.(7.4) See 17 for PATIENT COUNSELING INFORMATION. Revised: 6/2015

7. Rothstein EP, Madore DV, Girone JAC, et al. Compari¬ son of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines. Pediatr Infect Dis J 1991;10:311-314. 8. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129:1307-1326. 9. Robbins JB, Parke JC, Schneerson R, et al. Quantitative measurement of "natural" and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 1973;7:103-110. 10. Peltola H, Kaythy H, Sivonen A, et al. Haemophilus in¬ fluenzae type b capsular polysaccharide vaccine in chil¬ dren: A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-737. 11. Kaythy H, Peltola H, Karanko V, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983;147:1100. 12. Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1984;149:1034. 16 HOW SUPPLIED/STORAGE AND HANDLING MENHIBRIX is available in single-dose vials of lyophilized vaccine, accompanied by vials containing 0.85 mL of saline diluent (packaged without syringes or needles). Supplied as package of 10 doses (NDC 58160-801-11): NDC 58160-809-01 Vial of lyophilized vaccine in Package of 10: NDC 58160-809-05 NDC 58160-813-01 Vial of saline diluent in Package of 10: NDC 58160-813-05 16.1

Storage Before Reconstitution

Lyophilized vaccine vials: Store refrigerated between 2° and 8°C (36° and 46°F). Protect vials from light. Diluent: Store refrigerated or at controlled room tempera¬ ture between 2° and 25°C (36° and 77°F). Do not freeze. Dis¬ card if the diluent has been frozen. 16.2

Storage After Reconstitution

After reconstitution, administer MENHIBRIX immediately. Do not freeze. Discard if the vaccine has been frozen. 17 PATIENT COUNSELING INFORMATION • Inform parents or guardians of the potential benefits and risks of immunization with MENHIBRIX, and of the im¬ portance of completing the immunization series. • Inform parents or guardians about the potential for ad¬ verse reactions that have been temporally associated with administration of MENHIBRIX or other vaccines contain¬ ing similar components. • Instruct parents or guardians to report any adverse events to their healthcare provider. • Give parents or guardians the Vaccine Information State¬ ments, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immuniza¬ tion. These materials are available free of charge at the Centers for Disease Control and Prevention (CDCl website ' ww w.cdc.govAaccines). HIBERIX, MENHIBRIX. and PEDIARIX are registered trademarks of the GlaxoSmithKline group of companies. Manufactured by GlaxoSmithKline Biologicals Rixensart. Belgium. US License 1617, and Distributed by GlaxoSmithKline Research Triangle Park. NC 27709

©2013, GlaxoSmithKline group of companies. All rights reserved. MNX:2PI MEPRON

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Prevention of Pneumocystis jiroveci Pneumo¬

nia 1.2

^

[m&'prdn] (atovaquone) oral suspension HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MEPRON suspension safely and effectively. See full prescribing information for MEPRON suspension. MEPRON (atovaquone) oral suspension Initial U.S. Approval: 1992

-INDICATIONS AND USAGEMEPRON suspension is a quinone antimicrobial drug indi¬ cated for: (1) • Prevention of Pneumocystis jiroveci pneumonia (PCP) in adults and adolescents aged 13 years and older who can¬ not tolerate trimethoprim-sulfamethoxazole (TMP-SMX). (1.1) • Treatment of mild-to-moderate PCP in adults and adoles¬ cents aged 13 years and older who cannot tolerate TMPSMX. (1.2) Limitations of Use (1.3): • Treatment of severe PCP (alveolar arterial oxygen diffu¬ sion gradient [(A-a)D02l >45 mm Hg) with MEPRON has not been studied. • The efficacy of MEPRON in subjects who are failing ther¬ apy with TMP-SMX has also not been studied. -DOSAGE AND ADMINISTRATION• Prevention of PCP: 1,500 mg (10 mL) once daily with food

1.3 2

-DOSAGE FORMS AND STRENGTHSOral suspension: 750 mg per 5 mL. (3)

Limitations of Use

DOSAGE AND ADMINISTRATION 2.1 Dosage for the Prevention of P. jiroveci Pneu¬

monia 2.2 Dosage for the Treatment of Mild-toModerate P. jiroveci Pneumonia 2.3 Important Administration Instructions 3 4 5

DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

5.1 5.2 6

7

Pregnancy Nursing Mothers Pediatric Use Geriatric Use

OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY

12.1 12.3 12.4 13

Rifampin/Rifabutin Tetracycline Metoclopramide Indinavir

USE IN SPECIFIC POPULATIONS

8.1 8.3 8.4 8.5 10 11 12

Clinical Trials Experience Postmarketing Experience

DRUG INTERACTIONS

7.1 7.2 7.3 7.4 8

Risk of Limited Oral Absorption Hepatotoxicity

ADVERSE REACTIONS

6.1 6.2

(2.1)

• Treatment of PCP: 750 mg (5 mL) twice daily with food for 21 days (2.2) • Supplied in Foil Pouches and Bottles: ° Foil Pouch: For a 5-mL dose, take entire contents by mouth either by dispensing into a spoon or cup or di¬ rectly into the mouth. For a 10-mL dose, take two pouches. (2.3) ° Bottle: Shake hottle gently before use. (2.3)

Treatment of Mild-to-Moderate Pneumocystis

jiroveci Pneumonia

Mechanism of Action Pharmacokinetics Microbiology

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14

CLINICAL STUDIES

14.1 14.2 16 17

Prevention of PCP Treatment of PCP

HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

-CONTRAINDICATIONS-

Known serious allergic/hvpersensitivity reaction (e.g.. angioedema. bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of MEPRON. (4)

FULL PRESCRIBING INFORMATION 1 1.1

INDICATIONS AND USAGE Prevention of Pneumocystis jiroveci Pneumonia

-WARNINGS AND PRECAUTIONS-

MEPRON* suspension is indicated for the prevention of

• Failure to administer MEPRON suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Patients with gastrointes¬ tinal disorders may have limited absorption resulting in suboptimal atovaquone concentrations. (5.1) • Hepatotoxicity: Elevated liver chemistry tests and cases of hepatitis and fatal liver failure have been reported. (5.2)

Pneumocystis jiroveci pneumonia (PCP) in adults and ado¬

-ADVERSE REACTIONS-

1.3

lescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). 1.2

Treatment

of

Mild-to-Moderate

Pneumocystis

jiroveci Pneumonia

MEPRON suspension is indicated for the acute oral treat¬ ment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX Limitations of Use

• PCP Prevention: The most frequent adverse reactions Clinical experience with MEPRON for the treatment of PCP has been limited to subjects with mild-to-moderate PCP (£25% that required discontinuation i were diarrhea, rash, I (alveolar-arterial oxygen diffusion gradient KA-aiDOj] headache, nausea, and fever. (6.1)

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Look for PDR drug information and services in your EHR S45 mm Hg). Treatment of more severe episodes of PCP with MEPRON has not been studied. The efficacy of MEPRON in subjects who are failing therapy with TMPSMX has also not been studied. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage for the Prevention of P. jiroveci Pneumonia The recommended oral dosage is 1,500 mg ilO mLI once daily administered with food. 2.2 Dosage for the Treatment of Mild-to-Moderate P. jiroveci Pneumonia The recommended oral dosage is 750 mg (5 mLI twice daily (total daily dose = 1,500 mgl administered with food for 21 days. 2.3 Important Administration Instructions Administer MEPRON oral suspension with food to avoid lower plasma atovaquone concentrations that may limit re¬ sponse to therapy [see Warnings and Precautions (5.1), Clin¬ ical Pharmacology (12.3)1. MEPRON Foil Pouch • Open each 5-mL pouch by removing tab at perforation and tear at notch. • For a 5-mL dose, take entire contents either by placing di¬ rectly into the mouth or by dispensing into a dosing .spoon (5 mLl or cup prior to administration by mouth. • For a 10-mL dose, take the entire contents of two pouches. MEPRON Bottle Shake bottle gently before administering the recommended dosage. 3

DOSAGE FORMS AND STRENGTHS

MEPRON is a bright yellow, citrus-flavored, oral suspension containing 750 mg of atovaquone in 5 mL. MEPRON is sup¬ plied in 210-mL bottles or 5-mL foil pouches. 4

CONTRAINDICATIONS

MEPRON suspension is contraindicated in patients who de¬ velop or have a history of hypersensitivity reactions (e.g., angioedema, bronchospasm, throat tightness, urticaria) to atovaquone or any of the components of MEPRON. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Limited Oral Absorption Absorption of orally administered MEPRON suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer MEPRON suspen¬ sion with food may result in lower plasma atovaquone con¬ centrations and may limit response to therapy. Consider therapy with other agents in patients who have difficulty taking MEPRON suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications /see Clinical Pharmacology (12.3)1. 5.2 Hepatotoxicity Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone /see Adverse Reactions (6.2)1. If treating patients with severe hepatic impairment, closely monitor patients following administration of MEPRON. 6

MEPRON • GLAXOSMITHKLINE/1037 verse reactions (nausea, diarrhea, and vomiting) were more frequently reported in subjects treated with MEPRON sus¬ pension (Table 1). Table 1. Percentage (>2%) of Subjects with Selected Adverse Reactions Requiring Discontinuation of Treatment in the Dapsone Comparative PCP Prevention Trial All Subjects MEPRON Suspension 1,500 mg/day (n = 536) %

Dapsone 100 mg/day (n = 521) %

Rash

6.3

8.8

Nausea

4.1

0.6

Diarrhea

3.2

0.2

Vomiting

2.2

0.6

Adverse Reaction

Table 3. Percentage (S10%) of Subjects with Selected Adverse Reactions in the TMP-SMX Comparative PCP Treatment Trial MEPRON Tablets (n = 203) %

TMP-SMX (n = 205) %

Rash (including maculopapular)

23

34

Nausea

21

44

Diarrhea

19

7

Headache

16

22

Vomiting

14

35

Fever

14

25

Insomnia

10

9

Adverse Reaction

Aerosolized Pentamidine Comparative Trial: In the aero¬ solized pentamidine comparative trial (n = 549), the major¬ ity of subjects were white (79%), male (92%), and were pri¬ mary prophylaxis patients at enrollment (58%); the mean age was 38 years. Subjects received MEPRON suspension once daily at a dose of 750 mg (n = 188) or 1,500 mg (n = 175) or received aerosolized pentamidine 300 mg every 4 weeks (n = 186); the median durations of exposure were 6.2, 6.0, and 7.8 months, respectively. Table 2 summarizes the clini¬ cal adverse reactions reported by >20% of the subjects re¬ ceiving either the 1,500-mg dose of MEPRON suspension or aerosolized pentamidine. Rash occurred more often in subjects treated with MEPRON suspension (46%) than in subjects treated with aerosolized pentamidine (28%). Treatment-limiting adverse reactions occurred in 25% of subjects treated with MEPRON suspension 1,500 mg once daily and in 7% of sub¬ jects treated with aerosolized pentamidine. The most fre¬ quent adverse reactions requiring discontinuation of dosing in the group receiving MEPRON suspension 1,500 mg once daily were rash (6%), diarrhea (4%), and nausea (3%). The most frequent adverse reaction requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%). Table 2. Percentage (>20%) of Subjects with Selected Adverse Reactions in the Aerosolized Pentamidine Comparative PCP Prevention Trial MEPRON Suspension 1,500 mg/day (n = 175) %

Aerosolized Pentamidine (n = 186) %

Diarrhea

42

35

Rash

39

28

Headache

28

22

Nausea

26

23

Fever

25

Rhinitis

24

ADVERSE REACTIONS

The following adverse reactions are discussed in other sec¬ tions of the labeling: • Hepatotoxicity /see Warnings and Precautions (5.2)1. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Additionally, because many subjects who participated in clinical trials with MEPRON had complications of advanced human immunodeficiency virus (HfV) disease, it was often difficult to distinguish adverse reactions caused by MEPRON from those caused by underlying medical conditibns. PCP Prevention Trials In two clinical trials, MEPRON suspension was compared with dapsone or aerosolized pentamidine in HIV-l-infected adolescent (13 to 18 years) and adult subjects at risk of PCP (CD4 count 10% of subjects receiving the recommended dose of MEPRON suspension (1,500 mg once daily) included vomiting, sweating, flu syndrome, sinusitis, pruritus, insomnia, depression, and myalgia. PCP Treatment Trials Safety information is presented from 2 clinical efficacy trials of the MEPRON tablet formulation: 1) a randomized, dou¬ ble-blind trial comparing MEPRON tablets with TMPSMX in subjects with acquired immunodeficiency syndrome (AIDS) and mild-to-moderate PCP |(A-a)D02| 145 mm Hg and Pa02 >60 mm Hg on room air; 2) a randomized, openlabel trial aimparing MEPRON tablets with intravenous (IV) pentamidine isethionate in subjects with mild-to-mod¬ erate PCP who could not tolerate trimethoprim or Bulfa an¬ timicrobials. TMP-SMX Comparative Trial: In the TMP-SMX compara¬ tive trial (n = 408), the majority of subjects were white (66%) and male (95%); the mean age was 36 years. Subjects received MEPRON 750 mg (three 250-mg tablets) 3 times daily for 21 days or TMP 320 mg plus SMX 1,600 mg 3 times daily for 21 days; median durations of exposure were 21 and 15 days, respectively.

Adverse Reaction

Laboratory abnormality was reported as the reason for dis¬ continuation of treatment in 2 of 73 subjects (3%) who re¬ ceived MEPRON, and in 14 of 71 subjects (20% > who re¬ ceived pentamidine. One subject 11%) receiving MEPRON had elevated creatinine and BUN levels and 1 subject 11%) had elevated amylase levels. In this Inal, elevated levels of amylase occurred in subjects (8% versus 4% l receiving MEPRON tablets or pentamidine, respectively.

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1038/GLAXOSMITHKLINE • MEPRON Table 6. Relationship between Plasma Atovaquone Concentration and Successful Treatment Successful Treatment* No. Successes/No. in Group (%) Steady-state Plasma Atovaquone Concentrations (mcg/mL)

Predicted6 7 8

Observed 0/6

0%

1.5/6

25%

5 to 25%) included local injection site reactions (pain, redness, and swelling', fever (>100.4°F\ drowsiness, irritability/fussiness and loss of appetite. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-8227967 or www vaers hhs.gov -DRUG INTERACTIONSDo not mix PEDIARIX with any other vaccine in the same syringe or vial. (7.11

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Recommended Dose and Schedule 2.3 Modified Schedules in Previously Vaccinated Children 2.4 Booster Immunization Following PEDIARIX 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Encephalopathy 4.3 Progressive Neurologic Disorder 5 WARNINGS AND PRECAUTIONS 5.1 Fever 5.2 Guillain-Barre Syndrome 5.3 Latex 5.4 Syncope 5.5 Adverse Events Following Prior Pertussis Vaccination 5.6 Children at Risk for Seizures 5.7 Apnea in Premature Infants 5.8 Preventing and Managing Allergic Vaccine Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Safety Surveillance Study 6.3 Postmarketing Spontaneous Reports for PEDIARIX 6.4 Postmarketing Spontaneous Reports for INFANRDC and/or ENGERIX-B 7 DRUG INTERACTIONS 7.1 Concomitant Vaccine Administration 7.2 Immunosuppressive Therapies 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.4 Pediatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility * 14 CLINICAL STUDIES 14.1 Efficacy of INFANRIX 14.2 Immunological Evaluation of PEDIARIX 14.3 Concomitant Vaccine Administration 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1

INDICATIONS AND USAGE

PEDIARIX® is indicated for active immunization against diphtheria, tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and poliomyelitis. PEDIARIX is approved for use as a three-dose series in in¬ fants born of hepatitis B surface antigen (HBsAg)-negative mothers. PEDIARIX may be given as early as 6 weeks of age through 6 years of age (prior to the 7th birthday). 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration Shake vigorously to obtain a homogeneous, turbid, white suspension. Do not use if resuspension does not occur with vigorous shaking. Parenteral drug products should be in¬ spected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. Attach a sterile needle and administer intramuscularly. The preferred administration site is the anterolateral as¬ pect of the thigh for children younger than 1 year. In older children, the deltoid muscle is usually large enough for an intramuscular injection. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk. Gluteal injections may result in suboptimal hepatitis B immune response. Do not administer this product intravenously, intradermally, or subcutaneously. 2.2 Recommended Dose and Schedule Immunization with PEDL4RIX consists of 3 doses of 0.5 mL each, by intramuscular injection, at 2, 4, and 6 months of age (at intervals of 6 to 8 weeks, preferably 8 weeks). The first dose may be given as early as 6 weeks of age. Three doses of PEDIARIX constitute a primary immunization course for diphtheria, tetanus, pertussis, and poliomyelitis and the complete vaccination course for hepatitis B.

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Look for PDR drug information and services in your EHR 2.3 Modified Schedules in Previously Vaccinated Chil¬ dren Children Previously Vaccinated With Diphtheria and Tetanus Toxoids and Acellular Pertussin Vaccine Adsorbed (DTaP): PEDIARIX may be used to complete the first 3 doses of the DTaP series in children who have received 1 or 2 doses of INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed), manufactured by GlaxoSmithKline, identical to the DTaP component of PEDIARIX [see Description (ID] and are also scheduled to receive the other vaccine components of PEDIARIX. Data are not available on the safety and effectiveness of using PEDIARIX following one or more doses of a DTaP vaccine from a different manufacturer. Children Previously Vaccinated With Hepatitis B Vac¬ cine: PEDIARIX may be used to complete the hepatitis B vaccination series following 1 or 2 doses of another hepatitis B vaccine (monovalent or as part of a combination vaccine), including vaccines from other manufacturers, in children born of HBsAg-negative mothers who are also scheduled to receive the other vaccine components of PEDIARIX. A 3-dose series of PEDIARIX may be administered to in¬ fants born of HBsAg-negative mothers and who received a dose of hepatitis B vaccine at or shortly after birth. How¬ ever, data are limited regarding the safety of PEDIARIX in such infants [see Adverse Reactions (6.1)1. There are no data to support the use of a 3-dose series of PEDIARIX in infants who have previously received more than one dose of hepatitis B vaccine. Children Previously Vaccinated With Inactivated Poliovirus Vaccine (1PV): PEDIARIX may be used to complete the first 3 doses of the IPV series in children who have received 1 or 2 doses of IPV from a different manufacturer and are also scheduled to receive the other vaccine components of PEDIARIX. 2.4 Booster Immunization Following PEDIARIX Children who have received a 3-dose series with PEDIARIX should complete the DTaP and IPV series according to the recommended schedule.1 Because the pertussis antigens contained in INFANRIX and KINRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine), manufactured by GlaxoSmithKline, are the same as those in PEDIARIX, these children should receive INFANRIX as their fourth dose of DTaP and either INFANRIX or KINRIX as their fifth dose of DTaP, according to the respective prescribing infor¬ mation for these vaccines. KINRIX or another manufactur¬ er's IPV may be used to complete the 4-dose IPV series ac¬ cording to the respective prescribing information. 3

DOSAGE FORMS AND STRENGTHS

PEDIARIX is a suspension for injection available in 0.5-mL single-dose prefilled TIP-LOK® syringes. 4 CONTRAINDICATIONS 4.1 Hypersensitivity A severe allergic reaction (e.g., anaphylaxis) after a previ¬ ous dose of any diphtheria toxoid-, tetanus toxoid-, pertussis antigen-, hepatitis B-, or poliovirus-containing vaccine or any component of this vaccine, including yeast, neomycin, and polymyxin B, is a contraindication to administration of PEDIARIX /see Description 3 hours, occurring within 48 hours; • Seizures with or without fever occurring within 3 days. 5.6 Children at Risk for Seizures For children at higher risk for seizures than the general population, an appropriate antipyretic may be administered at the time of vaccination with a vaccine containing a pertussis component, including PEDIARIX, and for the en¬ suing 24 hours to reduce the possibility of post-vaccination fever. 5.7 Apnea in Premature Infants Apnea following intramuscular vaccination has been ob¬ served in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including PEDIARIX, to infants born prematurely should be based on consideration of the individual infant’s medical status, and the potential benefits and possible risks of vaccination. 5.8 Preventing and Managing Allergic Vaccine Reac¬ tions Prior to administration, the healthcare provider should re¬ view the immunization history for possible vaccine sensitiv¬ ity and previous vaccination-related adverse reactions to al¬ low an assessment of benefits and risks. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical tri¬ als of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. A total of 23,849 doses of PEDIARIX have been adminis¬ tered to 8,088 infants who received one or more doses as part of the 3-dose series during 14 clinical studies. Common adverse events that occurred in >25% of subjects following any dose of PEDIARIX included local injection site reactions (pain, redness, and swelling), fever, drowsiness, irritability/ fussiness, and loss of appetite. In comparative studies (in¬ cluding the German and US studies described below), ad¬ ministration of PEDIARIX was associated with higher rates of fever relative to separately administered vaccines Isee Warnings and Precautions (5.1)]. The prevalence of fever was highest on the day of vaccination and the day following vaccination. More than 96% of episodes of fever resolved within the 4-day period following vaccination (i.e., the pe¬ riod including the day of vaccination and the next 3 days). In the largest of the 14 studies, conducted in Germany, safety data were available for 4.666 infants who received PEDIARIX administered concomitantly at separate sites with I of 4 Haemophilusinfluenzae type b (Hib) conjugate vaccines (GlaxoSmithKline (licensed in the US only for booster immunization], Wyeth Pharmaceuticals Inc. |no longer licensed in the US], Sanofi Pasteur SA lUS-licensedl. or Merck & Co, Inc. lUS-licensedl) at 3, 4, and 5 months of age and for 768 infants in the control group that received separate US-licensed vaccines (INFANRIX. Hib conjugate vaccine ISanofi Pasteur SA|, and oral poliovirus vaccine IOPV) (Wyeth Pharmaceuticals, Inc.; no longer licensed in the US) I. In this study, information on adverse events that occurred within 30 days following vaccination was collected. More than 95% of study participants were white. In a US study, the safety of PEDIARIX administered to 673 infants was compared to the safety of separately adminis¬ tered INFANRIX, ENGERIX-B® (Hepatitis B Vaccine (Recombinant)(, and IPV’ (Sanofi Pasteur SA) in 335 infants. In both groups, infants received Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US) and 7-valent pneumococcal conjugate vaccine (Wyeth Phar¬ maceuticals Inc.) concomitantly at separate sites. All vac¬ cines were administered at 2, 4, and 6 months of age Data on solicited local reactions and general adverse events were collected by parents using standardized diary cards for 4 consecutive days following each vaccine dose (i.e., day of vaccination and the next 3 days). Telephone follow-up was conducted 1 month and 6 months after the third vaccination to inquire about serious adverse events. At the 6-month

i | | I

I [ I

follow-up, information also was collected on new onset of chronic illnesses. A total of 638 subjects who received PEDIARIX and 313 subjects who received INFANRIX. ENGERIX-B, and IPV completed the 6-month follow-up Among subjects in both study groups combined. 69% were white, 18% were Hispanic. 7% were black. 3% were Orien¬ tal, and 3% were of other racial/ethnic groups. Solicited Adverse Events: Data on solicited local reactions and general adverse events from the US safety study are presented in Table 1. This study was powered to evaluate fever >101.3°F following dose 1. The rate of fever >100.4°F following each dose was significantly higher in the group that received PEDIARIX compared to separately adminis¬ tered vaccines. Other statistically significant differences be¬ tween groups in rates of fever, as well as other solicited ad¬ verse events, are noted in Table 1. Medical attention (a visit to or from medical personnel) for fever within 4 days follow¬ ing vaccination was sought in the group who received PEDIARIX for 8 infants after the first dose (1.2%), 1 infant following the second dose (0.2%), and 5 infants following the third dose (0.8%) (Table 1). Following dose 2, medical atten¬ tion for fever was sought for 2 infants (0.6% ) who received separately administered vaccines (Table li. Among infants who had a medical visit for fever within 4 days following vaccination, 9 of 14 who received PEDIARIX and 1 of 2 who received separately administered vaccines, had one or more diagnostic studies performed to evaluate the cause of fever. [See table 1 at top of next page) Serious Adverse Events: Within 30 days following any dose of vaccine in the US safety study in which all subjects received concomitant Hib and pneumococcal conjugate vac¬ cines, 7 serious adverse events were reported in 7 subjects (1% (7/673)) who received PEDIARIX (1 case each of py¬ rexia, gastroenteritis, and culture negative clinical sepsis and 4 cases of bronchiolitis) and 5 serious adverse events were reported in 4 subjects (1% [4/335)1 who received INFANRIX, ENGERIX-B, and IPV (uteropelvic junction ob¬ struction and testicular atrophy in one subject and 3 cases of bronchiolitis). Deaths: In 14 clinical trials, 5 deaths were reported among 8,088 (0.06%) recipients of PEDIARIX and 1 death was reported among 2,287 (0.04% ) recipients of comparator vaccines. Causes of death in the group that received PEDIARIX included 2 cases of Sudden Infant Death Syn¬ drome (SIDS) and one case of each of the following: convul¬ sive disorder, congenital immunodeficiency with sepsis, and neuroblastoma. One case of SIDS was reported in the com¬ parator group. The rate of SIDS among all recipients of PEDIARIX across the 14 trials was 0.25/1,000. The rate of SIDS observed for recipients of PEDIARIX in the Orman safety study was 0.2/1,000 infants (reported rate of SIDS in Ormany in the latter part of the 1990s was 0.7/1,000 new¬ borns). The reported rate of SIDS in the United States from 1990 to 1994 was 1.2/1,000 live births. By chance alone, some cases of SIDS can be expected to follow receipt of pertussis-containing vaccines. Onset of Chronic Illnesses: In the US safety study in which all subjects received concomitant Hib and pneumo¬ coccal conjugate vaccines, 21 subjects (3% ) who received PEDIARIX and 14 subjects (4% ) who received INFANRIX, ENGERIX-B. and IPV reported new onset of a chronic ill¬ ness during the period from 1 to 6 months following the last dose of study vaccines. Among the chronic illnesses reported in the subjects who received PEDIARIX. there were 4 cases of asthma and 1 case each of diabetes mellitus and chronic neutropenia. There were 4 cases of asthma in subjects who received INFANRIX, ENGERIX-B. and IPV Seizures: In the German safety study over the entire study period. 6 subjects in the group that received PEDIARIX (N = 4.666) reported seizures. Two of these sub¬ jects had a febrile seizure. 1 of whom also developed afebrile seizures The remaining 4 subjects had afebrile seizures, in¬ cluding 2 with infantile spasms. Two subjects reported sei¬ zures within 7 days following vaccination (1 subject had both febrile and afebrile seizures, and 1 subject had afebrile seizures), corresponding to a rate of 0.22 seizures per 1.000 doses i febrile seizures 0.07 per 1,000 doses, afebrile seizures 0.14 per 1,000 doses). No subject who received concomitant INFANRIX, Hib vaccine, and OPV (N = 768) reported sei¬ zures. In a separate German study that evaluated the safety of INFANRIX in 22,505 infants who received 66,867 doses of INFANRIX administered as a 3-dose primary se¬ ries, the rate of seizures within 7 days of vaccination with INFANRIX was 0.13 per 1,000 doses l febrile seizures 0.0 per 1,000 doses, afebrile seizures 0.13 per 1,000 doses). Over the entire study period in the US safety study in which all subjects received concomitant Hib and pneumococcal conjugate vaccines, 4 subjects in the group that received PEDIARIX i N = 673) reported seizures Three of these subjects had a febrile seizure and 1 had an afebrile seizure. Over the entire studv period, 2 subjects in the group that received INFANRIX,'ENGERDC-B, and IPV (N = 335) reported febrile seizures. There were no afebrile seizures in this group. No subject in either study group had seizures within 7 days following vaccination.

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1042/GLAXOSMITHKLINE • PEDIARIX

Table 1. Percentage of Infants With Solicited Local Reactions or General Adverse Events Within 4 Days of Vaccination" at 2, 4, and 6 Months of Age With PEDIARIX Administered Concomitantly With Hib Conjugate Vaccine and 7-valent Pneumococcal Conjugate Vaccine (PCV7) or With Separate Concomitant Administration of INFANRIX, ENGERIX-B, IPV, Hib Conjugate Vaccine, and PCV7 (Modified Intent To Treat Cohort) PEDIARIX, Hib Vaccine, 8c PCV7

Dose 1

Dose 2

Dose 3

INFANRIX, ENGERIX-B. IPV, Hib Vaccine, 8i PCV7 Dose 1

Dose 2

Dose 3 *'

Localb N

671

653

648

335

323

315

Pain, any Pain, grade 2 or 3 Pain, grade 3

36.1 11.5 2.4

36.1 10.9 2.5

31.2 10.6 1.7

31.9 9.0 2.7

30.0 8.7 1.5

29.8 8.9 1.3

Redness, any Redness, >5 mm Redness, >20 mm

24.9C 6.0° 0.9

37.2 9.6C 1.2°

40.1 12.7C 2.8

18.2 1.8 0.3

32.8 5.9 0.0

39.0 7.3 1.9

Swelling, any Swelling, >5 mm Swelling, >20 mm

17.3C 5.8C 1.9

26.5C 9.6C 2.5°

28.7 9.3C 3.1

9.6 1.8 0.6

20.4 5.0 0.0

24.8 4.1 1.3

667

644

645

333

321

311

27.9° 7.0 2.2C 0.4 1.2C

38.8C 14. lc 3.6 1.4 0.2

33.5° 8.8 3.4 1.1 0.8

19.8 4.5 0.3 0.0 0.0

30.2 9.7 3.1 0.3 0.6

23.8 5.8 2.3 0.3 0.0

N

671

653

648

335

323

315

Drowsiness, any Drowsiness, grade 2 or 3 Drowsiness, grade 3

57.2 15.8 2.5

51.6 13.8 1.2

40.9 11.4 0.9

54.0 17.6 3.6

48.3 12.4 0.6

38.4 11.1 1.9

Irritability/Fussiness, any Irritability/Fussiness, grade 2 or 3 Irritability/F ussiness, grade 3

60.5 19.8 3.4

64.9 27.9C 4.4

61.1 25.2C 3.5

61.5 19.4 3.9

61.6 21.1 3.4

56.5 19.4 3.2

Loss of appetite, any Loss of appetite, grade 2 or 3 Loss of appetite, grade 3

30.4 6.6 0.7

30.6 7.8C 0.3

26.2 5.9 0.2

27.8 5.1 0.6

26.6 3.4 0.3

23.8 5.4 0.0

General N Fever11, Fever11, Feverd, Feverd, Feverd,

£100.4°F >101.3°F >102.2°F >103.1°F M.A.

Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA). Modified intent to treat cohort = all vaccinated subjects for whom safety data were available. N = number of infants for whom at least one symptom sheet was completed; for fever, numbers exclude missing temperature recordings or tympanic measurements. M.A. = medically attended (a visit to or from medical personnel). Grade 2 defined as sufficiently discomforting to interfere with daily activities. Grade 3 defined as preventing normal daily activities. “ Within 4 days of vaccination defined as day of vaccination and the next 3 days. b Local reactions at the injection site for PEDIARIX or INFANRIX. c Rate significantly higher in the group that received PEDIARIX compared to separately administered vaccines IP value 0.1 IU/mL is considered protective/' Pertussis: Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the dif¬ ferent components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no established serological correlate of protection for pertussis. Hepatitis B: Infection with hepatitis B virus can have se¬ rious consequences including acute massive hepatic necro¬ sis and chronic active hepatitis. Chronically infected per¬ sons are at increased risk for cirrhosis and hepatocellular carcinoma. Antibody concentrations >10 mlU/mL against HBsAg are recognized as conferring protection against hepatitis B vi¬ rus infection6 Poliomyelitis: Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Poliovirus neutralizing antibodies confer protection against poliomyelitis disease.' 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fer¬ tility PEDIARIX has not been evaluated for carcinogenic or mu¬ tagenic potential, or for impairment of fertility. 14

1 | 1

j ' | l i I 1

CLINICAL STUDIES

The efficacy of PEDIARIX is based on the immunogenicity of the individual antigens compared to licensed vaccines. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components. The efficacy of the pert ussis component, which does not have a well established correlate of protection, was determined in dinical trials of INFANRIX. 14.1 Efficacy of INFANRIX Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies. A double-blind, randomized, active Diphtheria and TVtanus Toxoids iDT(-controlled trial conducted in Italy, sponsored by the National Institutes of Health ( NTH), assessed the absolute protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. The population used in the primary analysis of the efficacy of INFANRIX included 4.481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days

or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (96% Cl: >6%. 89% ). When the definition of pertussis was expanded to in¬ clude clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was 71% (95% Cl: 60%, 78%) against >7 days of any cough and 73% (95% Cl: 63%, 80% > against >14 days of any cough. A longer unblinded follow-up period showed that after 3 doses and with no booster dose in the second year of life, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% Cl: 79% ,91% i among children followed to 6 years of age. For details see INFANRIX prescribing information A prospective efficacy trial was also conducted in Germany employing a household contact study design. In this study, the protective efficacy of INFANRIX administered to infants at 3,4, and 5 months of age, against WHO-defined pertussis was 89% (95% Cl: 77%. 95%). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic te-ling, the efficacy of INFANRIX against 27 days of any cough was 67% (95% Cl: 52% . 78% l and against >7 days of paroxysmal cough was 81% *95% Cl: 68%, 89% '. For detail* see INFANRIX prescribing information. 14.2 Immunological Evaluation of PEDIARIX In a US multicenter study, infants were randomized to 1 of 3 groups: (1) a combination vaccine group that received PEDIARIX concomitantly with Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the LIS’ and US-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.): (2> a separate vaccine group that received US-licensed INFANRIX. ENGERIX-B. and 1PV (Sanofi Pasteur SA) concomitantly with the same Hib and pneumococcal conjugate vaccines: and ' 3 > a staggered vaccine group that received PEDIARIX concomitantly with the same Hib conjugate vaccine but with the same pneumo¬ coccal conjugate vaccine administered 2 weeks later. The schedule of administration was 2. 4. and 6 months of age Infants either did not receive a dose of hepatitis B vaccine prior to enrollment or were permitted to receive one dose of hepatitis B vaccine administered at least 30 days prior to enrollment. For the separate vaccine group. ENGERIX-B was not administered at 4 months of age to subjects who received a dose of hepatitis B vaccine prior to enrollment. Among subjects in all 3 vaccine groups combined. 84'. were white, 7% were Hispanic, 6% were black, 0.7% were Orien¬ tal, and 2.4% were of other racial/ethnic group.*. The immune responses to the pertussis i PT, f HA. and pert¬ actin), diphtheria, tetanus, poliovirus, and hepatitis B anti¬ gens were evaluated in sera obtained one month 'range 20 to 60 daysi after the third dose of PEDIARIX or INFANRIX Geometric mean antibody concentrations (GMCsi adjusted for pre-vaccination values for PT. HIA, and pertactin and the sent protect ion rates for diphtheria, tetanus, and the po¬ lioviruses among subjects who received PEDIARIX in the

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1044/GLAXOSMITHKLINE • PEDIARIX combination vaccine group were shown to be non-inferior to those achieved following separately administered vaccines (Table 3). Because of differences in the hepatitis B vaccination sched¬ ule among subjects in the study, no clinical limit for non¬ inferiority was pre-defined for the hepatitis B immune re¬ sponse. However, in a previous US study, non-inferiority of PEDIARIX relative to separately administered INFANRIX, ENGERIX-B, and an oral poliovirus vaccine, with respect to the hepatitis B immune response was demonstrated.

14.3 Concomitant Vaccine Administration In a US multicenter study lsee Clinical Studies (14.2)], there was no evidence for interference with the immune re¬ sponses to PEDIARIX when administered concomitantly with 7-valent pneumococcal conjugate vaccine (Wyeth Pharmaceuticals Inc.) relative to 2 weeks prior. Anti-PRP (Hib polyribosyl-ribitol-phosphate) seroprotection rates and GMCs of pneumococcal antibodies one month (range 20 to 60 days) after the third dose of vaccines for the combination vaccine group and the separate vaccine group from the US multicenter study [see Clinical Studies (14.2)], are presented in Table 4.

Table 3. Antibody Responses Following PEDIARIX as Compared to Separate Concomitant Administration of INFANRIX, ENGERIX-B, and IPV (One Month’ After Administration of Dose 3) in Infants Vaccinated at 2, 4, and 6 Months of Age When Administered Concomitantly With Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7)

Table 4. Anti-PRP Seroprotection Rates and GMCs (meg/ mil of Pneumococcal Antibodies One Month’ Following the Third Dose of Hib Conjugate Vaccine and Pneumococcal Conjugate Vaccine (PCV7) Administered Concomitantly With PEDIARIX or With INFANRIX, ENGERIX-B, and IPV

PEDIARIX, Hib Vaccine, & PCV7

INFANRIX, ENGERIX-B, IPV, Hib Vaccine, 8< PCV7

(N = 154-168)

(N = 141-155)

Anti-Diphtheria Toxoid % >0.1 IU/mLb

99.4

98.7

Anti-Tbtanus Tbxoid % >0.1 IU/mLb

100

98.1

Anti-PT % VRC GMCb

98.7 48.1

95.1 28.6

Anti-FHA % VRC GMCb

98.7 111.9

96.5 97.6

Anti-Pertactin % VRC GMCb

91.7 95.3

95.1 80.6

Anti-Polio 1 % 51:8b d

100

100

Anti-Polio 2 % >l:8bd Anti-Polio 3 % >1:8m

Anti-HBsAg" % >10 mIU/mLf GMC (mlU/mL)1

100

100

(N = 114-128)

IN = 111-121)

97.7 1032.1

99.2 614.5

17

PATIENT COUNSELING INFORMATION

The parent or guardian should be: • informed of the potential benefits and risks of immuniza¬ tion with PEDIARIX, and of the importance of completing the immunization series. • informed about the potential for adverse reactions that have been temporally associated with administration of PEDIARIX or other vaccines containing similar compo¬ nents. • instructed to report any adverse events to their healthcare provider. • given the Vaccine Information Statements, which are re¬ quired by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/nip). PEDIARIX, INFANRIX, KINRIX, TIP-LOK, and ENGERIX-B are registered trademarks of the GlaxoSmith¬ Kline group of companies. Manufactured by GlaxoSmithKline Biologicals Rixensart, Belgium, US License 1617, and Novartis Vaccines and Diagnostics GmbH Marburg, Germany, US License 1754 Distributed by GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline group of companies. All rights re¬ served. PDX:22PI

PEDIARIX, Hib Vaccine, 8i PCV7

INFANRIX, ENGERIX-B, IPV, Hib Vaccine, 8< PCV7

(N = 161-168)

(N = 146-156)

% (95% Cl)

% (95% Cl)

Anti-PRP >0.15 mcg/mL

100 (97.8, 100)

99.4 (96.5, 100)

Anti-PRP >1.0 mcg/mL

95.8 (91.6, 98.3)

91.0 (85.3, 95.0)

GMC (95% Cl)

GMC (95% Cl)

1.7 (1.5, 2.0)

2.1 (1.8, 2.4)

POTIGA (ezogabine) tablets, for oral use

Pneumococcal Serotype 4

100

100

NDC 58160-811-43 Syringe in Package of 10: NDC 58160811-52 Store refrigerated between 2° and 8”C (36° and 46“F). Do not freeze. Discard if the vaccine has been frozen.

6B

0.8 (0.7, 1.0)

0.7 (0.5, 0.9)

9V

1.6 (1.4, 1.8)

1.6 (1.4, 1.9)

14

4.7 (4.0, 5.4)

6.3 (5.4, 7.4)

18C

2.6 (2.3, 3.0)

3.0 (2.5, 3.5)

19F

1.1 (1.0, 1.3)

1.1 (0.9, 1.2)

23F

1.5 (1.2, 1.8)

1.8 (1.5, 2.3)

Hib conjugate vaccine (Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA). Assay method used: ELISA for anti-PRP and 7 pneumococcal serotypes. GMC = geometric mean antibody concentration. ‘ One month blood sampling, range 20 to 60 days.

Hib conjugate vaccine i Wyeth Pharmaceuticals Inc.; no longer licensed in the US); PCV7 (Wyeth Pharmaceuticals Inc.); IPV (Sanofi Pasteur SA). Assay methods used: ELISA tor anti-diphtheria, anti-tetanus, anti-PT, anti-FHA, anti-pertactin, and anti-HBsAg; micro-neutralization for anti-polio (1, 2, and 3). VR = vaccine response: In initially seronegative infants, appearance of antibodies (concentration >5 EL.UimL); in initially seropositive infants, at least maintenance of pre-vaccination concentration. GMC = geometric mean antibody concentration. GMCs are adjusted for pre-vaccination levels. * One month blood sampling, range 20 to 60 days. b Seroprotection rate or GMC for PEDIARIX not inferior to separately administered vaccines lupper limit of 90% Cl on GMC ratio (separate vaccine group/combination vaccine group) 4% and twice placeboi were dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, dis¬ turbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -DRUG INTERACTIONSEzogabine plasma levels may be reduced by concomitant ad¬ ministration of phenytoin or carbamazepine. An increase in dosage of POTIGA should be considered when adding phen¬ ytoin or carbamazepine. (7.1) -USE IN SPECIFIC POPULATIONS• Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Safety and effectiveness in patients under 18 years of age have not been established. (8.4) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 5/2015 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2. Dosing Considerations to Mitigate the Risk of Visual Adverse Reactions 2.3 Dosing in Specific Populations 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Retinal Abnormalities and Potential Vision Loss 6.2 Urinary Retention 5.3 Skin Discoloration 5.4 Neuropsychiatric Symptoms 5.5 Dizziness and Somnolence 5.6 QT Interval Effect 5.7 Suicidal Behavior and Ideation 5.8 Withdrawal Seizures 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Antiepileptic Drugs 7.2 Alcohol

7.3 Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Signs, Symptoms, and Laboratory Findings 10.2 Management of Overdose 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.

1

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The initial dosage should be 100 mg 3 times daily (300 mg per day). The dosage should be increased gradually at weekly intervals by no more than 50 mg 3 times daily (in¬ crease in the daily dose of no more than 150 mg per day1 2 3 4 up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600 mg to 1,200 mg per day), based on individual patient response and tolerability. This information is summarized in Table 1 under Dosing in Specific Populations. In the con¬ trolled clinical trials, 400 mg 3 times daily showed limited evidence of additional improvement in seizure reduction, but an increase in adverse events and discontinuations, compared with the 300 mg 3 times daily dosage. The safety and efficacy of dosages greater than 400 mg 3 times daily (1,200 mg per day) have not been examined in controlled trials. POTIGA should be given orally in 3 equally divided doses daily, with or without food. POTIGA tablets should be swallowed whole. If POTIGA is discontinued, the dosage should be gradually reduced over a period of at least 3 weeks, unless safety con¬ cerns require abrupt withdrawal. 2.2. Dosing Considerations to Mitigate the Risk of Vis¬ ual Adverse Reactions Because POTIGA may cause retinal abnormalities with long-term use, patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. Testing of visual function should bexione at base¬ line and every 6 months during therapy with POTIGA. Pa¬ tients who cannot be monitored should usually not be treated with POTIGA. If retinal pigmentary abnormalities or vision changes are detected, POTIGA should be discon¬ tinued unless no other suitable treatment options are avail¬ able and the benefits of treatment outweigh the potential risk of vision loss /see Warnings and Precautions (5.1)]. 2.3 Dosing in Specific Populations No adjustment in dosage is recommended in patients with mild renal or hepatic impairment (see Table 1). Dosage ad¬ justment is recommended in geriatric and patients with moderate or severe renal or hepatic impairment (see Table 1). [See table 1 above)

FULL PRESCRIBING INFORMATION WARNING: RETINAL ABNORMALITIES AND PO¬ TENTIAL VISION LOSS POTIGA can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. Some patients with retinal abnormalities have been found to have abnormal visual acuity It is not possi¬ ble to determine whether POTIGA caused this de¬ creased visual acuity, as baseline assessments are not available for these patients. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. An earlier onset cannot be ruled out, and it is possible that retinal abnormalities were pres¬ ent earlier in the course of exposure to POTIGA. The rate of progression of retinal abnormalities and their reversibility are unknown. POTIGA should only be used in patients who have re¬ sponded inadequately to several alternative treat¬ ments and for whom the benefits outweigh the po¬ tential risk of vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitor¬ ing by an ophthalmic professional. Testing should in¬ clude visual acuity and dilated fundus photography. Additional testing may include fluorescein angio¬ grams (FA), optical coherence tomography (OCT), pe¬ rimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected. POTIGA should be discontinued unless

INDICATIONS AND USAGE

POTIGA* is indicated as adjunctive treatment of partialonset seizures in patients aged 18 years and older who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal ab¬ normalities and potential decline in visual acuity [see Warn¬ ings and Precautions (5.1)1.

3

j

DOSAGE FORMS AND STRENGTHS

50 mg, purple, round, film-coated tablets “RTG 50" on one side. 200 mg, yellow, oblong, film-coated tablets “RTG-200" on one side. 300 mg. green, oblong, film-coated tablets “RTG-300” on one side. 400 mg, purple, oblong, film-coated tablets ■RTG-400" on one side. 4

CONTRAINDICATIONS

' None.

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debossed with debossed with debossed with debossed with

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1046/GLAXOSMITHKLINE • POTIGA

continuations resulting from these reactions were more common in the drug-treated group (see Table 2). These ef¬ fects were dose-related and generally appeared within the Number (%) Discontinuing Number (%) with Adverse Reaction first 8 weeks of treatment. Half of the patients in the con¬ trolled trials who discontinued POTIGA due to hallucina¬ Placebo POTIGA Placebo POTIGA tions or psychosis required hospitalization. Approximately (n = 427) (n = 813) (n = 427) (n = 8131 Adverse Reaction two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in 4 ( and is not approved Warnings and Precautions (5.1)]. for the treatment of RLS. However, an immediateSyncope and Hypotension/Orthostatic Hypotension release form of ropinirole (REQUIP) is approved for Advise patients that they may experience syncope and may the treatment of moderate to severe primary RLS (see develop hypotension with or without symptoms such as diz¬ other side of this leaflet (. ziness, nausea, syncope, and sometimes sweating while tak¬ ing REQUIP, especially if they are elderly. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any Read this information completely before you start taking time (cases have been seen after weeks of treatment I.PoaREQUIP or REQUIP XL. Read the information each time you get more medicine There may be new information. This tural/ortho6tatic symptoms may be related to sitting up or leaflet provides a summary about REQUIP and REQUIP standing. Accordingly, caution patients against standing XL. It does not include everything there is to know about rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the ini¬ your medicine. This information should not lake the place of tiation of treatment with REQUIP /see Warnings and Pre¬ discussions with your healthcare provider about your med¬ cautions 15.2, 5.3)1. ical condition or treatment with REQUIP or REQLTP XL

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1066/GLAXOSMITHKLINE • REQUIP What is the most important information I should know about REQUIP and REQUIP XL? REQUIP and REQUIP XL can cause serious side effects, in¬ cluding: • Hypersensitivity/allergic reactions. You may experience a

hypersensitivity/allergic reaction characterized by hives, rash, itching, and/or swelling of the face, lips, mouth, tongue, or throat, which may cause problems in swallow¬ ing or breathing. If you experience any of these reactions, you should not take REQUIP or REQUIP XL again until you talk to a healthcare provider and seek their advice. • Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP or REQUIP XL. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking REQUlP or REQUIP XL are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting REQUIP or REQUIP XL, be sure to tell your healthcare provider if you take any medicines that make you drowsy. • Fainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or REQUIP XL or your dose is increased. Tell your healthcare provider if youfaint or feel dizzy or light-headed. • Decrease in blood pressure. REQLTIP and REQUIP XL can decrease your blood pressure. Decreases in your blood pressure (hypotension) can happen, especially when you start taking REQUIP or REQUIP XL or when your dose is changed. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above. • Increase in blood pressure. REQUIP XL may increase your blood pressure. • Changes in heart rate (decrease or increase). REQUIP and REQUIP XL can decrease or increase your heart rate. • Hallucinations

and

other

psychotic-like

behavior.

REQUIP and REQUIP XL can cause or worsen psychoticlike behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believ¬ ing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkin¬ son’s disease who are taking REQUIP or REQUlP XL or taking higher doses of these drugs. If you have hallucina¬ tions or any of these other psychotic-like changes, talk with your healthcare provider. • Uncontrolled sudden movements. REQUIP and REQUIP XL may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson’s medicine may need to be changed. • Unusual urges Some patients taking REQUIP or REQUIP XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrolla¬ ble urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behav¬ iors, talk to your healthcare provider. • Increased chance of skin cancer (melanoma). People with Parkinson’s disease may have a higher chance of getting melanoma. It is not known if REQUIP and REQUIP XL increase your chances of getting melanoma. You and your healthcare provider should check your skin on a regular basis. Tbll your healthcare provider right away if you no¬ tice any changes in your skin such as a change in the size, shape, or color of moles on your skin. What are REQUlP and REQUlP XL?

• REQUIP is a short-acting prescription medicine contain¬ ing ropinirole (usually taken 3 times a day) that is used to treat Parkinson’s disease. It is also used to treat a condi¬ tion called Restless Legs Syndrome (RLS). • REQUIP XL is a long-acting prescription medicine con¬ taining ropinirole (taken 1 time a day) that is used only to treat Parkinson’s disease but not to treat RLS. Having one of these conditions does not mean you have or will develop the other condition. You should not be taking more than 1 medicine containing ropinirole. TYll your healthcare provider if you are taking any other medicine containing ropinirole. It is not known if REQUIP and REQUIP XL are safe and effective for use in children younger than 18 years of age. Who should not take REQUlP or REQUlP XL?

Call your healthcare provider and get help right away if you have any of the following symptoms of an allergic reaction. Symptoms of an allergic reaction may include: • hives • rash • swelling of the face, lips, mouth, tongue, or throat • itching What should I tell my healthcare provider before taking REQUlP or REQUlP XL? Before you take REQUlP or REQUlP XL, tell your healthcare provider if you:

• have daytime sleepiness from a sleep disorder or have un¬ expected or unpredictable sleepiness or periods of sleep. • are taking any other prescription or over-the-counter medicines. Some of these medicines may increase your chances of getting side effects while taking REQUIP or REQUIP XL. • start or stop taking other medicines while you are taking REQUIP or REQUIP XL. This may increase your chances of getting side effects. • start or stop smoking while you are taking REQUIP or REQUIP XL. Smoking may decrease the treatment effect of REQUIP or REQUIP XL. • feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down. • drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP or REQUIP XL. • have high or low blood pressure. • have or have had heart problems. • are pregnant or plan to become pregnant. REQUIP and REQUIP XL should only be used during pregnancy if needed. • are breastfeeding. It is not known if REQUIP or REQUIP XL passes into your breast milk. Talk to your healthcare * provider to decide whether you will breastfeed or take REQUIP or REQUIP XL. • have any other medical conditions. How should 1 take REQUlP or REQUlP XL for Parkinson's disease?

• Take REQUIP or REQUIP XLexactly as directed by your healthcare provider. • Do not suddenly stop taking REQUIP or REQUIP XL without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness. • Before starting REQUIP or REQUIP XL, you should talk to your healthcare provider about what to do if you miss a dose. If you have missed the previous dose and it is time for your next dose, do not double the dose. • Your healthcare provider will start you on a low dose of REQUIP or REQUIP XL. Your healthcare provider will change the dose until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach a dose that controls your symp¬ toms. If you are taking REQUlP:

• REQUIP Tablets are usually taken 3 times a day for Par¬ kinson’s disease. If you are taking REQUlP XL:

• Take REQUIP XLExtended-Release Tablets 1 time each day for Parkinson’s disease, preferably at or around the same time of day. • Swallow REQUIP XL Extended-Release Tablets whole. Do not chew, crush, or split REQUIP XL Extended-Release Tablets. • REQUIP XL Extended-Release Tablets release drug over a 24-hour period. If you have a condition where medicine passes through your body too quickly, such as diarrhea, the tablet(s) may not dissolve completely and you may see tablet residue in your stool. If this happens, let your healthcare provider know as soon as possible.

• are allergic to ropinirole or any of the ingredients in REQUIP or REQUIP XL. See the end of this page for a complete list of the ingredients in REQUIP and RE QUIP XL

How should I store REQUlP and REQUlP XL?

• Store REQUIP or REQUIP XL at room temperature be¬ tween 68°F to 77°F (20°C to 25°C). • Keep REQUIP or REQUIP XL in a tightly closed container and out of direct sunlight. Keep REQUlP or REQUlP XL and all medicines out of the reach of children. General information about the safe and effective use of REQUlP and REQUlP XL.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take REQUIP or REQUIP XL for a condition for which it was not prescribed. Do not give REQUIP or REQUIP XL to other people, even if they have the same symptoms you have. It may harm them. This side of the patient information leaflet summarizes the most important information about REQUIP and REQUlP XL for Parkinson's disease. If you would like more informa¬ tion, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for informa¬ tion about REQUIP and REQUIP XL that is written for healthcare professionals. For more information go to www.gsk.com or call 1-888-825-5249 (toll-free). What are the ingredients in REQUlP and REQUlP XL? The following ingredients are in REQUlP:

ropinirole (as ropinirole hydrochloride i croscarmellose sodium, hydrous lac¬ tose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 alu¬ minum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, tita¬ nium dioxide. Active ingredient:

Inactive ingredients;

The following ingredients are in REQUlP XL:

ropinirole (as ropinirole hydrochloride) carboxymethylcellulose sodium, col¬ loidal silicon dioxide, glycerol behenate, hydrogenated cas¬ tor oil, hvpromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake. FD&C Blue No.2 aluminum lake, ferric oxides (black, red. yellow), polyethylene glycol 400, titanium dioxide. Patient Information Active ingredient:

Inactive ingredients:

REQUlP® (RE-qwip) (ropinirole) Tablets If you have Restless Legs Syndrome (RLS), read this side. If you have Parkinson's disease, read the other side.

Important Note: REQUlP XL* has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS.

If you are taking either REQUlP or REQUlP XL:

• Contact your healthcare provider if you stop taking REQUIP or REQUIP XL for any reason. Do not restart without talking with your healthcare provider. • Your healthcare provider mav prescribe REQUIP or REQUIP XL alone, or add REQUIP or REQUIP XL to medicine that you are already taking for Parkinson’s dis¬ ease. • You should not substitute REQUIP for REQUIP XL, or REQUIP XL for REQUIP without talking with your healthcare provider. • You can take REQUIP or REQUIP XL with or without food.

Read this information completely before you start taking

XL?

REQUlP. Read the information each time you get more med¬ icine. There may be new information. This leaflet provides a summary about REQUlP. It does not include everything there is to know about your medicine. This information should not take the place of discussions with your health¬ care provider about your medical condition or treatment with REQUIP. People with RLS should take REQUIP differently than peo¬ ple with Parkinson's disease (see "How should I take REQUlP for RLS?" for the recommended dosing for RLS A lower dose is generally needed for people with RLS, and is taken once daily before bedtime.

REQUlP and REQUlP XL can cause serious side effects, in¬

What is the most important information I should know

cluding: • See 'What is the most important information I should

about REQUlP?

What are the possible side effects of REQUlP and REQUlP

know about REQUlP and REQUlP XL?'

Do not take REQUlP or REQUlP XL H you:

• hallucinations (seeing or hearing things that are not real1 • dizziness • nausea or vomiting • uncontrolled sudden movements • leg swelling • fatigue, tiredness, or weakness • confusion • headache • upset stomach, abdominal pain or discomfort • increased sweating Ttell your healthcare provider if you have any side effect that bothers you or does not go away. This is not a complete list of side effects and should not take the place of talking with your healthcare provider. Your healthcare provider or pharmacist can give you a more com¬ plete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 -800-FDA-1088. *

The most common side effects of REQUIP and REQUIP XL include: • fainting • sleepiness or drowsiness

REQUlP can cause serious side effects, including: • Hypersensitivity/allergic reactions. You may experience a

hypersensitivity/allergic reaction characterized by hives, rash, itching, and/or swelling of the face, lips, mouth, tongue, or throat, which may cause problems in swallow¬ ing or breathing. If you experience any of these reactions

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR after starting REQUIP, you should not take REQUIP again until you talk to a healthcare provider and seek their advice. • Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP. You may suddenly fall asleep without be¬ ing drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing nor¬ mal activities while taking REQUIP are greater if you take other medicines that cause drowsiness.Tell your healthcare provider right away if this happens. Before starting REQUIP, be sure to tell your healthcare provider if you take any medicines that make you drowsy. • Fainting. Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or your dose is increased. Tfell your healthcare provider if you faint or feel dizzy or light¬ headed. • Decrease in blood pressure. REQUIP can decrease your blood pressure (hypotensionI, especially when you start taking REQUIP or when your dose is changed. If you feel faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it careftilly and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above. • Changes in heart rate (decrease or increase). REQUIP can decrease or increase your heart rate. • Unusual urges. Some patients taking REQUIP get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and be¬ haviors, or an uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you-are developing any unusual behaviors, talk to your healthcare provider. • Increased chance of skin cancer (melanoma). It is not known if REQUIP increases your chance of getting mela¬ noma. You and your healthcare provider should check your skin on a regular basis. 1V11 your healthcare provider right away if you notice any changes in your skin such as a change in the size, shape, or color of moles on your skin. • Changes in Restless Legs Syndrome symptoms. REQUIP may cause Restless Legs symptoms to come back in the morning (rebound I, happen earlier in the evening, or even happen in the afternoon. What is REQUIP?

REQUIP is a prescription medicine containing ropinirole used to treat moderate-to-severe primary Restless Legs Syndrome (RLS>. It is also used to treat Parkinson's dis¬ ease. Having one of these conditions does not mean you have or will develop the other condition. You should not be taking more than 1 medicine containing ropinirole. Tfell your healthcare provider if you are taking any other medicine containing ropinirole. It is not known if REQUIP is safe and effective for use in children younger than 18 years of age. Who should not take REQUIP? Do not take REQUIP if you:

• are allergic to ropinirole or any of the ingredients in REQU1P. See the end of this leaflet for a complete list of the ingredients in REQUIP. Call your healthcare provider and get help right away if you have any of the following symptoms of an allergic reaction. Symptoms of an allergic reaction may include: • hives • rash • swelling of the face, lips, mouth, tongue, or throat • itching What should I tell my healthcare provider before taking REQUIP? Before you take REQUIP, tell your healthcare provider if you:

• have daytime sleepiness from a sleep disorder or have un¬ expected or unpredictable sleepiness or periods of sleep. • are taking any other prescription or over-the-counter medicines. Some of these medicines may increase your chances of getting side effects while taking REQUIP. • start or stop taking other medicines while you are taking REQUIP This may increase your chances of getting side effects. • start or stop smoking while you are taking REQUIP. Smoking may decrease the treatment effect of REQUIP. • feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down. • dnnk alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP. • have high or low blood pressure • have or have had heart problems. • are pregnant or plan to become pregnant. REQUIP should only be used during pregnancy if needed.

REQUIP XL • GLAXOSMITHKLINE/1067 • are breastfeeding. It is not knoun if REQUIP passes into your breast milk. Talk to your healthcare provider to de¬ cide whether you will breastfeed or take REQUIP. • have any other medical conditions.

-INDICATIONS AND USAGE-

How should I take REQUIP for RLS?

-DOSAGE AND ADMINISTRATION-

• Take REQUIP exactly as directed by your healthcare pro¬ vider. • The usual way to take REQUIP is once in the evening, 1 to 3 hours before bedtime. • Your healthcare provider will start you on a low dose of REQUIP. Your healthcare provider may change the dose until you are taking the right amount of medicine to con¬ trol your symptoms. • If you miss your dose, do not double your next dose. Take only your usual dose 1 to 3 hours before your next bed¬ time. • Contact your healthcare provider if you stop taking REQUIP for any reason. Do not restart without consulting your healthcare provider. • You can take REQUIP with or without food. What are the possible side effects of REQUIP? REQUIP can cause serious side effects, including: • See "What is the most important information I should know about REQUIP?"

The most common side effects of REQUIP include: • nausea or vomiting • drowsiness or sleepiness • dizziness • fatigue, tiredness, or weakness Tell your healthcare provider if you have any side effect that bothers you or does not go away. This is not a complete list of side effects and should not take the place of talking with your healthcare provider. Your healthcare provider or pharmacist can give you a more com¬ plete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REQUIP?

• Store REQUTP at room temix-raturo between 68F to 77F (20C to 250. • Keep REQUIP in a tightly closed container and out of di¬ rect sunlight. Keep REQUIP and all medicines out of the reach of children. General information about the safe and effective use of REQUIP.

Medicines are sometimes proscribed for purposes other than those listed in a Patient Information leaflet. Do not take REQUIP for a condition for which it was not prescribed. Do not give REQUIP to other people, even if they have the same symptoms you have. It may harm them. This side of the patient information leaflet summarizes the most important information about REQUIP for Restless Legs Syndrome (RLS). If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about REQUIP that is written for healthcare professionals. For more information go to www.gsk.com or call 1-888-8255249 (toll-free). What are the ingredients in REQUIP? Active ingredient: ropinirole (as ropinirole hydrochloride) Inactive ingredients: croscarmellose sodium, hydrous lac¬

tose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine. FD&C Blue No. 2 alu¬ minum lake, FD&C Yellow No. tt aluminum lake, hypramellose, iron oxides, polyethylene glycol, polysorbate 80, tita¬ nium dioxide. This Patient Information has been approved by the U.S. Food and Drug Administration. REQUIP and REQUIP XL are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park. NC 27709 02014, the GSK group of companies. All rights reserved. August 2014 REP:3PIL

REQUIP XL is a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (LI)

• REQUIP XL tablets are taken once daily, with or without food; tablets must be swallowed whole and must not be chewed, crushed, or divided (2.1) • The recommended starting dose is 2 mg taken once daily for 1 to 2 weeks; the dose should be increased by 2 mg/day at 1 week or longer intervals; the maximum dose is 24 mg/day (2.2, 14.2) • Renal Impairment: In patients with end-stage renal dis¬ ease on hemodialysis, the maximum recommended dose is 18 mg/day (2.2) • If REQUIP XL must be discontinued, it should be tapered gradually over a 7-day period; retitration of REQUIP XL may be warranted if therapy is interrupted (2.1, 2.2) • Patients may be switched directly from immediate-relea.-e ropinirole to REQUIP XL; the initial switching dose of REQUIP XL should most closely match the total daily dose of immediate-release ropinirole (2.3) -DOSAGE FORMS AND STRENGTHSTablets:

2 mg, 4 mg, 6 mg, 8 mg, and 12 mg (3)

-CONTRAINDICATIONSHistory of hypersensitivity/allergic reaction (including urti¬ caria, angioedema, rash, pruritus) to ropinirole or to any of the excipients (4) -WARNINGS AND PRECAUTIONS• Sudden onset of sleep and somnolence may occur (5.11 • Syncope may occur (5.2) • Hypotension, including orthostatic hypotension raav occur (6.3) • Elevation of blood pressure and changes in heart rate may occur (5.4) • Mav cause hallucinations and psychotic-like behaviors (5.5) • May cause or exacerbate dyskinesia (5.6) • May cause problems with impulse control or compulsive behaviors (5.7) -ADVERSE REACTIONS• Most common adverse reactions (incidence for REQl'IP XL at least 5% greater than placebo) in advanced Parkin¬ son’s disease with concomitant L-dopa were dyskinesia, nausea, dizziness, and hallucination (6.1) • Most common adverse reactions (incidence for REQUIP XL at least 5';) in early Parkinson’s disease without L-dopa were nausea, somnolence, abdominal pain/discom¬ fort. dizziness, headache, and constipation (6.1 > To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -DRUG INTERACTIONS• Inhibitors or inducers of CYP1A2: May alter the clear¬ ance of ropinirole; dose adjustment may be required (7.1, 12.3) • Hormone replacement therapy (HRTi: Starting or stop¬ ping HRT treatment mav require dose adjustment of REQUIP XL (7.2, 12.3) • Dopamine antagonists o g, neuroleptic* no to, I.>pr,imide): May reduce efficacy of REQUIP XL. (7.3) -USE IN SPECIFIC POPULATIONSPregnancv: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2014 FULL PRESCRIBING INFORMATION CONTENTS"

REQUIP XL

I{

|r£' kwip]

1 2

(ropinirole extended-release tablets) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use REQUIP XL safely and effectively See full prescrib¬ ing information for REQUIP XL. REQUIP XL (ropinirole) extended-release tablets for oral use

3 4 5

Initial U.S. Approval: 1997

-RECENT MAJOR CHANGESDosage and Administration 15 beats/minute). The increased incidence for various elevations of systolic and/or diastolic blood pressure and/or changes in pulse was observed in both the titration and maintenance phases as well as persisting into the maintenance period after devel¬ oping in the titration phase. Elevation of blood pressure and/or changes in heart rate in patients taking REQUIP XL should be considered when treating patients with cardiovascular disease. 5.5 Hallucinations/Psychotic-like Behavior In the double-blind, placebo-controlled, advanced Parkin¬ son’s disease trial, 8% (17 of 202) of patients receiving REQUIP XL reported hallucination compared with 2% (4 of 191) patients receiving placebo [see Adverse Reactions (6.1)1. Hallucinations led to discontinuation of treatment in 2% (4 of 202) of patients on REQUIP XL and 1% (2 of 191) of pa¬ tients on placebo. The incidence of hallucination is increased in elderly pa¬ tients (i.e., older than 65 years) treated with REQUIP XL /see Use in Specific Populations (8.5)1. Postmarketing reports indicate that patients may experi¬ ence new or worsening mental status and behavioral changes, which may be severe, including psychotic-like be¬ havior during treatment with ropinirole or after starting or increasing the dose of ropinirole. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have sim¬ ilar effects on thinking and behavior. This abnormal think¬ ing and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hal¬ lucinations, confusion, psychotic-like behavior, disorienta¬ tion, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL because of the risk of exac¬ erbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of REQUIP XL tsee Drug Interactions (7.3)]. 5.6 Dyskinesia REQUIP XL may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesiain patients treated with L-dopa for Parkinson’s dis¬ ease. In the double-blind, placebo-controlled trial in pa¬ tients with advanced Parkinson’s disease dyskinesia was reported as an adverse event in 13% of patients taking REQUIP XL and 3% of patients on place bo/see Adverse Re¬ actions (6.1)1. Decreasing the dose of the dopaminergic drug may ameliorate this adverse reaction. 5.7 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other in¬ tense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP XL, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the devel¬ opment of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP XL. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL. 5.8 Withdrawal-emergent Hyperpyrexia and Confusion A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscu¬ lar rigidity, altered consciousness, and autonomic instabil¬ ity), with no other obvious etiology, has been reported in as¬ sociation with rapid dose reduction, withdrawal of. or changes in dopaminergic therapy. Therefore, it is recom¬ mended that the dose be tapered at the end of treatment with REQUIP XL as a prophylactic measure /see Dosage and Administration (2.2)1. 5.9 Melanoma Epidemiological studies have shown that patients with Par¬ kinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. In the clinical devel¬ opment program 2% of Patients Treated with REQUIP XL and >% with Placebo!* REQUIP XI. (n = 202) %

Placebo (n = 191) %

Ear and labyrinth disorders Vertigo

4

2

Gastrointestinal disorders Nausea Constipation Abdominal pain/discomfort Diarrhea Dry mouth

11 4 6 3 2

4 2 3 2 . Ti tration rate of REQUIP IR was slower than that of the REQUIP XL. Patients were titrated, during the 12-week ti¬ tration period, to their optimal dosage, based upon toler¬ ance and therapeutic response. This was followed by three consecutive 8-week maintenance periods, during which pa¬ tients were either maintained on the prior formulation or switched to the alternative formulation. All switches were performed overnight by using the approximately equivalent doses of ropinirole. The primary efficacy endpoint was the change of UPDRS motor score within each maintenance pe¬ riod. Patients in all four groups started out with similar UPDRS motor scores (about 21) at baseline. All groups exhibited similar improvement in UPDRS total motor scores from baseline until the completion of the titration phase, with a change in score of about -9 observed for the groups started on REQUIP IR and of about -10 for the groups started on REQUIP XL. No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeu¬ tic dosage equivalence between formulations of REQUIP IR and REQUIP XL The optimal daily dose at the end of the titration period for patients on REQUIP IR was substantially lower imean 7 mg) compared with the dose at the end of the titration pe¬ riod for patients on REQUIP XL (mean 18 mg). In this trial, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared with the lower doses /see Dosage and Administra¬

tion 12.2)]. 16

HOW SUPPLIED/STORAGE AND HANDLING

treatment group. The mean baseline dose of L-dopa in the

Each biconvex, capsule-shaped, film-coated tablet contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows: • 2 mg: pink tablets debossed with “GS" and “3V2", in bottles of 30 (NDC 0007-4885-13) and 90 (NDC 00074885-59).

have not been studied in patients with hepatic impairment.

group

•

Because ropinirole is extensively metabolized by the liver,

776 mg/day for the placebo group. Patients initiated treat¬

these patients may have higher plasma levels and lower

ment at 2 mg/day for 1 week followed by increases of 2 mg/ day at weekly intervals to a minimum dose of 6 mg/day. The

Hepatic Impairment:

The pharmacokinetics of ropinirole

clearance of ropinirole than patients with normal hepatic function.

had experienced a minimum of 3 hours awake time “ofl" time “off", and had a mean baseline UPDRS motor score of

receiving

REQUIP

XL

w as

824 mg/day

and

following week, the total daily dose of REQUIP XL could be

Population pharmacokinetic analysis re-

further increased (based upon therapeutic response and tol¬

veiled no change in the clearance of ropinirole in patients

erability ) to 8 mg/day. Once a daily dose of 8 mg/day was

with concomitant diseases such as hypertension, depres¬ sion, osteoporosis/arthritis, and insomnia compared with patients with Parkinson's disease only.

Thereafter, the daily dose could be increased by up to

Other Diseases:

13

Carcinogenesis, Mutagenesis. Impairment of Fer¬

Two-year carcinogenicity studies of ropinirole were con¬ ducted in mice at oral doses of 5, 15, and 50 mg/kg/dav and in rats at oral doses of 1.5, 15, and 50 mg/kg/day. all

doses

tested.

The

lowest

dose

duction, and/or tolerability. The maximum allowed daily dosage for REQUIP XL was 24 mg/day. The primary efficacy endpoint was mean change from base¬ line in total awake time spent “off" at Week 24. At baseline

In rats, there was an increase in testicular Leydig cell ad¬ at

tolerability). The mean dose of REQUIP XL at the end of Week 24 was 18.8 mg/day. Dose titrations were based upon the degree of symptom control, planned L-dopa dosage re¬

Carcinogenesis

enomas

4 mg/day approximately every 2 weeks until an optimal dose was achieved i based upon therapeutic response and

NONCUNICAL TOXICOLOGY

13.1 tility

reached, the background L-dopa dosage was reduced.

the mean total awake time spent “off" was approximately 7

4 mg: light brow n tablets debossed with “GS" and “WXG“, in bottles of 30 (NDC 0007-4887-13) and 90 (NIX' 00074887-59). • 6 mg: white tablets debossed with “GS" and “11F“ in bottles of 30 (NDC 0007-4883-13). • 8 mg: red tablets debossed with ‘GS’ and “5CC". in bottles of 30 (NDC 0007-4888-13) and 90 (NDC 00074888-59). • 12 mg green tablets debossed with “GS" and “YX7", in bottles of 30 (NDC 00074882-13). Storage Store at 25*C i77*F); excursions permitted to 15-30*C '59-86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient label¬ ing (Patient Information). Dosing Instructions Instruct patients to take REQUIP XL only as prescribed If a dose is missed, advise patients not to double their next dose. REQUIP XL can be taken with or without food. Inform

tested

hours in each treatment group. At Week 24. the total awake

(1.5 mg/kg/day) is less than the MRHD for Parkinson's dis¬ ease (24 mg/dayl on a mg/ro2 basis. The endocrine mecha¬

time spent “off", on average, had decreased by approxi¬ mately 2 hours in the group receiving REQUIP XL and by

nisms believed to be involved in the production of these tu¬ mors in rats are not considered relevant to humans.

approximately half an hour in the placebo group. The ad¬

patients to swallow REQUIP XL tablets whole and not to chew, crush, or divide the tablets I see Dosage and Adminis¬

justed mean difference in total awake time spent “off" be¬

In mice, there was an increase in benign uterine endome¬ trial polyps at a dose of 50 mg/kg/day. The highest dose not

tration 12.1)].

tween REQUIP XL and placebo was -1.7 hours, which was

Ropinirole is the active ingredient in both REQUIP XL and

associated with this finding (15 mg/kg/day) is three times the MRHD on a mg/m* basis.

this endpoint showing the statistical superiority of REQUIP XL over placebo are presented in Table 3.

statistically significant (ANCOVA. P< 0.00011

Results for

REQUIP tablets (the immediate-release formulation). Ask your patients if they are taking another medication contain¬ ing ropinirole

Free mobile PDR app for fast drug references on Apple or Android devices

1072/GLAXOSMITHKLINE • REQUIP XL

Help patients save on Rx drugs: PDR.net/PharmacyDiscountCard

Hypersensitivity/Allergic Reactions Advise patients about the potential for developing a hyper¬ sensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions after starting REQUIP or REQUIP XL, to immediately contact their healthcare pro¬ fessional IseeContraindications (4)1. Falling Asleep during Activities of Daily Living and Somno¬ lence Alert patients to the potential sedating effects caused by REQUIP XL, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Be¬ cause somnolence is a frequent adverse reaction with poten¬ tially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with REQUIP XL to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in poten¬ tially dangerous activities until they have contacted their physician. Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other cen¬ tral nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with REQUIP XL or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and Precautions (5.1)]. Syncope and Hypotension/Orthostatic Hypotension Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as diz¬ ziness, nausea, syncope, and sometimes sweating while tak¬ ing REQUIP XL, especially if they are elderly. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Pos¬ tural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the ini¬ tiation of treatment with REQUIP XL [see Warnings and Precautions (5.2, 5.3)]. Elevation of Blood Pressure and Changes in Heart Rate Alert patients to the possibility of increases in blood pres¬ sure during treatment with REQUIP XL. Exacerbation of hypertension may occur. Medication dose adjustment may be necessary if elevation of blood pressure is sustained over multiple evaluations. Alert patients with cardiovascular disease, who may not tolerate marked changes in heart rate, to the possibility that they may experience significant increases or decreases in heart rate during treatment with REQUIP XL [see Warnings and Precautions (5.4)1. Hallucinations/Psychotic-like Behavior Inform patients that they may experience hallucinations (unreal visions, sounds, or Bensations) and other psychoticlike behavior can occur while taking REQUIP XL. The el¬ derly are at greater risk than younger patients with Parkin¬ son's disease. This risk is greater in patients who are taking REQUIP XL with L-dopa or taking higher doses of REQUIP XL, and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell pa¬ tients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.5)1. Dyskinesia Inform patients that REQUIP XL may cause and/or exacer¬ bate pre-existing dyskinesias /see Warnings and Precau¬ tions (5.6)1. Impulse Control/Compulsive Behaviors Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications linchiding REQUIP XL) that increase central dopaminergic tone, that are generally used for the treat¬ ment of Parkinson's disease. Advise patients to inform their physician or healthcare provider if they develop new or in¬ creased gambling urges, sexual urges, uncontrolled spend¬ ing, binge or compulsive eating, or other urges while being treated with REQUIP XL. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL/see Warnings and Pre cautions (5.7)/. Withdrawal-emergent Hyperpyrexia and Confusion Advise patients to contact their healthcare provider if they wish to discontinue REQUIP XL or decrease the dose of REQUIP XL/sec Warnings and Precautions (5.8)1. Melanoma Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to have

their skin examined on a regular basis by a qualified health¬ care provider (e.g., dermatologist) when using REQUIP XL [see Warnings and Precautions (5.9)1. Nursing Mothers Because of the possibility that ropinirole may be excreted in breast milk, a decision should be made whether to discon¬ tinue nursing or to discontinue the drug, taking into ac¬ count the importance of the drug to the mother [see Use in Specific Populations (8.3)1. Advise patients that REQUIP XL could inhibit lactation because ropinirole inhibits prolac¬ tin secretion. Pregnancy Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy /sec Use in Specific Populations (8.1)]. REQUIP and REQUIP XL are registered trademarks of the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC27709 ©2014, the GSK group of companies. All rights reserved. RXL:6PI ■ PHARMACIST—DETACH HERE AND GIVE INSTRUC¬ TIONS TO PATIENT

• Changes in heart rate (decrease or increase). REQUIP and REQUIP XL can decrease or increase your heart rate.

• Hallucinations

and

other

psychotic-like

behavior.

REQUIP and REQUIP XL can cause or worsen psychoticlike behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believ¬ ing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkin¬ son’s disease who are taking REQUIP or REQUIP XL or taking higher doses of these drugs. If you have hallucina¬ tions or any of these other psychotic-like changes, talk with your healthcare provider. • Uncontrolled sudden movements. REQUIP and REQUIP XL may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson’s medicine may need to be changed. • Unusual urges. Some patients taking REQUIP or REQUIP XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrolla¬ ble urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behav¬ iors, talk to your healthcare provider. • Increased chance of skin cancer (melanoma). People with

Patient Information REQUIP® (RE-qwip) (ropinirole) Tablets REQUIP XL® (RE-qwip) (ropinirole) Extended-release Tablets If you have Parkinson's disease, read this side. If you have Restless Legs Syndrome (RLS), read the other side. Important Note: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not ap¬ proved for the treatment of RLS. However, an immediate-release form of ropinirole (REQUIP) is approved for the treatment of moderate to severe primary RLS (see other side of this leaflet).

Parkinson’s disease may have a higher chance of getting melanoma. It is not known if REQUIP and REQUIP XL increase your chances of getting melanoma. You and your healthcare provider should check your skin on a regular basis. Tell your healthcare provider right away if you no¬ tice any changes in your skin such as a change in the size, shape, or color of moles on your skin.

What are REQUIP and REQUIP XL? • REQUIP is a short-acting prescription medicine contain¬ ing ropinirole (usually taken 3 times a day) that is used to treat Parkinson’s disease. It is also used to treat a condi¬ tion called Restless Legs Syndrome (RLS). • REQUIP XL is a long-acting prescription medicine con¬ taining ropinirole (taken 1 time a day) that is used only to treat Parkinson’s disease but not to treat RLS. Having one of these conditions does not mean you have or will develop the other condition. You should not be taking more than 1 medicine containing

Read this information completely before you start taking ropinirole. Tell your healthcare provider if you are taking REQUIP or REQUIP XL. Read the information each time you any other medicine containing ropinirole. get more medicine. There may be new information. This It is not known if REQUIP and REQUIP XL are safe and leaflet provides a summary about REQUIP and REQUIP effective for use in children younger than 18 years of age. XL. It does not include everything there is to know about Who should not take REQUIP or REQUIP XL? your medicine. This information should not take the place of Do not take REQUIP or REQUIP XL if you: discussions with your healthcare provider about your med¬ • are allergic to ropinirole or any of the ingredients in ical condition or treatment with REQUIP or REQUIP XL. REQUIP or REQUIP XL. See the end of this page for a What is the most important information I should know complete list of the ingredients in REQUIP and REQUIP about REQUIP and REQUIP XL? XL. REQUIP and REQUIP XL can cause serious side effects in¬ Call your healthcare provider and get help right away if you cluding: have any of the following symptoms of an allergic reaction. • Hypersensitivity/allergic reactions. You may experience a Symptoms of an allergic reaction may include: hypersensitivity/allergic reaction characterized by hives, • hives rash, itching, and/or swelling of the face, lips, mouth, • rash tongue, or throat, which may cause problems in swallow¬ • swelling of the face, lips, mouth, tongue, or throat ing or breathing. If you experience any of these reactions, • itching you should not take REQUIP or REQUIP XL again until you talk to a healthcare provider and seek their advice. What should I tell my healthcare provider before taking • Falling asleep during normal activities. You may fall REQUIP or REQUIP XL? asleep while doing normal activities such as driving a car, Before you take REQUIP or REQUIP XL, tell your healthcare doing physical tasks, or using hazardous machinery while provider if you: taking REQUIP or REQUIP XL. You may suddenly fall • have daytime sleepiness from a sleep disorder or have un¬ asleep without being drowsy or without warning. This expected or unpredictable sleepiness or periods of sleep. may result in having accidents. Your chances of falling • are taking any other prescription or over-the-counter asleep while doing normal activities while taking REQUIP medicines. Some of these medicines may increase your or REQUIP XL are greater if you take other medicines chances of getting side effects while taking REQUIP or that cause drowsiness. Tell your healthcare provider right REQUIP XL. away if this happens. Before starting REQUIP or REQUIP • start or stop taking other medicines while you are taking XL, be sure to tell your healthcare provider if you take any REQUIP or REQUIP XL. This may increase your chances medicines that make you drowsy. of getting side effects. • Fainting. Fainting can happen, and sometimes your heart • start or stop smoking while you are taking REQUTP or rate may be decreased. This can happen especially when REQUIP XL. Smoking mav decrease the treatment effect you start Liking REQUIP or REQUIP XL or your dose is of REQUIP or REQUIP XL. increased. Tell your healthcare provider if you faint or feel • feel dizzy, nauseated, sweaty, or faint when you stand up dizzy or light-headed. from sitting or lying down. • Decrease in blood pressure. REQUIP and REQUIP XL • drink alcoholic beverages. This may increase your chances can decrease your bluod pressure. Decreases in your bUxxi of becoming drowsy or sleepy while taking REQUIP or pressure l hypotension i can happen, especially when you REQUIP XL. start taking REQUIP or REQUIP XL or when your dose is • have high or low blood pressure. changed. If you faint or feel dizzy, nauseated, or sweaty • have or have had heart problems. when you stand up from sitting or lying down (orthostatic • are pregnant or plan to become pregnant. REQUIP and hypotension), this may mean that your blood pressure is J REQUIP XL should only be used during pregnancy if decreased. When you change position from lying down or needed. sitting to standing up, you should do it carefully and • are breastfeeding. It is not known if REQUIP or REQUIP slowly. Call your healthcare provider if you have any of the XL passes into your breast milk. Talk to your healthcare symptoms of decreased blood pressure listed above. provider to decide whether you will breastfeed or take • Increase in blood pressure. REQUIP XL may increase REQUIP or REQUIP XL your blood pressure. • have any other medical conditions.

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Look for PDR drug information and services in your EHR REQUIP XL • GLAXOSMITHKLINE/1073 How should I take REQUIP or REQUIP XL for Parkinson s disease? • Take REQl. IP or REQUIP XL exactly as directed by vour healthcare provider. • Do not suddenly stop taking REQUIP or REQUIP XL without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness. • Before starting REQUIP or REQUIP XL, you should talk to your healthcare provider about what to do if you miss a dose. If you have missed the previous dose and it is time for your next dose, do not double the dose • Your healthcare provider will start you on a low dose of REQL IP or REQUIP XL. Your healthcare provider will change the dose until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach a dose that controls your symp¬ toms. If you are taking REQUIP: • REQUIP Tablets are usually taken 3 times a day for Par¬ kinson’s disease. If you are taking REQUIP XL: • Take REQUIP XL Extended-Release Tablets 1 time each day for Parkinson’s disease, preferably at or around the same time of day. • Swallow REQUIP XL Extended-Release Tablets whole. Do not chew, crush, or split REQUIP XL Extended-Release

Tablets. • REQUIP XL Extended-Release Tablets release drug over a 24-hour period. If you have a condition where medicine passes through your body too quickly, such as diarrhea, the tablet(s) may not dissolve completely and you may see tablet residue in your stool. If this happens, let your healthcare provider know as soon as possible. If you are taking either REQUIP or REQUIP XL: • Contact your healthcare provider if you stop taking REQUIP or REQUIP XL for any reason. Do not restart without talking with your healthcare provider. • Your healthcare provider may prescribe REQUIP or REQUIP XL alone, or add REQUIP or REQUIP XL to medicine that you are already taking for Parkinson’s dis¬ ease. • You should not substitute REQUIP for REQUIP XL or REQUIP XL for REQUIP without talking with your healthcare provider. • You can take REQUIP or REQUIP XL with or without food. What are the possible side effects of REQUIP and REQUIP XL? REQUIP and REQUIP XL can cause serious side effects in¬ cluding: • See "What is the most important information I should know about REQUIP and REQUIP XL?" The most common side effects of REQUIP and REQUIP XL include:

• fainting • sleepiness or drowsiness • hallucinations (seeing or hearing things that are not real) • dizziness • nausea or vomiting

• uncontrolled sudden movements

can ask your healthcare provider or pharmacist for informa¬ tion about REQUIP and REQUIP XL that is written for healthcare professionals. For more information go to www.gsk.com or call 1-888-825-5249 (toll-free).

What are the ingredients in REQUIP and REQUIP XL? The following ingredients are in REQUIP: Active ingredient: ropinirole (as ropinirole hydrochloride) Inactive ingredients: croscarmellose sodium, hydrous lac¬ tose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 alu¬ minum lake, FD&C Yellow' No. 6 aluminum lake, hvpromellose, iron oxides, polyethylene glycol, polysorbate 80. tita¬ nium dioxide.

The following ingredients are in REQUIP XL: Active ingredient: ropinirole (as ropinirole hydrochloride I Inactive ingredients: carboxymethvlcellulose sodium, colloi¬ dal silicon dioxide, glycerol behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stea¬ rate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No, 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

Patient Information REQUIP®(RE-qwip) (ropinirole) Tablets If you have Restless Legs Syndrome (RLS), read this side. If you have Parkinson's disease, read the other side. Important Note: REQUIP XL® has not been studied in Restless Legs Syndrome (RLS) and is not ap¬ proved for the treatment of RLS.

This is not a complete list of side effects and should not take the place of talking with your healthcare provider. Your healthcare provider or pharmacist can give you a more com¬ plete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to EDA at 1-800-FDA-1088. How should I store REQUIP and REQUIP XL? • Store REQUIP or REQUIP XL at room temperature be¬ tween 68°F to 77°F (20'C to 25°C).

• Keep REQl IP or REQUIP XL in a tightly closed container and out of direct sunlight. Keep REQUIP or REQUIP XL and all medicines out of the reach of children. General information about the safe and effective use of REQUIP and REQUIP XL: Medicines are sometimes prescribed for purposes other than

should not take the place of discussions with your health¬ care provider about your medical condition or treatment with REQUIP. People with RLS should take REQUIP differently than peo¬ ple with Parkinson’s disease (see “How should I take

REQUIP for RLS?" for the recommended dosing for RLS). A

What is the most important information I should know about REQUIP? REQUIP can cause serious side effects including: • Hypersensitivity/allergic reactions. You may experience a hypersensitivity/allergic reaction characterized by hives, rash, itching, and/or swelling of the face, lips, mouth, tongue, or throat, which may cause problems in swallowing or breathing. If you experience any of these reactions after starting REQUIP, you should not take REQUIP again until you talk to a healthcare provider and seek their advice.

• Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while

healthcare provider right away if this happens. Before starting REQUIP, l>e sure to tell your healthcare provider if you take any medicines that make you drowsy.

• Fainting. Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or your dose is increased. Tell your healthcare provider if you faint or feel dizzy or light¬ headed.

• Decrease in blood pressure. REQUIP can decrease your blood pressure (hypotension), especially when you start taking REQUTP or when your dose is changed. If you feel faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that vour blood pressure is decreased. i

your healthcare provider if you have any of the symptoms of decreased blood pressure listed above. decrease or increase vour heart rate. to behave in a way unusual for them. Examples of this are

people, even if they have the same symptoms you have. It may harm them.

haviors, or an uncontrollable urge to shop, spend money,

an unusual urge to gamble, increased sexual urges and be¬ or eat. If you notice or your family notices that you are

This side of the patient information leaflet summarizes the most important information about REQUIP and REQUIP

developing any unusual behaviors, talk to your healthcare provider.

XL for Parkinson s disease. If you would like more informa¬

• Increased chance of skin cancer (melanoma) It is not known if REQUIP increases your chance of getting mela-

• drowsiness or sleepiness • dizziness • fatigue, tiredness, or weakness

• Changes in heart rate (decrease or increase). REQUIP can

REQUIP or REQl IP XL for a condition for which it was not prescribed. Do not give REQUIP or REQUIP XL to other

tion, talk with your healthcare provider or pharmacist. You

• nausea or vomiting

When vou change position from lying down or sitting to standing up, you should do it carefully and slowly. Call

• Unusual urges. Some patients taking REQUIP get urges

Call your healthcare provider and get help right away H you have any of the following symptoms of an allergic reaction Symptoms of an allergic reaction may include: • hives • rash

• start or stop smoking while you are taking REQUIP. Smoking may decrease the treatment effect of REQUIP. • feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down. • drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP. • have high or low blood pressure, • have or have had heart problems. • are pregnant or plan to become pregnant. REQUIP should only be used during pregnancy if needed. • arr breastfeeding It is not known if REQl TP pMMd Ml your breast milk. Talk to your healthcare provider to de¬ cide whether you w ill breastfeed or take REQUIP. • have any other medical conditions. How should I take REQUIP for RLS? • Take REQUIP exactly as directed by your healthcare pro¬ vider. • The usual way to take REQUIP is once in the evening. 1 to 3 hours before bedtime. • Your healthcare provider will start you on a low dose of REQUIP. Your healthcare provider may change the dose until you are taking the right amount of medicine to con¬ trol your symptoms. • If you miss your dose, do not double your next dose. Take only your usual dost* 1 to 3 hours before your next bed¬ time. • Contact your healthcare provider if you stop taking REQUIP for any reason. Do not restart without consulting your healthcare provider. • You can take REQUIP with or w ithout food What are the possible side effects of REQUIP7 REQUIP can cause serious side effects including: • See "What is the most important information I should know about REQUIP?" The most common side effects of REQUIP include.

lower dose of REQUIP is generally needed for people with RLS, and is taken once daily before bedtime.

those listed in a Patient Information leaflet. Do not take

Who should not take REQUIP? Do not take REQUIP if you: • are allergic to ropinirole or any of the ingredients in REQUIP. See the end of this leaflet for a complete list of the ingredients in REQUIP.

• have daytime sleepiness from a sleep disorder or have un¬ expected or unpredictable sleepiness or periods of sleep. • are taking any other prescription or over-the-counter medicines. Some of these medicines may increase your chances of getting side effects while taking REQUIP. • start or stop taking other medicines while you are taking REQUIP. This may increase your chances of getting side effects.

summary about REQUIP. It does not include everything there is to know about your medicine. This information

take other medicines that cause drowsiness. Tell your

TW1 your healthcare provider if you have any side effect that bothers you or dot's not go away.

children younger than 18 years of age.

Before you take REQUIP, tell your healthcare provider if you:

icine. There may be new information. This leaflet provides a

ing drowsy or without warning. This may result in having

• upset stomach, abdominal pain or discomfort

You should not be taking more than 1 medicine containing ropinirole. Tfell your healthcare provider if you are taking any other medicine containing ropinirole. It is not known if REQl TP is safe and effective for use in

What should I tell my healthcare provider before taking REQUIP?

Read this information completely before you start taking REQUIP. Read the information each time you get more med¬

accidents. Your chances of falling asleep while doing nor¬ mal activities while taking REQUIP are greater if vou

• increased sweating

REQLTP is a prescription medicine containing ropinirole used to treat moderate-to-severe primary Restless Legs Syndrome. It is also used to treat Parkinson’s disease. Having one of these conditions does not mean you have or will develop the other condition.

• swelling of the face, lips, mouth, tongue, or throat • itching

taking REQUIP. You may suddenly fall asleep without be¬

• leg swelling

• fatigue, tiredness, or weakness • confusion • headache

noma. You and your healthcare provider should check your skin on a regular basis. Tell your healthcare provider right away if you notice any changes In vour skin such as a change in the size, shape, or color of moles on your skm. • Changes in Restless Legs Syndrome symptoms REQUIP may cause Restless Legs symptoms to come back in the morning (rebound), happen earlier in the evening, or even happen in the afternoon. What is REQUIP?

I

Tell your healthcare provider if you have any side effect that bothers you or does not go away. This is not a complete list of side effects and should not take the place of talking with your healthcare provider. Your healthcare provider or pharmacist can give you a more com¬ plete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at I-800-FDA-1088 How shouid I store REQUIP? • Store REQUIP at room temperature between 68*F to 77'F (20°C to 25*0.

Free mobilePDR app for fast drug references on Apple or Android devices

Help patients save on Rx drugs: PDR.net/PharmacvDiscountCard

1074/GLAXOSMITHKLINE • REQUIP XL

• Administration of ROTARIX in infants suffering from acute diarrhea or vomiting should be delayed. Safety and effectiveness of ROTARIX in infants with chronic gastro¬ intestinal disorders have not been evaluated. (5.2) j • Safety and effectiveness of ROTARIX in infants with REQUIP. known primary or secondary immunodeficiencies have not Medicines are sometimes prescribed for purposes other than been established. (5.3) those listed in a Patient Information leaflet. Do not take | • In a postmarketing study, cases of intussusception were REQUIP for a condition for which it wak not prescribed. Do j observed in temporal association within 31 days following the first dose of ROTARIX, with a clustering of cases in the not give REQUIP to other people, even if they have the same symptoms you have. It may harm them. first 7 days. (5.5, 6.2) This side of the patient information leaflet summarizes the | _ADVERSE REACTIONS--most important information about REQUIP for Restless j Common (>5%) solicited adverse events included fussiness/ Legs Syndrome (RLSl. If you would like' more information, talk with your healthcare provider or pharmacist. You can . irritability, cough/runny nose, fever, loss of appetite, and ask your healthcare provider or pharmacist for information ! vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact about REQUIP that is written for healthcare professionals. GlaxoSmithKline at 1-888-825-5249 or VAERS at 1-800-822For more information go to www.gsk.com or call 1-888-8257967 orwww.vaers.hhs.gov. _ 5249 (toll-free). See 17 for PATIENT COUNSELING INFORMATION What are the ingredients in REQUIP? and FDA-approved patient labeling. Active ingredient: ropinirole (as ropinirole hydrochloride) Inactive ingredients: croscarmellose sodium, hydrous lac¬ tose, magnesium stearate, microcrystalline cellulose, and FULL PRESCRIBING INFORMATION: CONTENTS* one or more of the following: carmine, FD&C Blue No. 2 alu¬ 1 INDICATIONS AND USAGE minum lake, FD&C Yellow No. 6 aluminum lake, hypromel2 DOSAGE AND ADMINISTRATION lose, iron oxides, polyethylene glycol, polysorbate 80, tita- j 2.1 Reconstitution Instructions for Oral Adminis¬ nium dioxide. tration 2.2 Recommended Dose and Schedule This Patient Information has been approved by the U.S. 2.3 Infant Feeding Food and Drug Administration. 3 DOSAGE FORMS AND STRENGTHS REQUIP and REQUIP XL are registered trademarks of the 4 CONTRAINDICATIONS GSK group of companies. 4.1 Hypersensitivity GlaxoSmithKline 4.2 Gastrointestinal Tract Congenital Malforma¬ Research Triangle Park, NC 27709 tion ©2014, the GSK group of companies. All rights reserved. 4.3 History of Intussusception August 2014 4.4 Severe Combined Immunodeficiency Disease RXL:4PIL 5 WARNINGS AND PRECAUTIONS

In the event that the infant spits out or regurgitates most of the vaccine dose, a single replacement dose may be consid¬ ered at the same vaccination visit.

. Keep REQUIP in a tightly closed container and out of di¬ rect sunlight. Keep REQUIP and all medicines out of the reach of children. General information about the safe and effective use of

ROTARIX

5

[rot's-rix] (Rotavirus Vaccine, Live, Oral) Oral Suspension

6

5.1

Latex

5.2 5.3

Gastrointestinal Disorders Altered Immunocompetence

5.4

Shedding and Transmission

5.5 5.6

Intussusception Post-Exposure Prophylaxis

-RECENT MAJOR CHANGES-

7

05/2014

vaccination with ROTARIX. 3

Each 1-mL dose contains a suspension of at least 10h 0 me¬ dian Cell Culture Infective Dose (CCIDM) of live, attenu¬ ated human G1P18] rotavirus after reconstitution. 4

Hypersensitivity

A demonstrated history of hypersensitivity to any compo¬ nent of the vaccine. Infants who develop symptoms suggestive of hypersensitiv¬ ity after receiving a dose of ROTARIX should not receive further doses of ROTARIX.

4.2

Gastrointestinal Tract Congenital Malformation

Infants with a history of uncorrected congenital malforma¬ tion of the gastrointestinal tract (such as Meckel’s divertic¬ ulum) that would predispose the infant for intussusception should not receive ROTARIX.

4.3

History of Intussusception

Infants with a history of intussusception should not receive ROTARIX [see Warnings and Precautions (5.5)]. In post¬ marketing experience, intussusception resulting in death following a second dose has been reported following a his- tory of intussusception after the first dose [see Adverse Re¬

actions (6.2)]. 4.4 Severe Combined Immunodeficiency Disease Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive ROTARIX. Postmarketing reports of gastroenteritis, including severe diarrhea and prolonged shedding of vaccine virus, have been reported in infants who were administered live, oral rotavirus vaccines and later identified as having SCID [see Adverse Reactions

(6.2)]. 5 WARNINGS AND PRECAUTIONS

5.1

7.1 7.2

The tip caps of the prefilled oral applicator^ of diluent may

Concomitant Vaccine Administration Immunosuppressive Therapies

USE IN SPECIFIC POPULATIONS

11 12

8.1 Pregnancy 8.4 Pediatric Use DESCRIPTION CLINICAL PHARMACOLOGY

14

CONTRAINDICATIONS

4.1

Clinical Trials Experience Postmarketing Experience

8

13

DOSAGE FORMS AND STRENGTHS

ROTARIX is available as a vial of lyophilized vaccine to be reconstituted with a liquid diluent in a prefilled oral appli-

DRUG INTERACTIONS

12.1 Warnings and Precautions, Intussusception (5.5)

Breast-feeding was permitted in clinical studies. There was no evidence to suggest that breast-feeding reduced the pro¬ tection against rotavirus gastroenteritis afforded by ROTARIX. There are no restrictions on the infant’s liquid consumption, including breast-milk, either before or after

ADVERSE REACTIONS

6.1 6.2

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ROTARIX safely and effectively. See full prescribing information for ROTARIX. ROTARIX (Rotavirus Vaccine, Live, Oral) Oral Suspension Initial U.S. Approval: 2008

2.3 Infant Feeding

Mechanism of Action

12.2 Pharmacodynamics NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES

Latex

contain natural rubber latex which may cause allergic reac¬ tions in latex-sensitive individuals.

5.2

Gastrointestinal Disorders

Administration of ROTARIX should be delayed in infants suffering from acute diarrhea or vomiting. Safety and effectiveness of ROTARIX in infants with chronic gastrointestinal disorders have not been evaluated.

[See Contraindications (4.2).] 5.3 Altered Immunocompetence Safety and effectiveness of ROTARIX in infants with known primary or secondary immunodeficiencies, including infants with human immunodeficiency virus (HIV), infants on im¬

-INDICATIONS AND USAGE-

14.1 14.2

Efficacy Studies Efficacy Through Two Rotavirus Seasons

munosuppressive therapy, or infants with malignant neo¬

ROTARIX is a vaccine indicated for the prevention of

14.3

Efficacy Against Specific Rotavirus Types

not been established.

rotavirus gastroenteritis caused by G1 and non-Gl types

plasms affecting the bone marrow or lymphatic system have

REFERENCES HOW SUPPLIED/STORAGE AND HANDLING

5.4

weeks to 24 weeks of age. (1)

16.1

-DOSAGE AND ADMINISTRATION-

16.2 Storage After Reconstitution PATIENT COUNSELING INFORMATION

peak excretion occurring around day 7 after dose 1. One clinical trial demonstrated that vaccinees transmit

FOR ORAL USE ONLY. (2.1) • Each dose is 1-mL administered orally. (2.2) • Administer first dose to infants beginning at 6 weeks of

* Sections or subsections omitted from the full prescribing

(G3, G4, and G9). ROTARIX is approved for use in infants 6

15 16

17

age. (2.2) • Administer second dose after an interval of at least 4 weeks and prior to 24 weeks of age. (2.2)

Storage Before Reconstitution

information are not listed.

Shedding and Transmission

Rotavirus shedding in stool occurs after vaccination with

vaccine virus to healthy seronegative contacts [see Clinical

Pharmacology (12.2)]. The potential for transmission of vaccine virus following vaccination should be weighed against the possibility of ac¬

FULL PRESCRIBING INFORMATION

quiring and transmitting natural rotavirua Caution is ad¬

1

vised when considering whether to administer ROTARIX to individuals with immunodeficient close contacts, such as in¬

INDICATIONS AND USAGE

-DOSAGE FORMS AND STRENGTHS-

ROTARIX® is indicated for the prevention of rotavirus gas¬

dividuals with malignancies, primary immunodeficiency or

• Vial of lyophilized vaccine to be reconstituted with a liquid

troenteritis caused by Gl and non-Gl types (G3, G4, and G9) when administered as a 2-dose series/sec Clinical Stud¬

receiving immunosuppressive therapy.

diluent in a prefilled oral applicator. (3) • Each 1-mL dose contains a suspension of at least 101’" me¬

ies (14.3)]. ROTARIX is approved for use in infants 6 weeks

Following administration of a previously licensed oral live

to 24 weeks of age.

rhesus rotavirus-based vaccine, an increased risk of intus-

dian Cell Culture Infective Dose (CCID50) of live, attenu¬ ated human G1P|8| rotavirus after reconstitution. (3)

2

DOSAGE AND ADMINISTRATION

-CONTRAINDICATIONS-

2.1 Reconstitution Instructions for Oral Administration For oral use only. Not for injection.

• A demonstrated history of hypersensitivity to the vaccine

Reconstitute only with accompanying diluent. Do not mix

or any component of the vaccine. (4.1, 11) • History of uncorrected congenital malformation of the gas¬

ROTARIX with other vaccines or solutions.

trointestinal tract that would predispose the infant to in¬ tussusception. (4.2) • History of intussusception. (4.3) • History- of Severe Combined Immunodeficiency Disease

-WARNINGS AND PRECAUTIONS• The tip caps of the prefilled oral applicators of diluent may contain natural rubber latex which may cause allergic re¬

Intussusception

susception was observed.1 The risk of intussusception with ROTARIX was evaluated in a pre-licensure randomized, placebo-controlled safety study (including 63,225 infants) conducted in Latin America and Finland. No increased risk of intussusception was observed in this clinical trial follow¬ ing administration of ROTARIX when compared with pla¬ cebo. I See Adverse Reactions (6.1).] In a post marketing, observational study conducted in Mex¬

tered orally. The first dose should be administered to in¬

ico, cases of intussusception were observed in temporal as¬

fants beginning at 6 weeks of age. There should be an inter¬

sociation within 31 days following the first doee of ROTARIX, with a clustering of cases in the first 7 days. [See

val of at least 4 weeks between the first and second dose. The 2-dose series should be completed by 24 weeks of age.

(SCID). (4.4, 6.2)

actions in latex-sensitive individuals. (5.1)

[See table at top of next pagel 2.2 Recommended Dose and Schedule The vaccination series consists of two 1-mL doses adminis¬

5.5

Adverse Reactions (6.2).]

Safety and effectiveness have not been evaluated if ROTARIX were administered for the first dose and another

Other postmarketing observational studies conducted in

rotavirus vaccine were administered for the second dose or

susception within the first 7 days following the second dose

vice versa.

Brazil and Australia also suggest an increased risk of intus¬ of ROTARIX. ^ l See Adverse Reactions '6.2).]

Sign up at PDR.net/registration to receive PDR Safety Communications

Look for PDR drug information and services in your EHR ROTARIX • GLAXOSMITHKLINE/1075 ROTARIX 0.2'.;) occurred at a statistically higher incidence

Transfer adapter

(95'i Cl of Relative Risk excluding 11 as compared with re¬ cipients of ROTARIX.

I

Deaths:

During the entire course of 8 clinical studies,

there were 68 (0.19% I deaths following administration of

Remove vial cap and push transfer adapter onto vial (lyophilized vaccine).

ROTARIX (N = 36,755) and 50 (0.15%) deaths following pla¬ cebo administration (N = 34,454). The most commonly re¬

Vial

ported cause of death following vaccination was pneumonia, which was observed in 19 (0.05%) recipients of ROTARIX and 10 (0.03% ) placebo recipients (Relative Risk’ 1 74 95% Cl: 0.76, 4.23). Intussusception:

In a controlled safety study conducted in

Latin America and Finland, the risk of intussusception was Shake diluent in oral applicator (white, turbid suspension).

evaluated in 63,225 infants (31,673 received ROTARIX and

Connect oral applicator to transfer adapter.

31,552 received placebo). Infants were monitored by active surveillance including independent, complementary meth¬ ods (prospective hospital surveillance and parent reporting at scheduled study visits) to identify potential cases of in¬ tussusception within 31 days after vaccination and, in a subset of 20,169 infants (10,159 received ROTARIX and

Push plunger of oral applicator to transfer diluent into vial.

10,010 received placebo), up to one year after the first dose.

Suspension will appear white and turbid.

No increased risk of intussusception following administra¬ tion of ROTARIX was observed within a 31-day period fol¬ lowing any dose, and rates were comparable to the placebo group after a median of 100 days (Table 2). In a subset of 20,169 infants (10,159 received ROTARIX and 10,010 re¬ ceived placebo) followed up to one year after dose 1, there were 4 cases of intussusception with ROTARIX compared with 14 cases of intussusception with placebo [Relative Risk: 0.28 (95% Cl: 0.10, 0.81)1. All of the infants who de¬ veloped intussusception recovered without sequelae.

Table 2. Intussusception and Relative Risk With ROTARIX Compared With Placebo

Withdraw vaccine into oral applicator.

Confirmed Cases of Intussusception

ROTARIX N = 31,673

Placebo N = 31,552

0

7

Within 31 days following diagnosis after any dose Relative Risk (95% Cl)

0.85 (0.30, 2.42)

Within 100 days following dose 1a

9

Relative Risk (95% Cl)

16

0.56(0.25, 1.24)

Cl = Confidence Interval.

Twist and remove the oral applicator.

’ Median duration after dose 1 I follow-up visit at 30 to 90 days after dose 2).

Among vaccine recipients, there were no confirmed cases of

j

intussusception within the 0- to 14-day period after the first dose (Table 3), which was the period of highest risk for the previously vaccine.1

licensed

oral

live

rhesus

rotavirus-based

[See table 3 at top of next pagel

-Xrr-

Kawasaki Disease: Kawasaki disease has been reported in 18 (0.035%) recipients of ROTARIX and 9 (0.021% ) pla¬ cebo recipients from 16 completed or ongoing clinical trials.

Do not use a needle with ROTARIX.

Of the 27 cases, 5 occurred following ROTARIX in clinical trials that were either not placebo-controlled or 1:1 random¬

Not for injection.

ized. In placebo-controlled trials, Kawasaki disease* was re¬ ported in 17 recipients of ROTARIX and 9 placebo recipients [Relative Risk: 1.71 (95% Cl: 0.71, 4.38)1. Three of the 27

Ready for oral administration.

cases were reported within 30 days post-vaccination: 2 cases (ROTARIX = 1, placebo = 1) were from placebo-controlled

In worldwide passive postmarkpting surveillance, cases of intussusception have been reported in temporal association w ith ROTARIX /see Advert- Reactions (6.2)1.

5.6

Post-Exposure Prophylaxis

Safety and eff contains at least 10h 11

as a 2-dose series with the first dose administered orally

median Cell Culture Infective Dose (CCIDW) of live, atten¬

from 6 through 14 weeks of age followed by one additional

uated rotavirus. The lyophilized vaccine contains amino acids, dextran, Dulbecco’s Modified Eagle Medium (DMEM), sorbitol, and su¬

dose administered at least 4 weeks after the first dose. The 2-dose series was completed by 24 weeks of age. For both

crose. DMEM contains the following ingredients: sodium chloride, potassium chloride, magnesium sulfate, ferric (III)

were male. The clinical case definition of rotavirus gastroenteritis was

nitrate, sodium phosphate, sodium pyruvate, D-glucose,

an episode of diarrhea (passage of 3 or more loose or watery

concentrated vitamin solution, L-cystine, L-tyrosine, amino

stools within a day), with or without vomiting, where rotavirus was identified in a stool sample. Severity of gas¬

7 DRUG INTERACTIONS 7.1 Concomitant Vaccine Administration In clinical trials, ROTARIX was administered concomi¬ tantly with US-licensed and non-US-licensed vaccines. In a US coadministration study in 484 infants, there was no ev¬ idence of interference in the immune responses to any of the antigens when PED1AR1X* (Diphtheria and Tfetanus Tbxoids and Acellular Pertussis Adsorbed, Hepatitis B i Recom¬ binant1 and Inactivated Poliovirus Vaccinel, a LS-licensed 7-valent pneumococcal conjugate vaccine (Wyeth Pharma¬ ceuticals Inc.), and a US-licensed Hib conjugate vaccine iSanofi Pasteur SA' were coadministered with ROTARIX as compared with separate administration of ROTARIX.

acids solution, L-glutamine, calcium chloride, sodium hy-

were enrolled to receive ROTARK (n = 2,646) or placebo (n = 1,348). Vaccine or placebo was given to healthy infants

vaccination groups, 98.3% of infants were white and 53%

drogenocarbonate, and phenol red. In the manufacturing process, porcine-derived materials

troenteritis was determined by a clinical scoring system, the

are used. Porcine circovirus type 1 (PCV-1) is present in

rhea and vomiting, the intensity of fever, use of rehydration

ROTARIX. PCV-1 is not known to cause disease in humans.

therapy or hospitalization for each episode. Scores range

Vesikari scale, assessing the duration and intensity of diar¬

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Look for PDR drug information and services in your EHR from 0 to 20, where higher scores indicate greater severity. An episode of gastroenteritis with a score of 11 or greater was considered severe.8 The primary efficacy endpoint was prevention of any grade of severity of rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 weeks after the second dose through one rotavirus season (according to protocol, ATP). Other efficacy evaluations included prevention of severe rotavirus gastroenteritis, as defined by the Vesikari scale, and reductions in hospitalizations due to rotavirus gastro¬ enteritis and all cause gastroenteritis regardless of pre¬ sumed etiology. Analyses were also done to evaluate the ef¬ ficacy of ROTARIX against rotavirus gastroenteritis among infants who received at least one vaccination (total vacci¬ nated cohort, TVC). Efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through one rotavirus season was 87.1% (95% Cl: 79.6, 92.1); TVC efficacy was 87.3% (95% Cl: 80.3, 92.0). Efficacy against severe rotavirus gastroenteritis through one rotavirus season was 95.8% (95% Cl: 89.6, 98.7); TVC efficacy was 96.0% (95% Cl: 90.2, 98.8) (Table 4). The protective effect of ROTARIX against any grade of se¬ verity of rotavirus gastroenteritis observed immediately fol¬ lowing dose 1 administration and prior to dose 2 was 89 8% (95% Cl: 8.9, 99.8). Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one rotavirus season was 100% (95% Cl: 81.8, 100); TVC efficacy was 100% (95% Cl: 81.7, 100) (Table 4). ROTARIX reduced hospitalizations for all cause gastroenteritis regardless of presumed etiology by 74.7% (95% Cl: 45.5, 88.9). [See table 4 above) A randomized, double-blind, placebo-controlled study was conducted in 11 countries in Latin America and Finland. A total of 63,225 infants received ROTARIX (n = 31,673) or placebo (n = 31,552). An efficacy subset of these infants con¬ sisting of 20,169 infants from Latin America received ROTARIX (n = 10,159) or placebo (n = 10,010). Vaccine or placebo was given to healthy infants as a 2-dose series with the first dose administered orally from 6 through 13 weeks of age followed by one additional dose administered at least 4 weeks after the first dose. The 2-dose series was com¬ pleted by the age of 24 weeks of age. For both vaccination groups, the racial distribution of the efficacy subset was as follows: Hispanic 85.8%, white 7.9%, black 1.1%, and other 5.2%; 51% were male. The clinical case definition of severe rotavirus gastroenter¬ itis was an episode of diarrhea (passage of 3 or more loose or watery stools within a day), with or without vomiting, where rotavirus was identified in a stool sample, requiring hospitalization and/or rehydration therapy equivalent to World Health Organization (WHO) plan B (oral rehydration therapy) or plan C (intravenous rehydration therapy) in a medical facility. The primary efficacy endpoint was prevention of severe rotavirus gastroenteritis caused by naturally occurring rotavirus from 2 weeks after the second dose through one year (ATP). Analyses were done to evaluate the efficacy of ROTARIX against severe rotavirus gastroenteritis among infants who received at least one vaccination (TVC). Reduc tion in hospitalizations due to rotavirus gastroenteritis was also evaluated (ATP). Efficacy of ROTARIX against severe rotavirus gastroenteri¬ tis through one year was 84.7% (95% Cl: 71.7, 92.4); TVC efficacy was 81.1% (95% Cl: 68.5, 89.3) (Table 5). Efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through one year was 85.0% (95% Cl: 69.6, 93.5); TVC efficacy was 80.8% (95% Cl: 65.7, 90.0) (Table 5). [See table 5 above) 14.2 Efficacy Through Two Rotavirus Seasons The efficacy of ROTARIX persisting through two rotavirus seasons was evaluated in two studies. In the European study, the efficacy of ROTARIX against any grade of severity of rotavirus gastroenteritis through two rotavirus seasons was 78.9% (95% Cl: 72.7.83.8). Efficacy in preventing any grade of severity of rotavirus gastroenteritis cases occurring only during the second season post¬ vaccination was 71.9% (95% Cl: 61.2, 79.8). The efficacy of ROTARIX against severe rotavirus gastroenteritis through two rotavirus seasons was 90.4% (95% Cl: 85.1, 94.1). Effi¬ cacy in preventing severe rotavirus gastroenteritis cases oc¬ curring only during the second season post-vaccination was 85.6% (95% CI: 75.8, 91.9). The efficacy of ROTARIX in reducing hospitalizations for rotavirus gastroenteritis through two rotavirus seasons was 96.0% 1.5% of 474 subjects with SVT who received RYTHMOL in US clinical trials are pre¬

CHF occurred in 1.9% of subjects studied with PAF or

sented in Table 1 by incidence and percent discontinuation,

and 85% had coronary artery disease. CHF attributable to propafenone HC1 developed rarely (1.5% of Subjects With SVT

RYTHMOL SR (all doses), compared with 1 (0.8%) subject (N = 480)

% of Subjects Who Discontinued

Incidence

receiving placebo. 5.6 Conduction Disturbances Propafenone slows atrioventricular conduction and may

tachycardia (VT) or ventricular fibrillation (VF) during the

also cause dose-related first-degree AV block. Average PR in¬ terval prolongation and increases in QRS duration are also

Unusual taste

14%

1.3%

trial. However, in 4 of the 9 subjects, the ventricular tachy¬ cardia was of atrial origin. Six of the 9 subjects that devel¬

dose-related. Do not give propafenone to patients with atrio¬ ventricular and intraventricular conduction defects in the

Nausea and/or vomiting

11%

2.9%

oped ventricular arrhythmias did so within 14 days of onset

absence of a pacemaker [see Contraindications (4), Clinical

of therapy. About 2.3% (11/474) of all subjects had a recur¬ rence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could repre¬

Pharmacology (12.2)].

Dizziness

9%

1.7%

The incidence of first-degree, second-degree, and thirddegree AV block observed in 2,127 subjects with ventricular

Constipation

8%

0.2%

sent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have

arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Devel¬ opment of second- or third-degree AV block requires a reduc¬

Headache

6%

0.8%

included increased premature ventricular contractions

tion in dosage or discontinuation of propafenone HC1. Bun¬

(PVCs), VT, VF, torsade de pointes, asystole, and death.

dle branch block (1.2%) and intraventricular conduction

Fatigue

6%

1.5%

Overall in clinical trials with RYTHMOL (which included subjects treated for ventricular arrhythmias, atrial fibrilla¬

delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%).

Blurred Vision

3%

0.6%

tion/flutter, and PSVT), 4.7% of all subjects had new or worsened ventricular arrhythmia possibly representing a

Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with

Weakness

3%

1.3%

proarrhythmic event (0.7% was an increase in PVCs; 4.0% a

propafenone. In a US trial in 523 subjects with a history of symptomatic

Dyspnea

2%

1.0%

Wide complex

2%

1.9%

CHF

2%

0.6%

Bradycardia

2%

0.2%

Palpitations

2%

0.2%

Tremor

2%

0.4%

worsening, or new appearance, of VT or VF). Of the subjects who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proar¬ rhythmia in subjects with less serious or benign arrhyth¬ mias, which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events

AF treated with RYTHMOL SR, sinus bradycardia (rate 1% of 2,127 subjects with clinical trials were evaluated by daily dose. The most com¬ mon adverse reactions appeared dose-related (but note that most subjects spent more time at the larger doses), espe¬ cially dizziness, nausea and/or vomiting, unusual taste, con¬ stipation, and blurred vision. Some less common reactions may also have been dose-related such as firsUdegree AV block, congestive heart failure, dyspepsia, and weakness. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension. In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in mar¬ keting experience. Causality and relationship to

ity and to a somewhat lesser extent in other demographic-

ally not associated with clinical symptoms, but there is one

groups. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6;

published case of drug-induced lupus erythematosis (posi¬ tive rechallenge); it resolved completely upon discontinua¬

propafenone therapy cannot necessarily be judged from

ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for

tion of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation

these events. Cardiovascular System:

CYP1A2) can be expected to cause increased plasma levels

of ANA titers is detected, consider discontinuing therapy.

cardiac arrest, flushing, hot flashes, sick sinus syndrome,

of propafenone.

5.13 Impaired Spermatogenesis Reversible disorders of spermatogenesis have been demon¬

sinus pause or arrest, supraventricular tachycardia.

strated in monkeys, dogs, and rabbits after high-dose intra¬ venous administration of propafenone. Evaluation of the ef¬

normal vision, confusion, depression, memory loss, numb¬ ness, paresthesias, psychosis/mania, seizures (0.3%), tinni¬

fects of short-term administration of RYTHMOL on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop i within

tus, unusual smell sensation, vertigo. Gastrointestinal: Cholestasis , elevated liver enzymes (al¬ kaline phosphatase, serum transaminases), gastroenteritis,

normal range) in sperm count.

hepatitis .

Increased exposure to propafenone may lead to cardiac ar¬ rhythmias and exaggerated beta-adrenergic blocking activ¬ ity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibi¬ tion in users of propafenone is potentially hazardous. There¬ fore, avoid simultaneous use of RYTHMOL with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

Nervous System:

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Atrial flutter. AV dissociation,

Abnormal dreams, abnormal speech, ab¬

Look for POR drug information and services in your EHR Hematologic-. Agranulocytosis, anemia, bruising, granulo¬ cytopenia, leukopenia, purpura, thrombocytopenia. Other: Alopecia, eye irritation, impotence, increased glu¬ cose, positive ANA (0.7%), muscle cramps, muscle weak¬ ness, nephrotic syndrome, pain, pruritus. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of RYTHMOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: A number of patients with liver abnor¬ malities associated with propafenone therapy have been re¬ ported in postmarketing experience. Some appeared due to hepatocellular injury, some were cholestatic, and some showed a mixed picture. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms including fulminant hepatitis and death. One case was rechallenged with a positive outcome. Blood and Lymphatic System: Increased bleeding time. Immune System: Lupus erythematosis. Nervous System: Apnea, coma. Renal and Urinary: Hyponatremia/inappropriate ADH se¬ cretion, kidney failure. 7 DRUG INTERACTIONS 7.1 CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, parox¬ etine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice i can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and eifrier CYP2D6 deficiency or CYP2D6 inhibition with admin¬ istration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simulta¬ neous use of RYTHMOL with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see Warnings and Precautions (5.4), Dosage and Administration (2JJ. Amiodarone: Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended. Cimetidine: Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy sub¬ jects resulted in a 20% increase in steady-state plasma con¬ centrations of propafenone. Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone C1Imx and AUC by 39*7 and 50%, respectively, and the R propafenone C^ and AUC by 71% and SO'*-, re¬ spectively. Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all pa¬ tients, in effect, slow metabolizers [see Clinical Pharmacol¬ ogy (12)1. Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone. A 100-mg dose of quinidine tripled steady-state concentra¬ tions of propafenone. Avoid concomitant use of propafenone and quinidine.

RYTHMOL • GLAXOSMITHKLINE/1081 7.5

I

j |

,

7.6

I

Beta-Antagonists

Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. The phar¬ macokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, sub¬ jects who were receiving beta-blockers concurrently did not experience an increased incidence of side effects. Lidocaine

No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their con¬ comitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine. 8 8 1

USE IN SPECIFIC POPULATIONS Pregnancy

j Pregnancy Category C. There are no adequate and well| controlled studies in pregnant women. RYTHMOL should be used during pregnancy only if the potential benefit justi¬ fies the potential risk to the fetus. Animal Data: Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg day (about 3 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) produced no evidence of embrvotoxicity in rats; post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/ day, about 1/3 the MRHD on a mg/m2 basis). Non-teratogenic Effects: In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m2 basis) resulted in reductions in neonatal survival, body weight gain, and physiological development. 8.2

Labor and Delivery

It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or in¬ creases the need for forceps delivery or other obstetrical in¬ tervention. 8.3

Nursing Mothers

Propafenone is excreted in human milk. Because of the po¬ tential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4

Pediatric Use

The safety and effectiveness of propafenone in pediatric patients have not been established. 8.5

Geriatric Use

Clinical trials of RYTHMOL did not include sufficient num¬ bers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in re¬ Rifampin: Concomitant administration of rifampin and sponses between the elderly and younger subjects. In gen¬ propafenone in extensive metabolizers decreased the eral, dose selection for an elderly patient should be cautious, plasma concentrations of propafenone by 67% with a corre¬ usually starting at the low end of the dosing range, reflect¬ sponding decrease of 5-OH-propafenone by 65%. The con¬ centrations of norpropafenone increased by 30%. In slow I ing the greater frequency of decreased hepatic, renal, or car¬ metabolizers, there was a 50% decrease in propafenone ! diac function, and of concomitant disease or other drug ther¬ apy. plasma concentrations and an increase in the AUC and Cm„, of norpropafenone by 74% and 20%, respectively. Urinary 10 OVERDOSAGE excretion of propafenone and its metabolites decreased sig¬ The symptoms of overdosage may include hypotension, som¬ nificantly. Similar results were noted in elderly patients: ! nolence, bradycardia, intra-atnal and intraventricular con¬ Both the AUC and C^,, of propafenone decreased by 84% , duction disturbances, and rarely, convulsions and highwith a corresponding decrease in AUC and C^ of 5-OHgrade ventricular arrhythmias. Defibrillation, as well as propafenone by 69% and 57%, respectively. infusion of dopamine and isoproterenol have been effective 7.2 Digoxin in controlling abnormal rhythm and blood pressure. Convul¬ Concomitant use of propafenone and digoxin increased sions have been alleviated with intravenous diazepam. Gen¬ steady-state serum digoxin exposure (AUC) in patients by eral supportive measures such as mechanical respiratory 60% to 270%, and decreased the clearance of digoxin by 31% [ assistance and external cardiac massage may be necessary. to 67%. Monitor plasma digoxin levels of patients receiving The hemodialysis of propafenone in patients with an over¬ propafenone and adjust digoxin dosage as needed. dose is expected to be of limited value in the removal of 7.3 Warfarin propafenone as a result of both its high protein binding The concomitant administration of propafenone and warfa¬ (>95%) and large volume of distribution. rin increased warfarin plasma concentrations at steady II DESCRIPTION state by 39% in healthy volunteers and prolonged the pro¬ thrombin time in patients taking warfarin. Adjust the RYTHMOL (propafenone hydrochloride) is an antiarrhvthwarfarin dose as needed by monitoring INR (international mic drug supplied in scored, film-coated tablets of 150 and normalized ratio). 225 mg for oral administration. Propafenone has some 7.4 Orlistat structural similarities to beta-blocking agents. Orlistat may limit the fraction of propafenone available for absorption. In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioven¬ tricular block, and acute circulatory failure.

Chemically, propafenone hydrochloride (HCI) is 2-|2hydroxy-3-( propylamine vpropoxyl-3-phinylprnpiophonone hydrochloride, with a molecular weight of 377.92. The mo¬ lecular formula is CJ,H2'jN03»HCl. The structural formula of propafenone HCI is given below:

Propafenone HCI occurs as colorless crystals or white crys¬ talline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform and ethanol. The following in¬ active ingredients are contained in the tablet: com starch, hypromellose, magnesium stearate, polyethylene glycol, polysorbate, povidone, propylene glycol, sodium starch glycolate, and titanium dioxide. 12 12.1

CLINICAL PHARMACOLOGY Mechanism of Action

I Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocari dial membranes. The electrophysiological effect of i propafenone manifests itself in a reduction of upstroke veI locity (Phase 0) of the monophasic action potential. In Pur’ kinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by so• dium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. Studies in anesthetized dogs and isolated organ prepara! tions show that propafenone has beta-sympatholytic activ¬ ity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by I calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium cur¬ rents in in vitro studies (i.e., the transient outward, the de¬ layed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and ! calcium channel activity, but about 10 times less beta¬ blocking activity (N-depropylpropafenone has weaker so¬ dium channel activity but equivalent affinity for betareceptors). 12.2 Pharmacodynamics Electrophysiology: Electrophysiology trials in subjects with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction | time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are pro¬ longed. In patients with Wolff-Parkinson-White syndrome, RYTHMOL reduces conduction and increases the effective refractory period of the accessory pathway in both direc¬ tions. Electrocardiograms: Propafenone slows prolongs the PR and QR.S intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval. |See table 2 at top of next pagel In any individual patient, the above ECO changes cannot be readily used to predict either efficacy or plasma concentra¬ tion. RYTHMOL causes a dose-related and concentration-related decrease in the rate of single and multiple premature ven¬ tricular contractions (PVCs) and can suppress recurrence of ventricular tachycardia. Based on the percent of patients at¬ taining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response When 600 mg/day propafenone was administered to sub¬ jects with paroxysmal atnal tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beata/min and 37 beats/min for subjects with paroxysmal atrial fibrillation/ flutter (PAF) and subjects with paroxysmal supraventricu¬ lar tachycardia (PSVT), respectively. Hemodynamics: Trials in humans have shown that propafenone HCI exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials in subjects with moderately impaired ventricular function (mean C.I. ■ 2.61 L/min/m21 utilizing intravenous propafenone infusions 'loading dose of 2 mg/kg over 10 min followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose that produces plasma levels of propafenone greater than recommended oral dosing)

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1082/GLAXOSMITHKLINE • RYTHMOL Table 2. Mean Changes in Electrocardiogram Intervals

’

Total Daily Dose (mg) 900 mg

675 mg

450 mg

337.5 mg msec

%

msec

%

msec

%

msec

%

Interval

-14.5

-1.8

30.6

3.8

31.5

3.9

41.7

5.1

RR

3.6

2.1

19.1

11.6

28.9

17.8

35.6

21.9

PR

8.4

15.6

17.3

1.2

14.7

3.7

QRS

5.6

6.4

5.5

6.1

7.7

QTc

2.7

0.7

-7.5

-1.8

5.0

» Change and percent change based on mean baseline values for each treatment group.

Table 3. Reduction of Arrhythmias in Subjects with PAF or PSVT Trial 2

Trial 1 Propafenone

Placebo

Propafenone

Placebo

PAF Percent attack free Median time to first recurrence

n = 30 53% >98 days

n = 30 13% 8 days

n= 9 67% 62 days

n =9 22% 5 days

PSVT Percent attack free Median time to first recurrence

n = 45 47% >98 days

n = 45 16% 12 days

n= 15 38% 31 days

n= 15 7% 8 days

showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances, and depression of cardiac output and cardiac index. 12.3

Pharmacokinetics

Absorption/Bioavailability: Propafenone HC1 is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after ad¬ ministration in most individuals. Propafenone exhibits ex¬ tensive saturable presystemic biotransformation (first-pass effect) resulting in a dose dependent and dosage form de¬ pendent absolute bioavaiiability; e.g., a 150-mg tablet had absolute bioavaiiability of 3.4%, while a 300-mg tablet had absolute bioavaiiability of 10.6%. A 300-mg solution which was rapidly absorbed had absolute bioavaiiability of 21.4%. At still larger doses, above those recommended, bioavaii¬ ability increases still further. Propafenone! HC1 follows a nonlinear pharmacokinetic dis¬ position presumably because of saturation of first-pass he¬ patic metabolism as the liver is exposed to higher concen¬ trations of propafenone and shows a very high degree of interindividual variability. For example, for an increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. The top 25% of sub¬ jects given 337.5 mg/day, however, had a mean concentra¬ tion of propafenone larger than the bottom 25%, and about equal to the second 25%, of subjects given a dose of 900 mg. Although food increased peak blood level and bioavaiiability in a single-dose trial, during multiple-dose administration of propafenone to healthy volunteers, food did not change bioavaiiability significantly. Distribution: Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2-compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about 5 minutes. The volume of the central com¬ partment was about 88 liters (1.1 IAg) and the total vol¬ ume of distribution about 252 liters. In serum, propafenone is greater than 95% bound to pro¬ teins within the concentration range of 0.5 to 2 mcg/mL. Metabolism: There are 2 genetically determined patterns of propafenone metabolism. In over 90% ot patients, the drug is rapidly and extensively metabolized with an elimi¬ nation half-life from 2 to 10 hours. These patients metabo¬ lize propafenone into 2 active metabolites: 5-hydroxy propafenone which is formed by CYP2D6 and N-depropylpropafenone inorpropafenone) which is formed by both CYP3A4 and CYP1A2. In leas than 10* . of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to me¬ tabolize debrisoquine and a variety of oilier drugs isuch as encainide, metoprolol, and dextromethorphan) whose me¬ tabolism is mediated by the CYP2D6 isozyme. In these pa¬ tients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.

There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the for¬ mer achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day. At low doses the differences are greater, with slow metabo¬ lizers attaining concentrations more than 5 times that of ex¬ tensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dos¬ ing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels require that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity I see Dosage and Administration (2) ]. Stereochemistry: RYTHMOL is a racemic mixture. The Rand S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Following administration of RYTHMOL immediate-release tablets, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. In ad¬ dition, no difference in the average values of the S/R ratios is evident between genotypes or over time. Special Populations: Hepatic Impairment: Decreased liver function increases the bioavaiiability of propafenone. Absolute bioavaiiability of RYTHMOL immediate-release tablets is inversely related to indocyanine green clearance, reaching 60% to 70% at clearances of 7 mUmin and below. Protein binding decreases to about 88% in patients with se¬ vere hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction /see Warnings and Pre¬ cautions (5.9)1. 13 13.1

NONCUNICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fer¬

tility

Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose |MRHD| on a mg/m2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) provided no evidence of a carcinogenic potential for propafenone HC1. Propafenone HC1 tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for dastogenicity in the hu¬ man lymphocyte chromosome aberration assay in vitro and in rat and Chinese hamster micrunucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia. Propafenone HC1, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermato¬ genesis. These effects were reversible, were not found fol¬ lowing oral dosing of propafenone HC1, were seen at lethal

or near lethal dose levels, and were not seen in rats treated either orally or intravenously Isee Warnings and Precau¬ tions (5.13)1. Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evi¬ dence of impaired fertility when propafenone HC1 was ad¬ ministered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m2 ba¬ sis). 13.2 Animal Toxicology and/or Pharmacology Renal changes have been observed in the rat following 6 months of oral administration of propafenone HC1 at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respec¬ tively, the MRHD on a mg/m2 basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accom¬ panying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats al¬ lowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HC1 at a dose of 270 mg/kg/ day (about 3 times the MRHD on a mg/m2 basis). There were no renal or hepatic changes at 90 mg/kg/day (equiva¬ lent to the MRHD on a mg/m2 basis). 14

CLINICAL STUDIES

In 2 randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days’ duration in subjects with paroxysmal supraventricular arrhythmias (paroxysmal atrial fibrilla¬ tion/flutter [PAF], or paroxysmal supraventricular tachycar¬ dia [PSVT]), propafenone reduced the rate of both arrhyth¬ mias, as shown in Table 3. [See table 3 above] The patient population in the above trials was 50% male with a mean age of 57.3 years. Fifty percent of the subjects had a diagnosis of PAF and 50% had PSVT. Eighty percent of the subjects received 600 mg/day propafenone. No subject died in the above 2 trials. In US long-term safety trials, 474 subjects (mean age: 57.4 ± 14.5 years) with supraventricular arrhythmias [195 with PAF, 274 with PSVT and 5 with both PAF and PSVT] were treated up to 5 years (mean: 14.4 months i with propafenone. Fourteen of the subjects died.‘tWhen this mor¬ tality rate was compared with the rate in a similar patient population (n = 194 subjects; mean age: 43.0 ± 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted difference in mortality. This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out. 16

HOW SUPPLIED/STORAGE AND HANDLING

RYTHMOL Tablets are supplied as white, biconvex, scored, round, film-coated tablets containing either 150 mg or 225 mg of propafenone hydrochloride and embossed (on the same side) with GS and TF5 for the 150-mg tablet, and GS and FIX for the 225-mg tablet, in the following package 150 mg - bottles of 100: NDC 0173-0792-20 225 mg - bottles of 100: NDC 0173-0794-20 Storage: Store at 25°C (77°F); excursions permitted to 15°C to 30“C (59°F to 86”F). Dispense in a tight, lightresistant container. 17

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information). 17.1

Information for Patients

• Patients should be instructed to notify their healthcare providers of any change in over-the-counter, prescription, and supplement use. The healthcare provider should as¬ sess the patients' medication history including all overthe-counter, prescription, and herbal/natural preparations for those that may affect the pharmacodynamics or kinet¬ ics of RYTHMOL Isee Warnings and Precautions (5.4)1. • Patients should also check with their healthcare provid¬ ers prior to taking a new over-the-counter medicine. • If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or pro¬ longed diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their healthcare provider. • Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time. RYTHMOL is a registered trademark of G. Petrik used un¬ der license by Abbott Laboratories. Manufactured for: GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. RML:6P1

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Look for PDR drug information and services in your EHR PHARMACIST-DETACH HERE AND GIVE INSTRUC¬ TIONS TO PATIENT

RYTHMOL SR • GLAXOSMITHKLINE/1083 ■ sore throat ■ chills

Usage Considerations: • Use in patients with permanent atrial fibrillation or with atrial flutter or paroxysmal supraventricular tachycardia IPSVT) has not been evaluated. Do not use to control ven¬ tricular rate during atrial fibrillation. (1) • In patients with atrial fibrillation and atrial flutter, use RYTHMOL SR with drugs that increase the atrioventric¬ ular nodal refractory period. (1) • The effect of propafenone on mortality has not been deter¬ mined. (1)

• Worsening of myasthenia gravis in people who already

PATIENT INFORMATION

have this condition. Tbll your doctor about anv change in

RYTHMOL* (RITH-Mall)

your symptoms.

(propafenone hydrochloride) Tablets What is RYTHMOL?

RYTHMOL is a prescription medicine that is used: • in certain people who have ventricular heart rhythm dis¬ orders • to increase the amount of time between having symptoms of heart rhythm disorders called atrial fibrillation (AF) or paroxysmal supraventricular tachycardia (PSVT) It is not known if RYTHMOL is safe and effective in chil¬ dren. Who should not take RYTHMOL? Do not take RYTHMOL if you have:

• heart failure (weak heart) • had a recent heart attack • a heart rate that is too slow, and you do not have a pace¬ maker • a heart condition called Brugada Syndrome • very low blood pressure • certain breathing problems that make you short of breath or wheeze • certain abnormal body salt (electrolyte) levels in your blood Talk to your doctor before taking RYTHMOL if you think you have any of the conditions listed above. What should I tell my doctor before taking RYTHMOL? Before you take RYTHMOL, tell your doctor if you:

• have liver or kidney problems • have breathing problems • have symptoms including diarrhea, sweating, vomiting, or loss of appetite or thirst that are severe. These symp¬ toms may be a sign of abnormal electrolyte levels in your blood. • have myasthenia gravis • have lupus erythematosis • have been told you have or had an abnormal blood test called Antinuclear Antibody Test or ANA Tbst • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if RYTHMOL will harm your unborn baby. • are breastfeeding or plan to breastfeed. RYTHMOL can pass into your milk and may harm your baby. You and your doctor should decide if you will breastfeed or take RYTHMOL. You should not do both. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RYTHMOL and certain other medi¬ cines can affect (interact with) each other and cause serious side effects. You can ask your pharmacist for a list of medi¬ cines that interact w ith RYTHMOL. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

• RYTHMOL may cause lower sperm counts in men. This c°uld affect the ability to father a child. Talk to your doctor if this is a concern for you. Common side effects of RYTHMOL include: 1. unusual taste 2. nausea -DOSAGE AND ADMINISTRATION3. vomiting • Initiate therapy with 225 mg given every 12 hours (2) 4. dizziness • Dosage may be increased at a minimum of 5-day intervals 5. constipation to 325 mg every 12 hours and, if necessary, to 425 mg ev¬ 6. headache ery 12 hours. (2V 7. tiredness • Dose reduction should be considered in patients with he¬ 8. irregular heart beats patic impairment, significant widening of the QRS com¬ Tell your doctor if you have any side effect that bothers you plex, or second-or third-degree AV hlock. (2) or that does not go away. -DOSAGE FORMS AND STRENGTHS_ These are not all the possible side effects of RYTHMOL. For [ Capsules: 225 mg, 325 mg, 425 mg. (3) more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You -CONTRAINDICATIONSmay report side effects to FDA at 1-800-FDA-1088. • Heart failure (4) How should I store RYTHMOL? I • Cardiogenic shock (4) • Store RYTHMOL at room temperature between 68°F to • Sinoatrial, atrioventricular, and intraventricular disor¬ 77°F (20°C to 25°C). ders of impulse generation and/or conduction in the ab¬ • Keep the bottle tightly closed. sence of pacemaker (4) Keep RYTHMOL and all medicines out of the reach of chil¬ • Known Brugada Syndrome (4) dren. ! • Bradycardia (4) General information about RYTHMOL • Marked hypotension (4) Medicines are sometimes prescribed for purposes other than • Bronchospastic disorders and severe obstructive pulmo¬ nary disease (4) those listed in a Patient Information Leaflet. Do not use • Marked electrolyte imbalance (4) RYTHMOL for a condition for which it was not prescribed. Do not give RYTHMOL to other people, even if they have -WARNINGS AND PRECAUTIONS_ the same symptoms you have. It may harm them. | • May cause new or worsened arrhythmias. Evaluate pa¬ If you would like more information, talk with your doctor. tients via ECG prior to and during therapy. (5.1) You can ask your doctor or pharmacist for information about • RYTHMOL SR may unmask Brugada or Brugada-like RYTHMOL that is written for health professionals. For Syndrome. Evaluate patients via ECG after initiation of more information about RYTHMOL, call 1-888-825-5249. therapy. (4, 5.2)r

What are the ingredients in RYTHMOL?

GlaxoSmithKline

Research Triangle Park. NC 27709 ©2014, the GSK group of companies. All rights reserved. March 2014 RML:3PIL

-ADVERSE REACTIONS-

How should I take RYTHMOL?

RYTHMOL SR

• Take RYTHMOL exactly as prescribed. Your doctor will tell you how many tablets to take and how often to take them. • TV) help reduce the chance of certain side effects, your doc¬ tor may start you with a low dose of RYTHMOL, and then slowly increase the dose. • You should not drink grapefruit juice during treatment with RYTHMOL. • If you miss a dose of RYTHMOL, take your next dose, at the usual time. Do not take 2 doses at the same time. • If you take too much RYTHMOL, call your doctor or go to the nearest hospital emergency room right away. • Call your doctor if your heart problems get worse.

[RITH-Mall] (propafenone hydrochloride)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYTHMOL SR safely and effectively. See full pre¬ scribing information for RYTHMOL SR. RYTHMOL SR (propafenone hydrochloride) ExtendedRelease Capsules for oral use Initial U.S. Approval: 1989

WARNING:

RYTHMOL can cause serious side effects including:

See full prescribing information for complete boxed warning

MORTALITY

sudden death or be life-threatening. Your doctor may do an electrocardiogram (ECG or EKG) before and during treatment to check your heart for these problems.

• An increased rate of death or reversed cardiac arrest

• New or worsened heart failure. Tell your doctor about any

that seen in patients assigned to placebo At pres¬

changes in your heart symptoms, including:

■ any new or increased swelling in your arms or legs ■ trouble breathing ■ sudden weight gain • Effects on pacemaker function. RYTHMOL may affect how an implanted pacemaker or defibrillator works. Your doctor should check how your pan'maker or defibrillator is working during and after treatment with RYTHMOL They may need to be re-programmed.

ft

Extended-Release Capsules for oral use

What are possible side effects of RYTHMOL? • New or worsened abnormal heart beats, that can cause

rate was seen in patients treated with encainide or flecainide (Class 1C antiarrhythmics) compared with ent it is prudent to consider any 1C antiarrhythmic to have a significant risk of provoking proarrhythmic events in patients with structural heart disease • Given the lack of any evidence that these drugs im¬ prove survival, antiarrhythmic agents should gener¬ ally be avoided in patients with non-life-threatening

The most commonly reported adverse events with propafenone t>5% and greater than placebo) excluding those not reasonably associated with the use of the drug in¬ cluded the following: dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, consti¬ pation, upper respiratory tract infection, edema, and influ¬ enza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA1088 or www.fda.gov/medwatch. -DRUG INTERACTIONS-

• Inhibitors of CYTP2D6, 1A2, and 3A4 may increase propafenone levels which may lead to cardiac arrhyth¬ mias. Simultaneous use with both a CYT3A4 and CYP2D6 inhibitor (or in patients with CYrP2D6 deficiency) should be avoided. (7.1) • Propafenone may increase digoxin or warfarin levels (7.2 7.3) • Orlistat may reduce propafenone concentrations. Abrupt cessation of orlistat in patients stable on RYTHMOL SR has resulted in convulsions, atrioventricular block, and circulatory failure. (7.4) • Concomitant use of lidocaine may increase central ner¬ vous system side effects. (7.6) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised. 2/2014

ventricular arrhythmias, even if the patients are ex¬ periencing unpleasant, but not life-threatening, symptoms or signs.

• Very low white blood cell levels in your blood (agranulo¬ cytosis). Your bone marrow may not produce enough of a

n-rtain type of white blood cells called neutrophils. If this happens, you are more likely to get infections TV1I your doctor right away if you have any of these symptoms, es¬ pecially during the first 3 months of treatment: ■ fever

• Avoid use with other antiarrhythmic agents or drugs that prolong the QT interval. (5.3) • Avoid simultaneous use of propafenone with both a cyto¬ chrome P450 2D6 inhibitor and a 3A4 inhibitor. (5.4) ' • May provoke overt heart failure. (5.5) • May cause dose-related first-degree AV block or other con¬ duction disturbances. Should not be given to patients with conduction defects in absence of a pacemaker. (5.6) • May affect artificial pacemakers. Pacemakers should be monitored during therapy. (5.7) • Agranulocytosis: Patients should report signs of infec¬ tion. (5.8) • Administer cautiously to patients with impaired hepatic and renal function. 95%) and large volume of distribution.

n (%)

11 DESCRIPTION RYTHMOL SR (propafenone hydrochloride) is an antiarrhythmic drug supplied in extended-release capsules of 225, 325 and 425 mg for oral administration. Chemically, propafenone hydrochloride is 2’-[2-Hydroxy3-(propylamino)-propoxy] -3-phenylpropiophenone hydro¬ chloride, with a molecular weight of 377.92. The molecular formula is C21H27N03»HC1. Propafenone HC1 has some structural similarities to beta¬ blocking agents. The structural formula of propafenone HC1 is given below:

Electrophysiology Electrophysiology trials in patients with ventricular tachy¬ cardia have shown that propafenone prolongs atrioventric¬ ular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, RYTHMOL immediate-release tablets reduce conduction and increase the effective refractory period of the accessory pathway in both directions. Electrocardiograms Propafenone prolongs the PR and QRS intervals. Prolonga¬ tion of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval. [See table 1 above) In RAFT [see Clinical Studies (14)), the distribution of the maximum changes in QTc compared with baseline over the trial in each patient was similar in the groups receiving RYTHMOL SR 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily, and placebo. Similar results were seen in the ERAFT trial. [See table 2 above) Hemodynamics Trials in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac cath¬ eterization trials in patients with moderately impaired ven¬ tricular function (mean C.I. = 2.61 L/min/m"1, utilizing in¬ travenous propafenone infusions (loading dose of 2 mg/kg over 10 min-i- followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose .that pro¬ duces plasma levels of propafenone greater than recom¬ mended oral dosing), showed significant increases in pulmo¬ nary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index. 12.3 Pharmacokinetics

Absorption/Bioavailability Maximal plasma levels of propafenone are'reached between 3 to 8 hours following the administration of RYTHMOL SR. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in a dose- and O. dosage form-dependent absolute bioavailability; e g., a 150-mg immediate-release tablet had an absolute bioavail¬ ability of 3.4%, while a 300-mg immediate-release tablet had an absolute bioavailability of 10.6%. Absorption from a O-CHj-CH-CHj-NH-CHj-CHj-CK, -HCI . 300-mg solution dose was rapid, with an absolute bioavail¬ OH ability of 21.4%. At still larger doses, above those recom¬ mended, bioavailability of propafenone from immediatePropafenone HC1 occurs as colorless crystals or white crys¬ release tablets increased still further. talline powder with a very bitter taste. It is slightly soluble Relative bioavailability assessments have been performed in water (20°C), chloroform and ethanol. RYTHMOL SR between RYTHMOL SR capsules and RYTHMOL capsules are filled with cylindrical-shaped 2x2 mm mi¬ immediate-release tablets. In extensive metabolizers, the crotablets containing propafenone and the following inac¬ bioavailability of propafenone from the SR formulation was tive ingredients: antifoam, gelatin, hypromellose, magne¬ less than that of the immediate-release formulation as the sium stearate, red iron oxide, shellac, sodium dodecyl more gradual release of propafenone from the prolongedsulfate, sodium lauryl sulfate, soy lecithin, and titanium di¬ release preparations resulted in an increase of overall firstoxide. pass metabolism Isee Metabolism/. As a result of the in¬ creased first-pass effect, higher daily doses of propafenone 12 CLINICAL PHARMACOLOGY were required from the SR formulation relative to the 12.1 Mechanism of Action immediate-release formulation, to obtain similar exposure Propafenone is a Class 1C antiarrhythmic drug with local to propafenone. The relative bioavailability of propafenone anesthetic effects, and a direct stabilizing action on myocar¬ from the 325-mg twice daily regimens of RYTHMOL SR ap¬ dial membranes. The electrophysiological effect of proximates that of RYTHMOL immediate-release 150-mg 3 propafenone manifests itself in a reduction of upstroke ve¬ times daily regimen. Mean exposure to locity (Phase 0) of the monophasic action potential. In Pur5-hydroxypropafenone was about 20% to 25% higher after kinje fibers, and to a lesser extent myocardial fibers, SR capsule administration than after immediate-release propafenone reduces the fast inward current carried by so¬ tablet administration. dium ions. Diastolic excitability threshold is increased and Food increased the exposure to propafenone 4-fold after effective refractory period prolonged. Propafenone reduces single-dose administration of 425-mg of RYTHMOL SR. spontaneous automaticity and depresses triggered activity. However, in the multiple-dose trial (425-mg dose twice Studies in anesthetized dogs and isolated organ prepara¬ daily), the difference between the fed and fasted state was tions show that propafenone has beta-sympatholytic activ¬ not significant. ity at about L/50 the potency of propranolol. Clinical studies Distribution employing isoproterenol challenge and exercise testing after Following intravenous administration of propafenone, single doses of propafenone indicate a beta-adrenergic plasma levels decline in a bi-phasic manner consistent with blocking potency (per mg) about 1/40 that of propranolol in a 2-compartment pharmacokinetic model. The average dis¬ man. In clinical trials with the immediate-release formula¬ tribution half-life corresponding to the first phase was about tion, resting heart rate decreases of about 8% were noted at 5 minutes. The volume of the central compartment was the higher end of the therapeutic plasma concentration about 88 liters (1.1 L/kg) and the total volume of distriburange. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium, but this j tion about 252 liters. In serum, propafenone is greater than 95% bound to pro¬ calcium antagonist effect probably does not contribute to anteins within the concentration range of 0.5 to 2 mcg/mL. tiarrhythmic efficacy. Moreover, propafenone inhibits a va¬ Metabolism riety of cardiac potassium currents in in vitro studies (i.e., There are 2 genetically determined patterns of propafenone the transient outward, the delayed rectifier, and the inward metabolism. In over 90% of patients, the drug is rapidly and rectifier current!. Propafenone has local anesthetic activity

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Look for PDR drug information and services in your EHR extensively metabolized with an elimination half-life from 2 to 10 hours. These patients metabolize propafenone into 2 active metabolites: 5-hydroxypropafenone which is formed by CY/P2D6, and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism ol propafenone is slower be¬ cause the 5-hydroxy metabolite is not formed or is mini¬ mally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs such as encainide, metoprolol, and dextromethorphan, whose metabolism is medi¬ ated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers. As a consequence of the observed differences in metabolism, administration of RYTHMOL SR to slow and extensive metabolizers results in significant differences in plasma con¬ centrations of propafenone, with slow metabolizers achiev¬ ing concentrations about twice those of the extensive metabolizers at daily doses of 850 mg/dav. At low doses the differences are greater, with slow metabolizers attaining concentrations about 3 to 4 times higher than extensive me¬ tabolizers. In extensive metabolizers, saturation of the hydroxylation pathway (CYP2D6I results in greater-thanlinear increases in plasma levels following administration of RYTHMOL SR Capsules. In slow metabolizers. propafenone pharmacokinetics is linear. Because the difference de¬ creases at high doses and is mitigated by the lack of the active 5-hydroxymetabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing reg¬ imen of RYTHMOL SR is the same for all patients. The larger inter-subject variability in blood levels require that the dose of the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity Isee Dosage and Administration 12)]. The 5-hydroxypropafenone and norpropafenone metabolites have electrophysiologic properties similar to propafenone in vitro. In man after administration of RYTHMOL SR, the 5-hydroxypropafenone metabolite is usually present in con¬ centrations less than 40% of propafenone. The norpropafcnone metabolite is usually present in concentrations less than 10% of propafenone. Inter-Subject Variability With propafenone, there is a considerable degree of inter¬ subject variability in pharmacokinetics which is due in large part to the first-pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. A higher de¬ gree of inter-subject variability in pharmacokinetic param¬ eters of propafenone was observed following both singleand multiple-dose administration of RYTHMOL SR Cap¬ sules. Inter-subject variability appears to be substantially less in the poor mctabolizer group than in the extensive metabolizer group, suggesting that a large portion of the vari¬ ability is intrinsic to CYP2D6 polymorphism rather than to the formulation. Stereochemistry RYTHMOL is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition character¬ istics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxy latum pathway ICYT2D6). This results in a higher ratio of S-propafenone to R-propafcnone at steady state. Both enantiomers have equivalent potency to block sodium channels: however, the S-enuntiomer is a more po¬ tent beta-antagonist than the R-enantiomer. Following ad¬ ministration of RYTHMOL immediate-release tablets or RYTHMOL SR Capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225-, 325-, and 425-mg RYTHMOL SR are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time. Special Populations Hepatic Impairment Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the RYTHMOL SR capsule formula¬ tion. Absolute bioavailability of RYTHMOL immediaterelease tablets is inversely related to indocyanine green clearance, reaching 60% to 70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in pa¬ tients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life in¬ creased in patients with significant hepatic dysfunction /see Warnings and Precautions (5.9)1. 13 NONCUN1CAL TOXICOLOGY 13.1 Carcinogenesis. Mutagenesis. Impairment of Fer¬ tility Lifetime maximally tolerated oral dose studies in mice lup to 360 mg/kg/day, about tw ice the maximum recommended

RYTHMOL SR • GLAXOSMITHKLINE/1087 Table 3 Analysis of Tachycardia-free Period (Days) from Day 1 of Randomization Dose of RYTHMOL SR 225 mg Twice Daily (N = 126) n 1%)

325 mg Twice Daily (N = 135) n (%)

425 mg Twice Daily (N = 136) n (%)

Placebo (N = 126) n 1%)

66 (521

56(41)

41(30)

87 (691

112

291

NAb

41

0 - 285

0-293

0-300

0 - 289

p-Value (Log-rank test)

0.014

3% Incidence in US Controlled Clinical Trials in Subjects with Chronic Obstructive Pulmonary Disease9 Percent of Subjects

4

2 2

occurred at a rate of >3