Martindale: The Complete Drug Reference [38 ed.] 978-0-85711-139-5, 978-0857111395, 9780857111395

Table of contents :
Introduction......Page 2
Contents......Page 6
About the authors......Page 7
Preface......Page 8
A guide to Martindale......Page 9
Abbreviations......Page 12
Contracted Names for Ions and Groups......Page 15
Atomic Weights of the Elements......Page 17
Analgesics Anti-inflammatory Drugs and Antipyretics......Page 18
Anthelmintics......Page 158
Antibacterials......Page 183
Antidementia Drugs......Page 403
Antidepressants......Page 412
Antidiabetics......Page 473
Antiepileptics......Page 521
Antifungals......Page 578
Antigout Drugs......Page 615
Antihistamines......Page 625
Antimalarials......Page 659
Antimigraine Drugs......Page 685
Antimyasthenics......Page 699
Antineoplastics......Page 706
Antiparkinsonian Drugs......Page 904
AntiprotozoaIs......Page 934
Antivirals......Page 966
Anxiolytic Sedatives Hypnotics and Antipsychotics......Page 1043
Blood Products Plasma Expanders and Haemostatics......Page 1136
Bone Modulating Drugs......Page 1182
Bronchodilators and Anti-asthma Drugs......Page 1210
Cardiovascular Drugs......Page 1257
Chelators Antidotes and Antagonists......Page 1552
Contrast Media......Page 1595
Corticosteroids......Page 1612
Cough Suppressants Expectorants Mucolytics and Nasal Decongestants......Page 1666
Dermatological Drugs and Sunscreens......Page 1696
Disinfectants and Preservatives......Page 1745
Electrolytes......Page 1790
Gases......Page 1812
Gastrointestinal Drugs......Page 1818
General Anaesthetics......Page 1911
Growth Hormone and its Modulators......Page 1933
Immunosuppressants......Page 1947
Local Anaesthetics......Page 1991
Miotics Mydriatics and Antiglaucoma Drugs......Page 2014
Muscle Relaxants......Page 2029
Neuromuscular Blockers......Page 2043
Nutritional Agents and Vitamins......Page 2057
Obstetric Drugs......Page 2144
Pesticides and Repellents......Page 2162
Pharmaceutical Excipients......Page 2178
RadiopharmaceuticaIs......Page 2237
Sex Hormones and their Modulators......Page 2246
Stimulants and Anorectics......Page 2329
Thyroid and Antithyroid Drugs......Page 2347
Urological Drugs......Page 2362
Vaccines Immunoglobulins and Antisera......Page 2388
Miscellaneous Drugs and Other Substances......Page 2441
Volume B......Page 2666
Preparations......Page 2668
Directory of Manufacturers......Page 4000
Pharmaceutical Terms in Various Languages......Page 4104
A......Page 4125
B......Page 4167
C......Page 4191
D......Page 4235
E......Page 4264
F......Page 4284
G......Page 4304
H......Page 4319
I......Page 4336
J......Page 4348
K......Page 4351
L......Page 4361
M......Page 4382
N......Page 4413
O......Page 4435
P......Page 4449
Q......Page 4482
R......Page 4484
S......Page 4498
T......Page 4528
U......Page 4552
V......Page 4556
W......Page 4568
X......Page 4570
Y......Page 4572
Z......Page 4574
A......Page 4581
Б......Page 4583
B......Page 4585
Г......Page 4586
Д......Page 4587
И......Page 4589
К......Page 4590
Л......Page 4593
M......Page 4594
H......Page 4596
O......Page 4598
П......Page 4599
P......Page 4601
C......Page 4602
T......Page 4604
Ф......Page 4606
Ц......Page 4608
Э......Page 4609
Я......Page 4611

Citation preview

·� Martindale

The Complete Drug Reference Thirty-eighth Edition

Volume 1: 1-1120 Volume 2: 1121-2314 Volume 3: 2315-3444 Volume 4: 3445-4596

(RP)

Pharmaceutical Press

·� Martindale

The Complete Drug Reference Thirty-eighth Edition

(RP)

Pharmaceutical Press

Published by Pharmaceutical Press 1 Lambeth High Street, London SE1 7JN, UK ©Pharmaceutical Press 2014

(RP)

is a trade mark of Pharmaceutical Press

Pharmaceutical Press is the publishing division of the Royal Pharmaceutical Society of Great Britain First edition of Martindale: The Extra Pharmacopoeia was published in 1883.

Squire's Companion was incorporated in the twenty-third edition in 1952. Thirty-eighth edition published 2014 Typeset by Data Standards Ltd Printed in Italy by LEGO S.p.A. ISBN 978 0 85711 139 5 ISSN 0263-5364 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, expressed or implied, with regard to the accuracy of the information contained in this book and shall not be liable, so far as is permissible by law, for any claim whether in contract or tort for losses arising out of or in connection with the use of the book The book should be interpreted in light of professional knowledge and supplemented as necessary by specialised publications and product literature. The reader should ensure that the information being used is consistent with normal, generally accepted healthcare practice.

A catalogue record for this book is available from the British Library

Contents Preface

p v

A guide to Martindale Abbreviations

p vi

p ix

Contracted Names for Ions and Groups Atomic Weights of the Elements

p xii

p xiv

Volume A • Monographs on drugs and ancillary substances Analgesics Anti-inflammatory Drugs and Antipyretics Anthelmintics

p 143

Antibacterials

p 168

p 3

p 388

Disinfectants and Preservatives

p 397

Electrolytes

p 458

Antidiabetics

Gases

p 506

Antiepileptics

p 1775

General Anaesthetics

p 1803 p 1896

Antigout Drugs

p 600

Growth Hormone and its Modulators

Antihistamines

p 610

Immunosuppressants

Antimalarials

p 644

Antimigraine Drugs Antineoplastics

Local Anaesthetics p 670

Antiprotozoals Antivirals

Muscle Relaxants

p 691 p 889

p 919

Obstetric Drugs

p 951 p 1028

Blood Products Plasma Expanders and Haemostatics

p 2042

Pharmaceutical Excipients Radiopharmaceuticals

p 2147 p 2163

p 2222

Sex Hormones and their Modulators p 1195

Stimulants and Anorectics

p 1242

Chelators Antidotes and Antagonists Contrast Media

p 1121

p 1167

Bronchodilators and Anti-asthma Drugs Cardiovascular Drugs

p 2028

p 2129

Pesticides and Repellents

Bone Modulating Drugs

p 1999

p 2014

Nutritional Agents and Vitamins

Anxiolytic Sedatives Hypnotics and Antipsychotics

Corticosteroids

p 1976

Neuromuscular Blockers

Antiparkinsonian Drugs

p 1918

p 1932

Miotics Mydriatics and Antiglaucoma Drugs

p 684

Antimyasthenics

p 1681

p 1730

p 1797

Gastrointestinal Drugs

p 563

Antifungals

p 1651

Decongestants

Dermatological Drugs and Sunscreens

Antidementia Drugs Antidepressants

Cough Suppressants Expectorants Mucolytics and Nasal

Thyroid and Antithyroid Drugs p 1537

Urological Drugs

p 1580

p 2332

p 2347

Vaccines Immunoglobulins and Antisera

p 1597

Volume B • Preparations p 2653 • Directory of Manufacturers p 3985 • Pharmaceutical Terms in Various languages • General Index p 4110 • Cyrillic Index p 4566

p 2231

p 2314

p 2373

Miscellaneous Drugs and Other Substances

p 4089

p 2426

iv About the authors

About the authors Martindale is published by the Pharmaceutical Press, the publishing division of the Royal Pharmaceutical Society. Content is created and updated by the Martindale Editorial Team, a group of pharmacists and life science graduates with relevant expertise who are given formal training in literature evaluation and searching techniques, as well as on-the-job training in internal procedures. The Editorial Team is supported by a number of external contributors.

Editor: Editorial Staff:

Alison Brayfield, BPharm, MRPharmS Catherine RM Cadart, BPharm, GradDipHospPharm, MRPharmS Elaina E Crehan, MChem Kathleen Eager, BPharm Elizabeth S Foan, MA (Cantab) Austin C Gibbons, BSc, MSc Chloe SAJ Hatwal, BSc, MRes Sue W Ho, BPharm, MRPharmS Sonia Z Khan, MPharm, PGCertPharmPrac Rebecca E Luckhurst, BSc Jean MacKershan, BSc, PgDip Deirdre McGuirk, BComm, MPharm, MRPharmS Sandra Sutton, BPharm, MSc Med, Cert ProjMngt

Contributors:

Ian A Baxter, B Sc, PhD, MRPharmS Mildred Davis, BA, BSc, PhD, MRPharmS Marian E Fenton, MSc, CMPP Eileen J Laughton, BPharm, PhD, MRPharmS Julie M McGlashan, BPharm, DiplnfSc, MRPharmS Rosalind McLarney, BPharm, MSc Gail C Neathercoat, BSc, MRPharmS Claire H Norton, BSc Priya Patel, MPharm, MRPharmS Sue J Shankie, BPharm, MSc, MRPharmS

Preface

v

Preface Drug information is constantly developing as the use of existing drugs

•

updated reviews on the treatment of acute lymphoblastic leukaemia

grows, new drugs emerge, new preparations are launched, and old

and non-small cell lung cancer, which prototype a new approach to

preparations are abandoned, reformulated, or redefined. The needs of

our treatment reviews •

revised paracetamol nomograms for the treatment of paracetamol

much more than a simple encyclopaedia of medicines. It aims to provide

•

extensive revision of the porphyria abstracts

healthcare professionals with evaluated, unbiased information on drugs

•

expansion of the coverage of proprietary preparations to cover 43

those practising pharmacy and medicine are also changing, and during its

poisoning

long history Martindale has evolved to meet those needs by becoming

and medicines used throughout the world. Our content is also carefully

countries and regions, including China

structured to enable readers to find this information easily and quickly,

The Martindale editorial team have been assisted by many individuals in

whether it is to answer specific questions about drugs or to give a broad

the production of this edition, and it is their valuable contribution that help

overview of pharmaceutical topics. Our readers should note that Martindale is not a book of standards: the

to ensure Martindale's validity. Thanks are due to Lina Bladh, Alessandro Gabbi, Judy van Engeldorp Gastelaars, Spela Godec, Jan Horn, Montserrat

inclusion of a substance or a preparation is not to be considered as a

Jane, Andrius Kairys, Maria Kouimtzi, Carla Oliveira, Kamila Ramesova,

recommendation for use, nor does it confer any status on the substance or

Elsa Simon, Gyongyver So6s, Carina Tukukino, Robert Wasilewski, Larry

preparation and readers are reminded that knowledge and best practice in

Callahan, and Frank Switzer.

this field are constantly changing. While considerable efforts have been

The team have also been able to call on the advice and expertise of other

made to check the material in Martindale, neither the publisher nor the

members of the Royal Pharmaceutical Society's Pharmaceutical Press

authors accept any responsibility for errors and omissions. The publisher

division. In particular, the Editor would like to thank Rachel Ryan and the

and authors make no representation, expressed or implied, that doses are

staff of the British National Formulary, Claire Preston and the staff of

correct for particular purposes and readers should check up to date product

Stockley's Drug Interactions, and Sam Driver and the Science team. Thanks

information, codes of conduct, and safety regulations. The reader is also

are also due to Tamsin Cousins and Linda Paulus, for their patience and

assumed to possess the necessary knowledge to interpret the information

guidance in handling the various aspects of producing a print publication,

It is the responsibility of practitioners to

and to David Granger, Mesfin Mebrate, Karl Parsons, and Ian White, for

determine dosages and treatments for individual patients, taking into

their technical expertise in producing digital and print datasets. We are also

account up to date therapeutic standards, and to take all appropriate safety

grateful for the support of Karen Baxter, Frank Gibson, and Alina Lourie.

that Martindale provides.

The Editor would also like to thank Sean Sweetman, Paul Blake, Gail

precautions. Further details on the basic editorial philosophy behind content creation,

Neathercoat, Anne Parsons, Susan Handy, Fauziah Hashmi, Joanna

as well as guidance on how the data is set out, are provided in the guide to

Humm, Kelli Kalb, Priya Patel, Gerda Viedge, Elizabeth King, and Christine

Martindale section on the next page.

Major changes for the

38TH

Edition

Iskandar. Their input over the years and to this edition has been greatly valued and is not forgotten. Our digital version of Martindale, which is updated quarterly, is available

There have been several changes to this new edition of Martindale, but the

on MedicinesComplete (www. medicinescomplete. com). It maintains the

most striking is its new format. The cover design has been refreshed and, to

familiar layout of the print publication but, as it is not limited in its size,

overcome a common problem, the page layout has been totally re-designed

extra content such as the archive chapter of deleted monographs and

with a new and larger font. This ensures that the page is easier to read as

graphical representations of the chemical structures of many of the drugs

well as making it quicker to find the information the reader is looking for

are also available. For more information about the digital product, please

on the page. Alongside this, and in response to user feedback, the layout of

visit our website.

the monographs has been restructured and readers will now find a monograph's uses at the start of a monograph; knowing how a drug acts

We continue to value our readers' feedback and anyone wishing to contact us may do so at our email address: [email protected]

and is used may help to contextualise any subsequent adverse effects and precautions related to that drug. In addition, a drug's nomenclature information is highlighted within its own shaded text box. To allow for these changes, the chemical structure graphics are no longer reproduced in the print editions of Martindale; however, they remain available on our digital platform, MedicinesComplete. Alongside much of the revalidation work that is undertaken with every edition of Martindale, other changes for this edition include: •

over 200 new monographs including: •

the sodium-glucose co-transporter 2 inhibitors, canagliflozin and dapagliflozin, have been added as a new drug group to the chapter on antidiabetic drugs

•

the antivirals, daclatasvir and sofosbuvir, for use in the management of hepatitis C

•

restructuring of the section on diabetes mellitus management in the antidiabetic drugs chapter, to improve its readability

London, February 2014

to Martindale

vi A

A guide to Martindale Martindale contains information on drugs in clinical use worldwide, as

cover both scheduled revision of the content. and revision of particular

well

points in reaction to new information as it arrives.

as

selected

herbal

and

excipients, vitamins

and

The revision procedure involves the editorial writer re-evaluating

nutritional agents, vaccines, radiopharmaceuticals, contrast media and

standing information, assessing newly-collected references for quality and

diagnostic agents, medicinal gases, drugs of abuse and recreational drugs,

relevance, and searching bibliographic databases and the Internet to

toxic substances, disinfectants, and pesticides.

identify further candidate information.

complementary

investigational

medicines,

and

veterinary

pharmaceutical

drugs,

The information on over 6000 drugs and other substances is arranged

Once the material for new content has been re-evaluated and updated, it

into monographs that contain details on nomenclature, properties, and

is rigorously reviewed by a second editorial writer to ensure not only that

actions. These text sections summarise the relevant information, notably

all changes are valid and appropriate, but also that important points have

for licensed uses, followed, if appropriate, by referenced abstracts or

not been missed.

reviews that expand upon the details given in the text or add additional

The material is then passed to the editor, who performs a final. high-level

information. Multicentre studies, meta-analyses, and systematic reviews

check and approval of the data. This process is designed to ensure

play an important role in the study of drug treatment, and their findings

consistency of approach and style, as well as offering an opportunity to pick

and conclusions are considered in much of our content. However, there is

up any errors that may have been missed. Changes and questions are fed

also a place for the anecdotal report and the small study, and information

back to the writer.

from such sources is included where appropriate. In compiling the text of a

Keying, proof-reading, and dose-checking. Once approved by the

Martindale monograph, use is made of the drug's licensed product

editor, content changes can be made in the database, which has remained

information as published in various countries and approved by the relevant

untouched until this stage as a security measure. These changes are then

regulatory authorities. Acknowledgement is also given to information

proofread for errors, corrected if necessary, and any corrections checked.

referenced from a number of authoritative sources including the British

Extensive electronic testing for spelling, style, and format is also carried out

National Formulary, the British National Formulary for Children, the British

at all stages.

the European Pharmacopoeia, the United States National

Pharmacopoeia,

The amended content then undergoes an independent review of the dose information against its recorded sources. This review is performed by a

Formulary, and the United States Pharmacopeia.

In addition, disease treatment reviews offer overviews of nearly 700

writer not involved in the original content generation process, and is an

diseases and the drugs used in their treatment. along with key references

additional safeguard against the inadvertent introduction of potentially

and guidelines. Cross-references are provided between these treatment

dangerous dose errors. Release. Once past all these stages, the data are cleared for release and

reviews and relevant drug monographs. Preparations summaries of more than 180,000 proprietary products from 43

countries or regions are

included.

Information is

provided on

can be published in the next update of the Martindale digital products; changes to the print version will appear in the next edition.

proprietary name, manufacturer or distributor, country/region of origin,

Additional checks for publication. Some additional checks are made

active ingredients, and a summary of the indications as given by the

before publishing a print edition of Martindale. A second independent dose

manufacturer. Page numbers link ingredients to an appropriate drug

review of all chapters is made by external experts.

monograph where possible.

How the information is arranged

Philosophy and methodology

Martindale is divided into 2 volumes:

Martindale's uses are as varied as its users. However, the primary aims are: •

to summarise clinically useful information on all drugs and medicines

Volume A covers: •

Monographs on drugs and ancillary substances. This section

contains over 6000 monographs arranged in 49 chapters. These

around the world •

to

comprehensive

chapters generally bring together monographs on drugs and groups of

information in a concise format

drugs that have similar uses or actions. The disease treatment reviews,

•

to provide a lead-in to the published evidence base from which we

which provide descriptions of diseases together with reviews of the

provide

accurate,

unbiased,

and

reasonably

choice of treatments, are usually located in the chapter introduction.

derive our information To achieve the above aims, working practices have to be safe and efficient,

The chapter titled Miscellaneous Drugs and Other Substances contains

while making optimum use of available information. This section describes

monographs on drugs not easily classified, herbals, and drugs no longer used clinically but still of interest. There are also monographs

some of these working practices.

on toxic substances, the effects of which may require drug therapy. Volume B includes:

Data collection The team proactively monitor the published literature for potential content

•

provided

and websites of regulatory authorities such as EMA, FDA. Health Canada, other sources

of high-quality systematic

reviews and

are

pharmacopoeial.

governmental.

and WHO

publications,

for

information relating to drugs and drug therapy.

over

180,000

proprietary

includes

the

proprietary

name,

the

manufacturer

or

monographs, and a summary of the indications as given by the •

Directory

of

manufacturers.

In

Martindale

the

names

of

manufacturers and distributors are abbreviated. Their full names are

The list of sources used has been developed over many years by analysis

given in this directory together with contact details if available. Manufacturers'

Licensed product information for 43 countries and regions is evaluated, to maintain the widest possible coverage of drugs in use internationally.

contains

manufacturer.

of previous citations, and is reviewed and updated regularly.

Preparation names, manufacturers, ingredients, and licensed uses are

section

distributor, the active ingredients with cross-references to the drug

guidelines, including the Cochrane library and NICE, are also monitored, as

This

preparations from a range of countries and regions. The information

updates. This involves regularly searching selected major medical journals and MHRA;

Preparations.

records

are

listed

alphabetically.

This

directory

contains over 20,000 entries. •

Pharmaceutical terms in various languages. This index lists

nearly 5600 of the commoner pharmaceutical forms and routes in 13

included in the internal Martindale database for review during the revision

major European languages. It is provided as an aid to the non-native

process.

speaker in interpreting packaging, product information, or prescrip­ tions written in another language.

Editorial processes

•

General index. To make the fullest use of the contents of Martindale

To maintain the quality and currency of

the general index should always be consulted. The exhaustive index,

our content, it is constantly revised and updated. Our revision processes

prepared from over 175,000 entries, including entries for drugs

Write, review, and approve.

A guide to Martindale vii

(approved names, synonyms, and chemical names), preparations,

o

the very nature of their origin they cannot be relied upon for definitive

pharmacological and therapeutic groups, and clinical uses (disease

identification of a substance. The use of such terms changes rapidly, and

treatment reviews). As in previous editions, the index is arranged

can vary between different geographical locations, and any given name

alphabetically 'word-by-word' rather than 'letter-by-letter'. The index

may potentially be applied to more than one substance or even to a

indicates the column in which the relevant entry appears as well as the

mixture of substances. Furthermore, established or well recognised generic

page and in which volume the entry may be found. To improve clarity

drug names or herbal names have sometimes been misused as street terms

and the ease of location of index entries, long chemical names have

for completely unrelated substances. In order to enable the reader to

been omitted from the index.

distinguish them from the better validated synonyms in the index, such

Cyrillic index. Both non-proprietary and proprietary names may be

names are included in italics and in quotation marks.

found in Cyrillic alphabetical order in this section.

The monographs

CAS Registry numbers. Chemical Abstracts Service (CAS) registry

numbers are provided, where available, for each monograph substance to help readers refer to other information systems. Numbers for various forms

Chapters within Martindale are composed of an introduction of varying

of the monograph substance are listed with the variation in form given in

length, and a set of monographs describing individual drugs. Each

parentheses.

monograph begins with its title, synonyms in English and other languages,

ATC codes. Codes from the Anatomical Therapeutic Chemical (ATC)

identificatory codes, and chemical and pharmaceutical information about

classification system (see http://www.whocc.no) have been provided,

the compound, including any pharmacopoeial standards. This is followed

where available, for each monograph substance to help readers refer to

by one or more sections describing pharmacological and therapeutic

other

information about the drug or substance. A typical monograph includes:

classification system for veterinary medicines (ATC Vet-see http://www.

information systems. The

codes assigned in

the

equivalent

o

Nomenclature

whocc.no/atcvet) and herbal medicines have been included where

o

Uses and Administration

possible.

o

Adverse Effects

o

Treatment of Adverse Effects

o

Precautions

where available. Numbers for various forms of the monograph or related

o

Interactions

substances are listed with the variation in form given in parentheses.

o

Pharmacokinetics

UNIT codes. The unique ingredient identifiers, which are generated by

the joint FDA/USP Substance Registration System have been provided,

Atomic and molecular weights. Atomic weights are based on the

Sections begin with unreferenced summary text, based on licensed product

table of Atomic Weights as revised in 2011 by the Commission on Isotopic

information and other high-quality validated sources. This may optionally

Abundances and Atomic Weights, International Union of Pure and Applied

be followed by abstracts or referenced text expanding on particular points,

Chemistry (IUPAC) and based on the 12C scale (see p. xiv). Molecular

and providing a lead-in to the published literature from which we derive

weights are given corrected to one place of decimals or to four significant

our information.

figures for relative weights of less than 100.

Lists of single and multi-ingredient proprietary and non-proprietary preparations are given at the end of each monograph.

Pharmacopoeias The selected pharmacopoeias in which each substance appears are listed. A

Nomenclature

description of the substance and a summary of the pharmaceutical

The nomenclature section of each monograph may include the following

information that appears in the British, European, or US Pharmacopoeias is

information:

also included. Current copies of the pharmacopoeias and their addenda

Titles and synonyms. The title of each monograph is in English, with

should be consulted for confirmation and for details of standards.

preference usually being given to International Nonproprietary Names

The pharmacopoeias covered include British, British Veterinary, Chinese,

(INN), British Approved Names (BAN), and United States Adopted Names

European, French, German, International, Italian, Japanese, Polish, Spanish,

(USAN). These 3 authorities are shown where appropriate. A European

Swiss, United States (including the National Formulary), and Vietnamese. The

Directive (92/27/EEC) requires the use of Recommended International

abbreviations for these pharmacopoeias are included in the list of

Nonproprietary Names (riNNs) in the labelling of medicinal products

abbreviations used in Martindale (see p. ix), which also includes details of

throughout member states of the European Union and where the BAN and

the edition and/or supplement(s) consulted.

INN differed in the past the BAN has been changed to accord with the riNN.

Several countries are parties to the Convention on the Elaboration of a

The major exception to this convention is the retention of the names

European Pharmacopoeia. This means that they must adopt the standards

adrenaline and noradrenaline, these being the terms used as the titles of

of the European Pharmacopoeia. These countries are currently Austria,

the monographs in the European Pharmacopoeia and therefore the official

Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, the Czech

names in the member states. In some approved names it is general policy to

Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary,

use 'f' for 'ph' in sulpha, 't' for 'th', and 'i' for 'y'; for this reason entries in

Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro,

alphabetical lists should be sought in alternative spellings if the expected

the Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak

spellings are not found. Inevitably there may be some inconsistencies of

Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, Ukraine, the

style with older approved names but wherever possible the names used for

United Kingdom, the Former Yugoslav Republic of Macedonia, and the

drugs or radicals in Martindale have been altered in accordance with the

European Union. Hence the European Pharmacopoeia is cited in the drug

guidelines on the use of INNs for pharmaceutical substances. For a table of

monograph lists of pharmacopoeias rather than these individual national

contracted names for ions and groups used in approved names and titles

pharmacopoeias.

see p. xii. This section also includes names given as synonyms such as commonly

Official preparations, mainly from the current British, European, and US Pharmacopoeias, are listed at the end of drug monographs.

used abbreviated names; Latin versions of the titles in the European Pharmacopoeia; English, American, Spanish, and Latin synonyms; names

Pharmaceutical information

used in other languages when these may not be readily identifiable;

Information on the chemical and physical properties of each substance is

manufacturers' code numbers; and chemical names. BAN names for

given when it is likely to be of use or interest, but only when it is certain

substance combinations and United States Pharmacy Equivalent Names

that it applies to the form of substance being described in the monograph.

(PEN) for dosage forms containing two or more active ingredients are given

Percentage strengths. Unless otherwise stated, solutions of solids in

in the text of the relevant monographs; these names start with the prefix

liquids are expressed as percentage w/v, of liquids in liquids as percentage

'Co-'.

v/v, and of gases in liquids as percentage w/w.

Official titles and synonyms used in the British, European, and US

Solubility. The figures given for solubility in each monograph have

Pharmacopoeias are given in the section on pharmacopoeias where the

generally been obtained from the major pharmacopoeias in which the

relevant pharmacopoeial substance is described.

substance is described, but should not be considered absolute. Unless

Street Names. Street terms and other slang names for drugs of abuse

are included for guidance only and should be used with caution. Because of

otherwise

indicated

in

the

text,

the

figures

are

for

solubility

at

temperatures between 15 degrees and 25 degrees. The information

viii A guide to Martindale

usually relates to w/v solubilities but in some cases is v/v if the monograph

information has been included to help determine the safety of continuing

substance itself is a liquid. Where solubilities are given in words, the

to breast feed while the mother is receiving a particular drug. Safety during

following terms describe the indicated solubility ranges:

breast feeding should not be inferred from the absence of a statement for

•

very soluble:

1 in less than 1

•

freely soluble:

1 in 1 to 1 in 10

•

soluble:

1 in 10 to 1 in 30

•

sparingly soluble:

1 in 30 to 1 in 100

the doses represent the average range of quantities that are generally

•

slightly soluble:

1 in 100 to 1 in 1000

regarded as suitable for adults when given orally. More information on

any drug. Doses. Doses are described under the Uses and Administration heading

with as much detail as is necessary and available. Unless otherwise stated

•

very slightly soluble:

1 in 1000 to 1 in 10,000

doses and drug administration may be given in the abstracts or reviews.

•

practically insoluble:

1 in more than 10,000

Unless otherwise specified,. glucose injection is 5% w/v and sodium

Storage. Substances and preparations should be stored under conditions

chloride injection is 0.9% w/v.

that prevent contamination and diminish deterioration, and the conditions

When doses for children are expressed as a range of quantities within

of storage given in the text indicate the precautions recommended in

specified age limits, the lower dose applies at the lower age and the higher

specific cases. The term 'a cool place' is generally used to describe a place in

dose at the higher age.

which the temperature is between 8 degrees and 15 degrees. In general, the storage conditions apply to the monograph substance and not its solutions or preparations. Temperature.

Temperatures

are

expressed

in

degrees

Celsius

The Preparations This part of Martindale contains brief details of proprietary preparations available in a number of countries or regions and includes those supplied

(centigrade) unless otherwise indicated.

on prescription as well as those sold directly to the public. They are

Drugs in Sport

provided to help the reader identify preparations and to suggest their uses.

Wherever possible we have attempted to indicate those drugs and

Inclusion is not an endorsement of the activity of any ingredient, nor of the

substances that may be subject to restriction in some or all sports, either in

preparation's indications.

their own right, or because they are a derivative of a restricted substance or

For this edition we have covered Argentina, Australia, Austria, Belgium,

a member of a prohibited group. Proprietary preparations containing such

Brazil, Canada, Chile, China, the Czech Republic, Denmark, Finland,

compounds are also marked in the preparation section. The guide used for

France, Germany, Greece, Hong Kong, Hungary, India, Indonesia, Ireland,

identifying restricted drugs is the Prohibited List issued by the World Anti­

Israel, Italy, Japan, Malaysia, Mexico, the Netherlands, New Zealand,

Doping Agency (WADA-see www.wada-ama.org). These regulations,

Norway, Philippines, Poland, Portugal, Russia, Singapore, South Africa,

which are issued annually, are subject to interpretation and therapeutic

Spain, Sweden, Switzerland, Thailand, Turkey, Ukraine, the United Arab

particular sporting

Emirates, UK, USA, and Venezuela. Generally, each entry consists of the

authorities may also issue additional restrictions, and competitors should

proprietary name, the manufacturer or distributor and country, the active

always check with the appropriate body. The rules are constantly evolving

ingredients

and the absence of any indication of restriction in Martindale should not be

manufacturer. Where possible, entries from different countries but with

exemption, and may vary from sport to sport;

and

a

summary

of

the

indications

as

given

by

the

taken as absolute confirmation that the substance may legitimately be

the same name and active ingredients have been amalgamated for clarity.

taken by a competitor.

Instances where a preparation name has been used for preparations with

Pharmacological and therapeutic information

be for actively marketed preparations or for preparations that have been

Information on uses and administration, adverse effects, treatment of

withdrawn from the market.

significantly different ingredients have been highlighted. Such names may

adverse effects, precautions (including contra-indications), interactions,

An entry may cover a range of dosage forms and strengths. Dosage forms

and pharmacokinetics of each substance is provided by concise statements

are only specified when different forms have the same proprietary name

and these may be elaborated and expanded by referenced reviews and

but different active ingredients. Furthermore, this section is not intended

abstracts from papers and other publications. This edition contains nearly

as a guide to prescribing; where a preparation is to be supplied the dose

14,000 such abstracts or reviews based on information in an ever widening

should be appropriate for that preparation and that particular patient, and

range of publications.

authoritative local sources should be consulted.

An increasing amount of information is published digitally and this

With the exception of homoeopathic preparations the names of the

material is available on the Internet as web pages. Because of the nature of

ingredients have been translated into English. Almost all the ingredients

the Internet, there is no way to guarantee that the material referred to by a

listed are described in the monographs in Drugs and Ancillary Substances,

URL will remain at that location, as many sites are subject to periodic

and readers are directed to an appropriate monograph by the page numbers

reorganisation; additionally, the content of Internet documents may

provided after the ingredient.

change without warning. The accession date given in the citation

Preparations that have been withdrawn from the market in the last few

represents the last date on which the content of the document referred to

years or are no longer being actively marketed may be identified by the

was revalidated.

symbol t. These preparations are retained in Martindale since they may

Much information has been found in sources such as WHO publications,

still be in circulation or their names may still be referred to in the literature

government reports and legislation, and other official and standard

and in practice. Readers should be aware that since this section was

publications. Licensed product information and manufacturers' literature

prepared other preparations are likely to have been withdrawn or

have been considered in the light of other available information.

introduced; also ingredients may change, as may indications.

The risks of administering drugs in pregnancy are well known and the general principle is to give a drug only when the benefit to the individual

The manufacturer's full name and contact details can be found in the Directory of Manufacturers.

mother outweighs the risk to the fetus. Where there is a clear risk it is noted

Each preparation title is listed in the General Index. Where thought

under the Precautions or Adverse Effects heading but safety should not be

helpful, preparation titles have been listed at the end of the relevant

inferred from the absence of a statement for any drug. Some drugs given to the mother are distributed into breast milk and therefore may pose a risk to a breast-fed infant. Whenever possible,

monograph. However, it should be noted that the absence of such a list at the end of a monograph is no indication as to the availability of a substance as many drugs are marketed as generic or unbranded preparations.

Abbreviations For abbreviations of the names of manufacturers or their distributors, see Directory of Manufacturers, in Volume B.

d e-German. d.c.-direct current. DEFRA-Department for Environment, Food, and Rural Affairs (UK).

ACE-angiotensin-converting enzyme.

Denm.-Denmark.

ADHD-attention deficit hyperactivity disorder.

DHSS-the former Department of Health and Social Security (UK).

agg.-aggregate (in botanical names), including 2 or more species which

dL--decilitre(s).

resemble each other closely. AIDS-acquired immunodeficiency syndrome.

a.m.-ante meridiem, 'before noon'. ARC-AIDS-related complex. Arg.-Argentina. ATC-Anatomical Therapeutic Chemical classification. AUC-area under the concentration-time curve. Austrai.-Australia. AV-atrioventricular. BAN-British Approved Name. BANM-British Approved Name Modified. Belg.-Belgium. BMA-British Medical Association. BMI-body mass index. BNF-British National Formulary. BNFC-British National Formulary for Children. b.p.-boiling point. BP-British Pharmacopoeia. Unless otherwise specified, BP references are to the 2014 edition. BP(Vet)-British Pharmacopoeia (Veterinary) 2014. BPC-British Pharmaceutical Codex. Br.-British. Braz.-Brazil. Bulg.-Bulgaria. BUN-Blood-urea-nitrogen. °C-degrees Celsius (centigrade). Unless otherwise indicated in the text, temperatures are expressed in this thermometric scale. Canad.-Canada. CAPO-continuous ambulatory peritoneal dialysis. CAS-Chemical Abstracts Service. CCPD-continuous cycle peritoneal dialysis. CDC-Centers for Disease Control and Prevention (USA) (formerly Centers for Disease Control). Chin. P.-Chinese Pharmacopoeia 2005. CHM-Commission on Human Medicines (UK). CI-Colour Index. CMV-cytomegalovirus. CNS-central nervous system. cP-centipoise(s). CPMP-Committee on Proprietary Medicinal Products of the European Union. cs-Czech. CSF-cerebrospinal fluid. CSM-Committee on Safety of Medicines (UK) (now subsumed within the

DNA-deoxyribonucleic acid. DoH-Department of Health (UK). DTF-Drug Tariff Formulary. ECG-electrocardiogram. ECT -electroconvulsive therapy. £cuad.-Ecuador. ed.-editor(s)

or edited by or edition.

EEC-European Economic Community, now the European Union. EEG-electro-encephalogram.

e.g.---exempli gratia 'for example'. ei-Greek. EMAIEMEA-European Medicines Agency. ENL-erythema nodosum leprosum. es-Spanish. ESRD-end-stage renal disease. et a l. -et

alii, 'and others': for three or more co-authors or co-workers.

et seq.-and what follows. £U-European Union. E:ur. P.-see Ph. Eur. Ext. D & C--designation applied in USA to dyes permitted for use in external drug and cosmetic preparations. 0f-degrees Fahrenheit. FAC-Food Additives and Contaminants Committee of the former Ministry of Agriculture, Fisheries and Food (UK). FAO-Food and Agriculture Organization of the United Nations. FAO/WHO-Food and Agriculture Organization of the United Nations

and the World Health Organization. FDA-Food and Drug Administration of USA. fdAC-Food Advisory Committee of the former Ministry of Agriculture, Fisheries and Food (UK). FD & C-designation applied in USA to dyes permitted for use in foods, drugs, and cosmetics. FEV 1-forced expiratory volume in I second. Fin.-Finland. FIP-Federation Intemationale Pharmaceutique. f.p.-freezing point. FPA-Family Planning Association (UK). fr-French. Fr.-France.

e

Fr. P.-French Pharmacopoeia 198 2 (Pharmacopee Francaise, X Edition) and updates up to 2003. g-gram(s). Ger.-Germany.

Commission on Human Medicines).

Ger. P.- German Pharmacopoeia (Deutsches Arzneibuch, 2007).

cSt-centistokes.

GFR-glomerular filtration rate.

Cz.-Czech Republic.

G6PD-glucose-6-phosphate dehydrogenase.

D & C--designation applied in USA to dyes permitted for use in drugs and

Gr.-Greece.

cosmetics.

HAART-highly active antiretroviral therapy.

Hb- haemoglobin.

ml-millilitre(s).

Hib-Haemophilus injluenzae type b.

mm-millimetre(s). 2 mm -square millimetre(s). 3 mm -cubic millimetre(s).

HIV-human immunodeficiency virus. HLA-human lymphocyte antigens. HLB-hydrophilic-lipophilic balance.

mmHg-millimetre(s) of mercury.

HRT-hormone replacement therapy.

mmol-millimole.

HSE-Health and Safety Executive (UK).

mol-mole.

hu-Hungarian.

mol. wt-molecular weight.

Hung.-Hungary.

Mon.-Monaco.

IARC-International Agency for Research on Cancer.

mosmol-milliosmole.

ibid.-ibidem, 'in the same place (journal or book)'.

m.p.-melting point.

idem-'the same': used for the same authors and titles.

MRC-Medical Research Council (UK).

i.e .-id

MRSA-meticillin-resistant

est, 'that is'.

lg-immunoglobulin.

Staphylococcus aureus.

J,!g-microgram(s).

lndon.-Indonesia.

J.Im-micrometre(s).

INN-International Nonproprietary Name.

N-normal.

INNM-International Nonproprietary Name Modified.

n.b.-nota bene, note carefully.

Int. P.-International Pharmacopoeia 4th ed., 2006, and Supplement 1,

Neth.-The Netherlands.

2008.

NICE-National Institute for Health and Clinical Excellence (formerly the

IPCS-International Programme on Chemical Safety.

National Institute for Clinical Excellence) (UK).

IQ-intelligence quotient.

NIH-National Institutes of Health (USA).

lri.-Ireland.

ni-Dutch.

ISH-International Society of Hypertension.

nm-nanometre(s).

it-Italian.

NMDA-N-methyl-D-aspartate.

lt. P.-Jtalian Pharmacopoeia 11th ed., 2002 (Farmacopea Ufficiale della

NNRTI-non-nucleoside reverse transcriptase inhibitor.

Repubblica Italiana, XI Edizione, 2002).

Norw.-Norway.

ltai.-Italy.

NRTI-nucleoside reverse transcriptase inhibitor.

IUD-intra-uterine device.

NSAID-nonsteroidal anti-inflammatory drug.

IUPAC-International Union of Pure and Applied Chemistry.

NYHA-New York Heart Association.

IVF-in- vitro fertilisation.

NZ-New Zealand.

J-joule(s).

OP-over proof.

Jpn-Japan.

o/w-oil-in-water.

Jpn P.-The Pharmacopoeia of Japan, 15th ed., 2006 and Supplement I .

P-probability.

K-kelvin.

Pa-pascal(s).

kcal-kilocalorie(s).

Pak.-Pakistan.

kg-kilogram(s).

pC02-plasma partial pressure (concentration) of carbon dioxide.

kJ-kilojoule(s).

PaC02-arterial plasma partial pressure (concentration) of carbon dioxide.

lb-pound(s) avoirdupois.

PEN-Pharmacy Equivalent Name, see page vi.

LDSO-a dose lethal to 5 0% of the specified animals or micro-organisms.

pg-picogram(s).

Lf-limes flocculation.

pH-the negative logarithm of the hydrogen ion concentration.

lt-Lithuanian.

Ph. Eur.-European Pharmacopoeia, 8th ed., 2014.

m-metre(s). 2 m -square metre(s). 3 m -cubic metre(s).

Report.

M-molar.

PHLS-Public Health Laboratory Service (UK).

MAFF-the former Ministry of Agriculture, Fisheries and Food (UK), now

piNN-Proposed International Nonproprietary Name.

Department of Environment, Food, and Rural Affairs (DEFRA).

piNNM-Proposed International Nonproprietary Name Modified.

Pharm. Soc. Lab. Rep.-Royal Pharmaceutical Society's Laboratory Philipp.-Philippines.

MAOI-monoamine oxidase inhibitor.

pKa-the negative logarithm of the dissociation constant.

max.-maximum.

pi-Polish.

MBC-minimum bactericidal concentration.

p.m.-post meridiem, 'afternoon'.

MCA-Medicines Control Agency, now MHRA (UK).

p02-plasma partial pressure (concentration) of oxygen.

mEq-milliequivalent(s). Mex.-Mexico.

Pa02-arterial plasma partial pressure (concentration) of oxygen. Poi.-Poland.

mg-milligram(s).

Pol. P.-Polish Pharmacopoeia 6th ed., 2002 (Farmakopea Polska VI, 2002)

MHRA-Medicines and Healthcare products Regulatory Agency (UK).

and Supplement 2005.

MIC-minimum inhibitory concentration.

Port.-Portugal.

min-minute.

ppm-parts per million.

min.-minimum.

PSGB-The Pharmaceutical Society of Great Britain. Now the Royal

MJ-megajoule(s).

Pharmaceutical Society.

Abbrevi ations xi pt-Portuguese.

Switz.-Switzerland.

PUVA-psoralen with UVA light irradiation.

Thai.-Thailand.

PVC-polyvinyl chloride.

TNF-tumour necrosis factor.

RCGP-Royal College of General Practitioners (UK).

THM-traditional herbal medicine.

RIMA-reversible inhibitor of monoamine oxidase type A.

THMP-traditional herbal medicinal product.

riNN-Recommended International Nonproprietary Name.

TPN-total parenteral nutrition.

riNNM-Recommended International Nonproprietary Name Modified.

Turk.-Turkey.

RNA-ribonucleic acid. RPSGB-The Royal Pharmaceutical Society of Great Britain. Now the Royal Pharmaceutical Society

•

RSV-respiratory syncytial virus. Rus.-Russia. SGOT -serum glutamic oxaloacetic transaminase (serum aspartate amino­ now

Ukr.-Ukraine. UNICEF-United Nations Children's Fund. UP-under proof.

S. Afr.-South Africa. transferase

UAE-United Arab Emirates. UK-United Kingdom.

preferred).

Urug.-Uruguay. US and USA-United States of America.

SGPT -serum glutamic pyruvic transaminase (serum alanine amino­

USAN-United States Adopted Name.

transferase

USNF-The United States 'National Formulary 31',2013.

now

preferred).

51-Statutory Instrument

or SysU:me International d'Unites (International

System of Units). sic-written exactly as it appears in the original. SLE-systemic lupus erythematosus. sp.-species (plural spp.). sp. gr.-specific gravity. Span.-Spanish. Span. P.-Spanish Pharmacopoeia 2nd ed., 2002 (Real Farmacopoea Espanola,Segunda Edici6n,2002) and Supplement 2.1. SSRI-selective serotonin reuptake inhibitor. St-stokes. subsp.-subspecies. suppl-supplement(s).

USP-The United States Pharmacopeia 36,2013. UV-ultraviolet. var.-variety. Venez.-Venezuela. Viet.-Vietnamese. Viet. P.-Vietnamese Pharmacopoeia 2002 (Pharmacopoeia Vietnamica, Editio III). vol.-volume(s). v/v-volume in volume. v/w-volume in weight. WHO-World Health Organization. w/o-water-in-oil.

sv-Swedish.

wt-weight.

Swed.-Sweden.

wt p er mL-weight per millilitre.

Swiss

P.-Swiss Pharmacopoeia 2006 (Pharmacopoea Helvetica, 10

Ausgabe,Deutsche Ausgabe).

w/v-weight in volume. w/w-weight in weight.

xii Contracted Names for Ions and

Contracted Names for Ions and Groups Contracted Name

Chemical Name

Contracted Name

Chemical Name

(2_E)-b ____________ _ _-e_n_ed _ io _ .:c.yI_ __ _ ' '_'_ _ u_t-2 _ _ ______ �

acefurate

acetate (ester) and furan-2-carboxylate (ester)

il crosfumar_

aceglumate

rae-hydrogen N-acetylglutmate

cyclamate

cyclohexylsulfarnate

aceponate

acetate (ester) and propionate (ester)

daloxate

acetonide

isopropylidenedioxy or propane-2,2-diylbis(oxy)

L-a1aninate (ester) and (5-methyl-2-oxo-1,3-di­ oxol-4-yl)methyl

aceturate

N-acetylglycinate

daropate (dapropate)

N,N-dimethyl-P-alaninate or 3-(dimethylamino)pro­ panoate

deanil

2-(dimethy1amino)ethyl

acibutate

acetate (ester) and 2-methylpropanoate (ester)

acistrate

acetate (ester) and stearate (salt)

decil

decyl

acoxil

acetoxymethyl or (acetyloxy)methyl

defalan

des-!B-L-phenylalanine-insulin

alfoscerate

(2R)-2,3-dihydroxypropyl hydrogen phosphate

alideximer

poly([oxy(2-hydroxyethane- l ,1-diyl)]{oxy[1(hydroxymethyl)ethane-1,2-diyl]}) partly a­ etherified with carboxymethyl groups with some carboxy groups amide linked to the tetrapeptide residue (glyglyglycyl-L-phenyla­ lanylglycyl)

amsonate

4,4r -diaminostilbene-2,2'-disulfonate or 2,2'­ ethene-1 ,2-diylbis(5-aminobenzene-1-sul­ fonate)

anisatil

2-(4-methoxyphenyl)-2-oxoethyl or p-methoxy­ phenacyl

arbamel

2-(dimethylamino)-2-oxoethyl N,N-dimethylglycolamide

argine

30Ba-L-argine-30Bp-L-argine

or

ester

with

aritox

ricin A chain-MAB immunotoxine

aspart

28B-L-aspartic acid-

axetil

(RS)-1-acetoxyethyl or rac-1-(acetyloxy)ethyl

beloxil

benzyloxy

benetonide

N-benzoyl-2-methyl-P-alanine (ester) and ace­ tonide

besilate (besylate)

benzenesulfonate

tetradecanoyl 2,6-di-tert-butylnaphthalene-1,5-disulfonate

dibunate

2,6-di-tert-butylnaphthalene-1-sulfonate

dicibate

dicyclohexylmethyl carbonate

diftitox

N-L-methionyl-387-L-histidine-388-L-alanine-1388-toxin (Corynebacterium diphtheriae strain C7) (388->2')-protein

digolil

2-(2-hydroxyethoxy)ethyl

diolamine

2,2'-azanediyldiethanol or diethanolamine

docosil

docosyl

_ _______________:______________ .:::..: .:: = ::..:: dofosfate

octadecyl hydrogen phosphate

ecamate

N-ethylcarbamate

edamine

ethane-1,2-diarnine or ethylenediamine

edeta_t �e �

e_th�y�len _____________ _ _ e.'dia _ _m_in _ e_ _�-'-'-'-'w_c_te_tr_a_-ac _ _ e_ta_te_ _______

edisilate (edisylate)

ethane-] ,2-disulfonate

embonate

4,4'-methylenebis(3-hydroxynaphthalene-2-car­ boxylate) or 4,4'-methylenebis(3-hydroxy-2naphthoate) ("'J)amoate)

emtansine

betadex

P-cyclodextrin

bezomil

(benzoyloxy)methyl

buciclate

trans-4-butylcyclohexanecarboxylate

bunapsilate

3,7-di-tert-butylnaphthalene-1,5-disulfonate

buteprate

butyrate (ester) and propionate (ester)

camsilate (camsylate)

camphor-10-sulfonate or (7,7-dimethyl-2-oxo­ bicyclo[2.2.l]heptan-l-yl)methanesulfonate

caproate

hexanoate

carbesilate

4-sulfobenzoate

ciclotate (cyclotate)

detemir dibudinate

4-methylbicyclo[2.2.2]oct-2-ene-1-carboxy1ate

cilexetil

(RS)-1-{[(cyclohexyloxy)carbonyl]oxy}ethyl or rac-1-{[(cyclohexyloxy)carbonyl]oxy}ethyl

cipionate (cypionate)

cyclopentanepropionate panoate

or

3-cyclopenty1pro­

4-({3-[(3-{[(IS)-2-{[(IS,2R,3S,5S,6S,16£,18£,20R,21S)- l l -chloro-21-hydroxy-12,20dimethoxy-2,5,9,16-tetramethyl-8 ,23-dioxo4 , 2 4 - d i o x a- 9, 22 - d i a z a t e t r a c y c l o [ 1 9.3 . I . 11 o,1403•5] h e x a c o s a I 0,12,14(26),16,18-pentaen-6-yl]oxy}-!-me­ thy1-2-oxoethyl]methylamino} -3 -oxopro­ p y l ) s u l f a n y l ] - 2 , 5 - d i o x o p y r r o li d i n - 1 yl}methyl)cyclohexylcarbonyle

enantate (enanthate)

heptanoate

enbutate

acetate (ester) and butanoate (ester)

epolamine

1-pyrrolidineethanol or 2-(pyrrolidin-1-yl)etha­ nol

erbumine

tert-butylarnine or 2-methylpropan-2-amine

esilate (esylate)

ethanesulfonate

estolate

propanoate (ester) and dodecyl sulfate (salt) or propionate dodecyl sulfate

etabonate

(ethoxycarbonyl)oxy (�ethyl carbonate)

etilsulfate

ethyl sulfate

cituxetan

rac-N-(4-{2-[bis(carboxymethy1)amino]-3-({2[ b i s ( c a r b o x y m e t h y l ) a m i n o] e t h y l }( c a r ­ boxymethyl)amino )propyl} phenyl)thiocar­ bamoyl

farnesil

(2E,6E)-3,7,11-trimethyldodeca-2,6,I0-trien-1yl

fendizoate

2-(6-hydroxybiphenyl-3-carbonyl)benzoate

clofibrol

2-(4-chlorophenoxy)-2-methylpropyl

fostedate

tetradecyl hydrogen phosphate

closilate (closylate)

4-chlorobenzene-1-sulfonate

furetonide

crobefate

rae-{3-[(3£)-4-methoxybenzylidene]-2-(4-meth­ oxyphenyl)chroman-6-yl phosphate(2-)}

1-benzofurane-2-carboxylate (ester) and pro­ pane-2,2-diylbis(oxy)

gamolenate

(6Z,9Z,122)-octadeca-6,9,12-trienoate

cromacate

2-[(6-hydroxy-4-methyl-2-oxo-2H-chromen-7yl)oxy]acetate

glargine

21A-glycine-308a-L-arginine-308P-L-arginine

6,7-dihydroxycoumarin-4-methanesulfonate or (6,7-dihydroxy-2-oxo-2H-chromen-4yl)methanesulfonate

gluceptate

cromesilate

o-glycera-o-gulo-heptanoate gulo-heptonate

is_in_e lu g-' ., _l_

or

o-glycero-D-

[3 ci _ _ly _ _,g:._lu-'tam _ d_ :_l _ _ 8_ -L_ ic _____________ _ . _ B_ _ L"-s_in_e_:.,29 _a_

____ _

Contracted Names for Ions and

XI I I

Contracted Name

Chemical Name

Contracted Name

Chem1cal Name

glutamer

glutaraldehyde polymer

pivalate

2,2-dimethylpropanoate (ester) or trimethylace­ tate

pivoxetil

rae-!-[(2-methoxy-2-methylpropanoyl)oxy]ethyl or 1-(2-methoxy-2-methylpropionyloxy)ethyl

guacil

2-methoxyphenyl

hemisuccinate

hydrogen butanedioate

hexacetonide

3,3-dimethylbutanoate (ester) and propan-2,2diylbis(oxy) or 3,3-dimethylbutyrate (ester) and acetonide

pivoxil

hibenzate (hybenzate)

2-(4-hydroxybenzoyl)benzoate

poliglumex

[poly(L-glutamic acid)z-(L-glutarnate-y-ester) -poly(L-glutamic acid)yln

hyclate

monohydrochloride drate

probutate

hydroxynaphtoate

3-hydroxynapthalene-2-carboxylate

17-(1-oxobutoxy) (ester) and 21-(1-oxopro­ poxy) (ester) or propionate (ester) and bu­ tyrate (ester)

isetionate (isethionate)

2-hydroxyethane-1-su1fonate

proxetil

1-[(isopropoxycarbonyl)oxy]ethyl or rac- 1 p_ [(� pr_o� an_-2-yloxy)carbonyl]oxy}ethyl {_

laurate

dodecanoate

lauril

dodecy1

hemi-ethanolate

laurilsulfate (lauryl sulphate)

dodecyl sulfate

lisetil

L-lysinate (ester) and diethyl (ester)

hemihy­

{N-[(5S)-5-carboxy-5-(3a,7a, l 2a-trihydroxy5 f3-cho1an-24-amido )penty1]carbamothio­ y1}amino

lisicol

lispro

288 -L-lysine-298 -L-proline

mafenatox

enterotoxin A (227-alanine) (Staphylococcus

aureus)

(2,2-dimethyl-1-oxopropoxy)methyl or [(2,2dimethylpropanoyl)oxy]methyl or (pivaloyl­ oxy)methyl

_________________

(2S,4R,6R,8S,11S,13S)-2,4,8,13-tetrakis(hyd r o x y m e t h y l ) - 4 , 6 , 11 - t r i s ( y l o m e t h y l ) 3,5,7, I 0,12-pentaoxatetradecane-1,14-diyl

raffimer

ic sa _e _t _l_ _,y'--la _

_2-hydroxybenzoate _ __________ __ _ (9Z)-octadec-9-enoate(1.5)

sesquioleate soproxil

{[(propan-2-yloxy)carbonyl] oxy}methyl

steaglate

2-(octadecanoyloxy)acetate (ester)

stearate

octadecanoate

stinoprate

N-acetylcysteinate (salt) and propanoate (ester) 3-carboxypropanoyl

medoxomil

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl

succinil

megallate

3,4,5-trimethoxybenzoate

sudotox

meglumine

N-methylglucamine

248-L-histidine-249-L-methionine-250-L­ alanine-251-L-glutarnic acid-248-613-endo­ toxin A (Pseudomonas aeruginosa reduced)

merpentan

4,5-bis(2-mercaptoacetarnido) valerie acid or {N,N'-[1-(3-oxopropyl)ethane-1,2-diyl]bis(2sulfanylacetamidato)}(4-)

suleptanate

monosodium 8-[methyl(2-sulfoethyl)amino)-8oxooctanoate or monosodium 7-[methyl(2sulfonatomethyl)carbamoyl)heptanoyl

mertansine

tetrakis {(4RS)-4[(3-{[( lS)-2{[(1 S,2R,3S,5S,6S, 16£, 18£,20R,21S)- l l ­ chloro-21-hydroxy-12,20-dimethoxy2,5,9,16-telramethyl-8,23-dioxo-4 24-dioxa9,22-diazatetracyclo[l 9,3. 1.110•14 0 l ,s]hexaco­ sa- l 0, 12,14(26),16,18-pentaen-6-yl]oxy}-1methy 1-oxoethyl] methylamino} -3 -oxopro­ pyl)disulfanyl]pentanoyl}

sulfoxylate

sulfinomethyl, monosodium salt

mesilate (mesylate)

methanesulfonate

metembonate

4,4'-methylenebis(3-methoxynaphthalene-2-car­ boxylate)

methonitrate

N-methyl, nitrate (salt)

metilsulfate

methyl sulfate

metiodide

N-methyl, iodide (salt)

id lb m _ _m _o _r _h _e _cy_ _t _e _

tartrate

_en_ terotoxin A (Staphylococcus aureus) ________ __ ____ _ (2R,3R)-2,3-dihydroxybutanedioate tert-butylacetate or 3,3-dimethylbutyrate

tebutate te e _ _o _a _t_ _n

th_i___, ophene-2-c_arb _ _ o_x_,_yla _ _te ________ ______________ _

teoclate

8-chloro-1,3-dimethyl-2,6-dioxo-3,6-dihydro1 H-purin-7-(2H)-ide or 8-chlorotheophyllin­ ate

teprosilate

3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro7H-purin-7-yl)propane-1-sulfonate

tidoxil

rac-2-(decyloxy)-3-(dodecylsulfany!)propyl

tiuxetan

N-(4-{(2S)-2-[bis(carboxymethyl)amino)-3[ (2RS)- {2-[bis( carboxymethyl )amino ] pro­ pyl} ( carboxymethyl)amino ) propy 1} phenyl) thiocarbamoyl

tocoferil

rac-(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12trimethyltridecyl]chroman-6-yl

tofesilate

3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro7H-purin-7-yl)ethane-_ l_ - su te ____ _ _ lfo _ _n_a_ _

tosilate (tosylate)

4-methylbenzene-1-sulfonate or toluene-4-sul­ fonate

2-aminoethanol or ethanolamine

triclofenate

2,4,5-trichlorophenolate

N_-_m ethyl, bromide (salt) _ __ _____ _____

mofetil

2-(morpholino)ethyl or 2-(morpholin-4-yl)ethyl

napadisilate

naphthalene-!,5-disulfonate

napsilate (napsylate)

naphthalene-2-sulfonate

nicotinate

pyridine-3-carboxylate

octil

octyl

olamine

to ta�e_ a_ n_ _x ___

------

oleate

(9Z)-octadec-9-enoate

triflutate

trifluoroacetate

oxoglurate

hydrogen 2-oxopentanedloate

trioleate

hexadecanoate

(9Z)-octadec-9-enoate(3) or tris[(9Z)-octadec-9enoate]

palmitate pamoate

4,4' -methylenebis(3-hydroxy-2-naphthoate) (�embonate)

pegol

a-(2-carboxyethyl)-ro-methoxypoly(oxyethane1,2-diyl)

troxundate

pendetide

1'1'-{N-[2-({2-[bis(carboxymethyl)arnino )-

undecanoate undecylate ----'----------------------

ethyl}(carboxymethy !Jamino)ethyl]-N-(carboxymethyl)glycyl )-N -(N-glycy1-L-tyrosyl)L-lysine

pentexil

(RS)-1-[(2,2-dimethylpropanoyl)oxy]ethyl

phenpropionate

3-phenylpropionate

octadecanoate(3) or tris( octadecanoate)

tristearate e n_ am t ro _ _ l_ _ _i_ _

eth_ an ,2_"-n 2_:_,2 __ _e _ _ _ o_ I a_ min __':._ _ _itr_ il_ otr _ _ an_ o_ _1_ o_ r_ _tr_i_ _ _ I·_eth _ ___ ______ _____ [2-(2-ethoxyethoxy)ethoxy]acetate or 3,6,9-tri­ oxaundecanoate

undecylenate

undec-10-enoate

valerate

pentanoate

xinafoate

1-hydroxynaphthalene-2-carboxylate droxy-2-naphthoate

or 1-hy­

of the Elements - 1 2 C = 1 2

xiv Atomic

Atomic Weigh ts of th e E l ements- 1 2c = 1 2 Atomic N u m ber 89 13 95 51 18 33 85 56 97 4 83 107 5 35 48 55 20 98 6 58 17 24 27 112 29 96 llO 105 66 99 68 63 100 114 9 87 64 31 32 79 72 108 2 67 1 49 53 77 26 36 57 103 82 3 ll6 71 12 25 109 101 80 42 60 10 93 28

Name 1 Actinium Aluminium 1 Americium Antimony Argon Arsenic 1 Astatine Barium 1 Berkelium Beryllium 2 Bismuth 1 Bohrium 3 Boron 3 Bromine

Sym bol

Ac AI Am Sb Ar As At Ba Bk Be Bi Bh B Br

Cadmium Caesium Calcium 1 Californium 3 Carbon Cerium 3 Chlorine Chromium

Cd Cs Ca Cf

Cobalt 1 Copemicium Copper 1 Curium 1 Darmstadtium 1 Dubnium Dysprosium 1 Einsteinium

Co Cn Cu Cm Ds Db Dy Es Er Eu Fm Fl F Fr Gd Ga Ge Au

Erbium Europium 1 Fermium 1 Flerovium Fluorine 1 Francium Gadolinium Gallium Germanium Gold Hafuium 1 Hassium Helium Holmium 3 Hydrogen Indium Iodine Iridium Iron Krypton Lanthanum 1 Lawrencium Lead 3 Lithium 1 Livermorium Lutetium 3 Magnesium Manganese 1 Meitnerium 1 Mendelevium Mercury Molybdenum Neodymium Neon 1 Neptunium Nickel

c Ce Cl Cr

Hf Hs He Ho H In I Ir Fe

Kr La Lr Pb Li Lv Lu Mg

Mn Mt Md Hg Mo Nd Ne Np Ni

Atomic Weight

N ame

Sym bol

Niobium 3 Nitrogen

Nb

92.90638

7

N

14.007

102

Nobelium

Atom i c N u mber 41

26.9815386 121.760 39.948 74.92160 137.327 9.012182 208.98040 10.81 79.904 112.411 132.9054519 40.078 12.011 140.116 35.45 51.9961 58.933195 63.546

0

46

Palladium

Pd

15

Phosphorus

p

78

Platinum

Pt

94 84

Plutonium 1 Polonium

19

Potassium

K

39.0983

59

Pr

140.90765

86

Praseodymium 1 Promethium 2 Protactinium 1 Radium 1 Radon

75

Rhenium

Re

186.207

45

Rhodium

Rh

102.90550

8

61 91 88

111

18.9984032 157.25 69.723 72.630 196.966569 178.49 4.002602 164.93032 1.008 l l 4.818 126.90447 192.217 55.845 83.798 138.90547 207.2 6.94 174.9668 24.305 54.938045

200.592 95.96 144.242 20.1797 58.6934

Os

1

Roentgenium

1

Rn

Rg Rb Ru

Rutherfordium

21

Scandium

106

1

Seaborgium Selenium 3 Silicon

85.4678 101.07

Rf Sm

1

231.0358 8

Ra

Rubidium

Samarium

30.973762 195.084

Pm Pa

Ruthenium

62

15.999 106.42

Po

37 104

190.23

Pu

44

14

167.259 151.964

No

Osmium 3 Oxygen

76

34 162.500

1

Atomic Weight

Sc

150.36 44.955912

Sg Se

78.96

Si

28.085 107.8682

47

Silver

Ag

11

Sodium

Na

38

Sr

87.62

16

Strontium SulW

s

32.06

22.98976928

73

Tantalum

43

Technetium

52

Tellurium

Te

127.60

65

Terbium

158.92535

Tl

204.38

90

3 Thallium 2 Thorium

Tb Th

232.03806

69

Thulium

Tm

168.93421

50

Tin

Sn

l l 8.710

22

Titanium

Ti

74

Tungsten

w

81

118

Ta

1

Ununoctium

1

92

1 Ununpentium 1 Ununseptium 1 Ununtrium 2 Uranium

23 54

ll5 ll7 113

180.94788

Tc

47.867 183.84

Uuo Uup Uus Uut 238.02891

Vanadium

u v

Xenon

Xe

131.293

50.9415

70

Ytterbium Yttrium

Yb y

173.054

39 30

Zinc

Zn

65.38

40

Zirconium

Zr

91.224

88.90585

1 . Elements with no stable isotopes. TIJPAC states "There is no general agreement on which of the isotopes of radioactive elements is, or is likely to be judged, 'important'. Various criteria, such as 'longest half-life', 'production in quantity', and 'used commercially' , have been applied in the past." 2. Radioactive elements with a characteristic terrestrial isotopic composition for which atomic weights are given. 3. Conventional atomic-weight value. These have been provided as representative values for elements that have a variation in atomic weight related to two or more stable isotopes in natural terrestrial occurrences. TIJPAC Commission on Isotopic Abundances and Atomic Weights. Atomic Weights of the Elements 20 1 1 . Available at http://www.chem.qmul.ac.uk/iupac/AtWtJ

Analgesics Anti-i nflam matory Drugs and Anti pyretics 3

Analgesics Anti-inflammatory Drugs and Antipyretic:;s

The drugs described in this chapter are used mainly in the relief of pain, inflammation and, in some cases, fever. They can be grouped broadly into one of the categories briefly described below.

P.��:�s.g.�?.':!P�................................................................. .

��pir.!'.' "f'.�.9.��:.c.�c:/i9.'!C1.��...................................... ..

Aspirin and other salicylates have analgesic, anti-inflammatory, and antipyretic properties. Like other NSAIDs (see below) they are inhibitors of the enzyme cyclo­ oxygenase; however, aspirin ( though not the non-acetylated salicylates) irreversibly acetylates the enzyme whereas other NSAIDs compete with arachidonic add for the active site. Salicylates are used for the relief of mild to moderate pain, minor febrile conditions, and for acute and chronic inflammatory disorders such as osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. Some salicylates are applied topically in rubefacient preparations for the relief of muscular and rheumatic pain. Aspirin also inhibits platelet aggregation and is used in cardiovascular disorders. Non­ acetylated salicylates do not have antiplatelet activity. For further discussion of the actions and uses of salicylates, see Aspirin, p. 2 2 . 2 . Described in this chapter are Aloxiprin, p. 20.3 Aluminium Aspirin, p. 20.3 Ammonium Salicylate, p. 21.1 Amyl Salicylate, p. 21.2 Aspirin, p. 22.2 Bornyl Salicylate, p. 30.1 Carbasalate Calcium, p. 36.2 Choline Magnesium Trisalicylate, p. 39.2 Choline Salicylate, p. 39.2 Diethylamine Salicylate, p. 51.3 Diflunisal, p. 51.3 Ethenzamide, p. 56.2 Ethyl Salicylate, p. 56.3

Glycol Salicylate, p. 66.2 Imidazole Salicylate, p. 71.2 Lysine Aspirin, p. 84.3 Magnesium Salicylate, p. 85.2 Methyl Butetisalicylate, p. 91.3 Methyl Salicylate, p. 92.1 Morpholine Salicylate, p. 97.1 Salamidacetic Add, p. 129.2 Salicylamide, p. 129.2 Salix, p. 129.2 Salol, p. 129.3 Salsalate, p. 130.1 Sodium Salicylate, p. 132.2 Thur!yl Salicylate, p. 137.1 Trolamine Salicylate, p. 141.2

e_;��.�.��'!!.�![r.!'.'f!...?..�t!�.��'!!.C:.�!.� �:.�f!.�.............

.. . Disease-modifying antirheumatic drugs (DMARDs) have anti-inflammatory properties thought to be mediated, in some cases, by the inhibition of the release or activity of cytokines. They are used in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis; some are also of benefit in ankylosing spondylitis and psoriatic arthritis. Many DMARDs also possess other therapeutic properties and are used in non-rheumatic conditions. The DMARD gold is referred to below; other DMARDs include sulfasalazine (p. 1 89 3 . 1 ) , penicillamine (p. 1 5 67. 1 ) , the antimalarials chloroquine (p. 6 5 0 . 1 ) and hydroxychloro­ quine (p. 6 5 5 . 2 ) , the monoclonal antibody rituximab (p. 8 5 2 . 1 ) , and the immunosuppressants azathioprine (p. 1 944. 3 ) , . dclosporin (p. 1 949.2), cyclophosphamide (p. 77 1 . 1 ) , and methotrexate (p. 822 . 2 ) . Described i n this chapter are Abatacept, p. 15.2 Actarit, p. 17.1 Adalimumab, p. 17.2 Anakinra, p. 21.2 Certolizumab, p. 39.1 Etanercept, p. 55.1

Golimurnab, p. 66.3 Infliximab, p. 74.2 Leflunomide, p. 81.3 Todlizumab, p. 77.3 Tofacitinib, p. 138.1

0.?.!�.�?.'!!.P.9.�.���·······························································

Gold compounds are u s e d mainly for their anti-inflammatory effect i n active progressive rheumatoid arthritis and progressive juvenile idiopathic arthritis; they may also be beneficial in psoriatic arthritis. The mechanism of action of gold compounds in rheumatic disorders is as yet unknown. For further discussion of the actions and uses of gold compounds, see Sodium Aurothiomalate, p. 1 3 0 . 2 . Described in this chapter are Auranofin, p. 27.3 Aurothioglucose, p. 28.2 Aurotioprol. p. 28.2 Gold Keratinate, p. 66.3

Sodium Aurothiomalate, p. 130.2 Sodium Aurotiosulfate, p. 132.1

�'?.'.'���C)_i�c:.�..C1.�t.!�_i�.fl.9.'!!'!!9.t.O.'Y. .�C".f!.�.................

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally unrelated organic acids that have analgesic, anti-inflammatory, and antipyretic properties (see p . 1 0 2 . 3 ) . NSAIDs are inhibitors of the enzyme cyclo-oxygenase, and so directly inhibit the biosynthesis of prostaglandins and thromboxanes from arachidonic add (see p. 2 5 9 8 . 1 ) . There are 2 forms of cyclo-oxygenase ( C OX ) , COX- I , which is the constitutive form of the enzyme, and C OX-2, which is the form induced in the presence of inflammation. Inhibition of COX-2 is therefore thought to be responsible for at least some of the analgesic, anti-inflammatory, and antipyretic properties of NSAIDs whereas inhibition of C OX- ! is thought to produce some of their toxic effects, particularly those on the gastrointestinal tract. Most NSAIDs available for clinical use inhibit both C OX- ! and COX-2, although some selective C OX-2 inhibitors such as celecoxib are also marketed. NSAIDs are used for the relief of mild to moderate pain, minor febrile conditions, and for acute and chronic inflammatory disorders such as osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. Indometacin and some other NSAIDs are used to close patent ductus arteriosus in premature neonates. Some NSAIDs are applied topically for the relief of muscular and rheumatic pain, and some are used in ophthalmic preparations for ocular inflammatory disorders. Aspirin (see above) is considered to be an NSAID, although it also has other properties. Described in this chapter are Aceclofenac, p. 16.2 Acemetacin, p. 16.3 Alminoprofen, p. 20.2 Aminophenazone, p. 21.1 Ampiroxicam, p. 21.1 Amtolmetin GuaciL p. 21.1 Azapropazone, p. 28.3 Bendazac, p. 29.1 Benzydam.ine, p. 29.2 Beta-aminopropionitrile, p. 30.1 Bromfenac, p. 30.1 Bufexamac, p. 30.2 Bumadizone, p. 30.2 Carprofen, p. 36.3 Celecoxib, p. 36.3 Clofexamide, p. 40.1 Clofezone, p. 40.1 Clonixin, p. 40.1 Dexibuprofen, p. 43.1 Dexketoprofen, p. 79.1 Diclofenac, p. 48.3

Dipyrone, p. 53.3 Eltenac, p. 54.2 Epirizole. p. 54.3 Etodolac, p. 57.1 Etofenamate, p. 57.2 Etoricoxib, p. 57.3 Felbinac, p. 58.3 Fenbufen, p. 59.1 Fenoprofen, p. 59.2 Fentiazac, p. 64.2 Fepradinol, p. 64.2 Feprazone, p. 64.3 Firocoxib, p. 64.3 Floctafenine, p. 64.3 Flufenamic Acid, p. 65.1 Flunixin, p. 65.1 Flurbiprofen, p. 65.2 Glucametadn, p. 66.2 Ibuprofen, p. 68.2 Indometacin, p. 71.2 Isonixin, p. 78.3 Kebuzone, p. 78.3

Ketoprofen, p. 79.1 Ketorolac, p. 80.2 Licofelone, p. 83.2 Lomoxicam, p. 83.2 Loxoprofen, p. 83.3 Lumiracoxib, p. 84.1 Meclofenamic acid, p. 85.2 Mefenamic Acid, p. 85.3 Meloxicam, p. 86.3 Mofezolac, p. 92.2 Morniflumate, p. 92.2 Nabumetone, p. 97.1 Naproxen, p. 98.2 Nepafenac, p. 101.1 Niflumic Acid, p. 101.2 Nimesulide, p. 101.3 Oxaprozin, p. 112.3 Oxyphenbutazone, p. 114.3 Parecoxib, p. 119.3 Phenazone, p. 124.1 Phenylbutazone, p. 125.1

Piketoprofen, p. 125.3 Piroxicam, p. 125.3 Pranoprofen, p. 127.1 Proglumetacin, p. 127.1 Propyphenazone, p. 127.3 Proquazone, p. 128.1 Rofecoxib, p. 128.3 Sulindac, p. 134.2 Suprofen, p. 135.3 Suxibuzone, p. 136.1 Tenoxicam, p. 136.2 Tepoxalin, p. 137.1 Tetridamine, p. 137.1 Tiaprofenic Acid, p. 137.1 Tiaram.ide, p. 137.3 Tinoridine, p. 138.1 Tolfenamic Acid, p. 138.3 Tolmetin, p. 139.1 Valdecoxib, p. 141.3 Vedaprofen, p. 142.1 Zaltoprofen.. p. 142.2

9.Pi9.i�..C1.�9.!f!.�!:�............................................................

Opioid analgesics include the opium alkaloids morphine and codeine and their derivatives as well as synthetic substances with agonist, partial agonist, or mixed agonist and antagonist activity at opioid receptors (see p. 1 0 8. 1 ) . The term opiate analgesics refers only to those opioids derived from opium, or their semisynthetic congeners. The term narcotic analgesics has legal connotations and is no longer used pharmacologically or clinically. Most opioids are used as analgesics, and morphine is the standard against which all other opioid analgesics are compared. Opioids such as codeine are used in the treatment of less severe pain, and are often combined with non-opioid analgesics such as aspirin, other NSAIDs, or paracetamol. More potent opioids such as morphine are used in severe acute and chronic pain, including cancer pain. Some opioids such as codeine, morphine, and diamorphine are also used as antitussives, although the latter two are usually reserved for use in terminal lung disease. Some opioid analgesics such as fentanyl and its congeners are used mainly as adjuncts to anaesthesia; some of these may also be used in higher doses as the sole anaesthetic drug. Some opioids are rarely if ever used as analgesics and are described elsewhere; they include the antitussives dextro­ methorphan (p. 1 660. 1 ) and pholcodine (p. 1 67 5 . 1 ) , and the antidiarrhoeals diphenoxylate (p. 1 838. 3 ) and loper­ amide (p. 1 8 57.2 ) . Opioids can produce physical dependence and with­ drawal symptoms if suddenly stopped. They are also subject to abuse. Described in this chapter are Alfentanil, p. 18.2 Anileridine, p. 22.2 Buprenorphine, p. 30.2 Butorphanol. p. 33.2 Carfentanil, p. 36.2 Codeine, p. 40.2 Dextromoram.ide, p. 43.2 Dextropropoxyphene, p. 43.2 Dezocine, p. 45.2 Diamorphine, p. 46.1 Dihydrocodeine, p. 52.2 Dipipanone, p. 53.2 Embutram.ide, p. 54.2 Ethoheptazine, p. 56.2 Ethylmorphine, p. 56.3

Etorphine, p. 58.3 Fentanyl, p. 60.1 Hydrochlorides of Mixed Opium Alkaloids, p. 112.2 Hydrocodone, p. 67.2 Hydromorphone, p. 67.3 Ketobemidone, p. 78.3 Levacetylmethadol, p. 83.1 Levomethadone, p. 83.1 Levorphanol, p. 83.2 Meptazinol, p. 87.3 Methadone, p. 88.3 Morphine. p. 92.3 Nalbuphine, p. 97.3 Nicomorphine, p. 101.1

4 Remifentanil, p. 128.1 Sufentanil, p. 132.3 Tapentadol, p. 136.1 Tilidine, p. 137.3 Tramadol, p. 139.2 Trimeperidine, p. 141.2

Opium, p. 111.3 Oxycodone, p. 113.1 Oxymorphone, p. 114.2 Papavcretum. p. 112.2 Pentazocine, p. 120.3 Pethidine, p. 121.3 Piritramide, p. 125.3

and may be described as deeply located, sharp or dull,

nagging, stabbing, throbbing, or pressure-like.

pain

and phenacetin have

generally been

anti-inflammatory

activity.

The

mechanism

of

.

Pain is defined by the International Association for the

Study of Pain as 'an unpleasant sensory and emotional with

actual

or

potential

tissue

damage, or described in terms of such damage: Under normal circumstances pain is the result of stimulation of peripheral receptors that transmit impulses through pain pathways to the brain. Pain receptors or nociceptors are of two basic types:

•

mechanoheat receptors

have a high stimulation threshold

and respond to intense or potentially damaging noxious stimuli. These receptors are associated with rapidly

conducting, thinly myelinated A li

fibres, and their

stimulation produces rapid sharp localised pain that

•

serves to activate withdrawal reflexes

polymodal nociceptors

respond to mechanical, thermal, or

chemical insults. These receptors are also activated by

cellular

components

that

are

released

after

tissue

damage. Their impulses are transmitted slowly along unmyelinated C type fibres and produce dull, aching,

and poorly localised pain with a slower onset Nerve fibres from nociceptors terminate in the dorsal root of the spinal cord before transmission by ascending pathways to the brain. There have been many theories on the processing of pain signals at the spinal level but the 'gate theory' proposed by Melzack and Wall is one of the best known. This theory postulates that the transmission of impulses to the brain is modulated by a gate mechanism in the substantia gelatinosa. Stimulation of small fibres opens the gate and facilitates transmission whereas stimulation of large fibres, which normally carry non-painful sensory input, can close the gate and inhibit transmission. Transmission also appears to be modulated by several other mechanisms which can influence the sensitivity of the gate. Inflammatory mediators such as bradykinin, histamine, serotonin, and prostaglandins produced in response to tissue damage can produce peripheral sensitisation so that receptors respond to low intensity or innocuous stimuli; central sensitisation also occurs. Pain associated with tissue damage hence results in increased sensitivity of the sensory system so that the pain can occur in the absence of a clear stimulus. Pain that occurs due to a stimulus that does not usually provoke pain is termed allodynia; this applies to conditions such as sunburn, inflammation, and trauma that may result in sensitisation of the skin. Hyperalgesia is defined as an increased response to a stimulus that is usually painful. Hyperaesthesia is an increased sensitivity to stimulation, excluding the special senses and includes allodynia and hyperalgesia. Hyperpathia is characterised by an abnormally painful reaction to a stimulus, particularly a repetitive stimulus, and may occur with allodynia, hyperalgesia, or hyperaesthesia.

•

Pain is often classified as being acute or chronic in nature.

Acute pain is associated with trauma or disease and usually has a well-defined location,

character,

and

timing. It is accompanied by symptoms of autonomic hyperactivity such as tachycardia, hypertension, sweat­

•

diabetic

central pain.

The

clinical signs of neuropathic pain can vary greatly. Some

than a few months. It may not be clearly associated with trauma or disease or may persist after the initial injury

has healed; its localisation, character, and timing are

dextropropoxyphene

pain than the non-opioid alone; efficacy in chronic pain is EMEA

and

the

FDA

have

recommended

that

all

dextropropoxyphene-containing preparations be no longer

available in the EU and USA respectively, because of the risk of toxicity in overdosage and of cardiotoxicity; such preparations remain on the market in other countries. More potent opioids such as

morphine are mainly used

in the treatment of severe acute non-malignant pain and

instability.

pain

Neuropathic

pain

responds

poorly

to

conventional analgesics and can be difficult to treat.

cancer pain (see p. 7 . 1 ) . Their use in chronic non-malignant is

somewhat

psychological

controversial

dependence

and

because

respiratory

of

fears

of

depression.

Early treatment of pain is important as unrelieved pain can

However, in practice such problems rarely occur and those

acute pain that is poorly managed initially can degenerate

analgesic

have profound psychological effects on the patient, and

into chronic pain, which may prove to be much more

difficult to treat. It is important to assess and treat the

mental and emotional aspects of the pain as well as its

physical aspects. Although drug therapy is a mainstay of pain treatment (see Choice of Analgesic, below), physical

methods such as physiotherapy (including massage and the

application of heat and cold), surgery, and nervous system

stimulation techniques such as acupuncture, spinal cord stimulation, and transcutaneous electrical nerve stimula­ tion (TENS) are also used.

Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150: 971-9.

2.

International Association for the Study of Pain. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain

Pain 1986; (suppl 3): S1-S225. 3. Lewis KS, et al. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm 1994; 5 1 : 1539-54. 4. Loeser JD, Melzack R. Pain: an overview. Lancet 1999; 353: 1607-9. 5. Ashburn MA, Staats PS. Management of chronic pain. Lancet 1999; 353: terms.

1865-9.

6.

Woolf

CJ,

Mannion

RJ.

Neuropathic

pain:

aetiology,

symptoms,

Lancet 1999; 353: 1959-64. 7. Carr DB, Goudas LC. Acute pain. Lancet 1999; 353: 2051-8. 8. Cervera F, Laird JM. Visceral pain. Lancet 1999; 353: 2145-8. mechanisms, and management.

9.

perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology

100:

1573-81.

Also

available

at:

http://www.asahq.org/

publicationsAndServices/pain.pdf (accessed 23/06/08) DB,

et al. American Pain Society recommendations for

improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force.

Arch Intern Med 2005; 165:

1574-80. Also available at: http://archinte.ama-assn.org/cgi/reprint/ 165/14/1574 (accessed 23/06/08) 11. Spacek A. Modem concepts of acute and chronic pain management.

Biomed Pharmacother 2006; 60: 329-35. 12. Markman JD, Philip A.lnterventional approaches to pain management.

Anesthesia/ Cfin 2007; 25: 883-898. 13. European Association of Urology. Guidelines on pain management (issued March 2007). Available at: http:/fwww.uroweb.org/fileadmin/ user_upload/Guidelines/21_Pain_Management_2007.pdf

(accessed

23/06/08)

et al. Pain management: a fundamental human right. Anesth Analg 2007; 105: 205-21. 15. Knape JT, et al. Board of Anaesthesiology of the European Union of 14. Brennan F,

may

also

be

of

value

in

Morphine is the opioid of choice in severe pain. It is

absorbed when given orally and has a short half-life so that

the use of immediate-release oral preparations offers a

flexible means of dosage titration in, for example, palliative

care. Once initial pain relief has been achieved, use of a modified-release preparation every 12 or 24 hours is more convenient for maintenance of analgesia in severe chronic

pain. It may also be given parenterally (e.g. for control of controlled

analgesia-see

also

p.

5 . 3 ), or rectally or

transdermally, where there would be problems with the

oral route.

Occasionally

other opioids may be usefuL Switching to

an alternative opioid may be effective in patients who have

inadequate pain control or intolerable adverse effects with morphine. Methadone

(which also acts as an NMDA

antagonist) or oxycodone have a longer duration of action than morphine, but it should be noted that methadone,

which has a long half-life, should not be given more than

of action is provided by alfentanil and fentanyl but use of

pethidine is no longer recommended. Diamorphine or hydromorphone may be preferred to morphine when the

parenteral route has to be used because they are more

soluble and can be given in a smaller volume. Tramadol,

which may impair respiratory and gastrointestinal function less than other opioids at equianalgesic doses, is also of benefit in neuropathic pain.

Adverse effects of opioids include sedation, nausea,

vomiting, constipation, and, most seriously, respiratory

depression. Tolerance generally develops to all of these effects except constipation, which may be prevented by regular use of laxatives.

Some other groups of drugs have significant roles in pain

management either alone or as

analgesic adjuvants. antidepressants

Subantidepressant doses of tricyclic

(usually amitriptyline) are considered to be useful in

by

refractory chronic pain, including neuropathic pain of the

et al. Evidence-based intervemional pain management: Pain Physidan 2007; 10:

and diabetic neuropathy; shooting pain has also been

Medical Specialists. Guidelines for non-anaesthesiology doctors. 16. Manchikanti L,

Opioids

twice daily when used long term because of the risk of

Management. Practice guidelines for acute pain management in the

2004;

therapy.

progressive CNS depression and overdosage. A rapid onset

American Society of Anesthesiologists Task Force on Acute Pain

10. Gordon

fears should not prevent patients being given effective

neuropathic pain in some patients.

acute severe pain in emergency departments or in patient­

General references to pain and its management.

1.

sedation

and/or

analgesia

Bur J Anaesthesiol 2007; 24: 563-7.

principles, problems, potential and applications. 329-56. 17. Cawley D, Bennett MI. Management of pain.

Br J Hosp Med 2009; 70:

197-201.

burning, dysaesthetic type such as postherpetic neuralgia

reported to respond. They may be used in addition to conventional analgesics, notably in the treatment of cancer pain of mixed aetiology. There is little evidence for benefit in acute pain although musculoskeletal pain has sometimes

ing, and mydriasis.

Chronic pain is usually regarded as pain lasting more

repeated use. Combinations of

stabbing (lancinating) pain. The pain may be associated

with areas of sensory deficit or some form of autonomic

..

associated

and

sensitivity and sensations of superficial burning or

A��.19..1:l�.i.�..?�.� ��·i·�··· ........................................... experience

neuralgia,

of the more common features include heightened pain

Phenacetin, p. 124.1 Propacetamol. p. 127.2

significant increase in analgesia compared with paracetamol

alone and are one of the most effective options for acute

pain, but the incidence of adverse effects increases with

unclear and adverse effects may become troublesome. The

trigeminal

thalamic syndrome) is referred to as

and peripherally. Paracetamol is used for the relief of mild to

are often given with non-opioid analgesics. Combinations of

postherpetic and

nervous tissue, such as in central post-stroke pain (the

moderate pain and minor febrile conditions.

Described in this chapter are Acetanilide, p. 17.1 Paracetamol, p. 115.1

codeine is the traditional choice; dilhydrocodeine and tramadoL They

with paracetamol or aspirin are no more effective in acute

neuropathy. Neuropathic pain associated with central

analgesic action remains to be fully elucidated, but may be

due to inhibition of prostaglandin synthesis both centrally

opioid-scnsitive pain

pain (or neurogenic pain). The term covers sympathe­ tically maintained pain including causalgia and reflex

sympathetic dystrophy, and painful conditions such as

Paracetamol has analgesic and antipyretic properties and

weak

For the treatment of moderate or moderate to severe

codeine with paracetamol at full doses produce a small but

Pain resulting from damage or dysfunction of peripheral

replaced by safer analgesics. Propacetamol is hydrolysed to

Giving paracetamol with an NSAID improves analgesia.

vomiting. Nociceptive pain usually responds to treatment

nerves/receptors or of the CNS is known as neuropathic

paracetamol in the plasma.

can produce severe or sometimes fatal hepatotoxicity.

alternatives include

with conventional analgesics.

•

gastrointestinal adverse effects of aspirin but large doses

body. Depending on the structure involved it is variously described as deeply located, aching, nagging, cramping,

or pressing and may be accompanied by nausea and

�?.r.CIC.�!?.fTIC>I.9.��..C>!h.e.r..P.Cir.9.�?.fri;�?.P.h.e.�?.ls...... Acetanilide

is generally less localised and more diffuse than

somatic pain and may be referred to remote areas of the

Paracetamol is the principal para-aminophenol derivative in

use.

Visceral

responded. Amitriptyline has also been found to be useful

�h..C>iC.f!.?.f..c:t'!?.'f!.��i�.... ........................

for tension-type headache and for the prophylaxis of

Paracetamol and NSAIDs are the first choice analgesics

for treating mild to moderate pain and are also used in

migraine. The role of other antidepressants in the treatment of neuropathic pain is less clear although venlafaxine may

more vague than with acute pain. Furthermore, as the

moderate to severe pain to potentiate the effects of opioids.

be usefuL

autonomic hyperactivity associated with acute pain

relief of acute pain can be achieved with oral NSAIDs and

recently, gabapentin and pregabalin) have been found

may consist of intermittent attacks of pain followed by

opioid-see below). Dependence and tolerance are not a

autonomic

nervous

system

adapts,

the

signs

of

disappear. Some forms of pain regarded as being chronic relatively long pain-free periods. Patients with chronic

They are suitable for use in acute or chronic pain. Effective

with paracetamol (particularly in combination with an

problem with non-opioid analgesics but they have a rather

pain have physical, psychological, social, and functional

flat dose-response curve: as the dose is increased, the

the pain.

non-selective

deterioration which contributes towards exacerbation of

Physiologically, pain may be divided into nociceptive pain

and neuropathic pain. • Nociceptive pain follows activation of nociceptors by noxious stimuli as described above but is not associated with injury to peripheral nerves or the CNS. It may be somatic or visceral, depending on which receptors or

nerves are involved.

Somatic pain

is usually well localised

All cross-references refer to entries in Volume A

Antiepileptics

(often

carbamazepine

and,

more

useful in the relief of neuropathic pain, especially when there is a stabbing (lancinating) element, as in trigeminal

neuralgia; there have also been reports of efficacy in the

treatment

of

diabetic

neuropathy

and

for

migraine

increase in pain relief may be quite small. Aspirin and other

prophylaxis.

adversely

baclofen or dantrolene are useful for relieving painful

NSAIDs

affect

the

inhibit

blood

gastrointestinal

platelet tract,

function,

and

can

Benzodiazepines and other muscle relaxants such as

precipitate hypersensitivity reactions including asthma.

muscle spasm in acute or chronic conditions.

be less with selective inhibitors of cyclo-oxygenase-2 (COX-

bisphosphonates may be useful in cancer pain arising from

restricted by concerns about serious cardiovascular effects.

and are second choice to NSA!Ds. Bisphosphonates may

The risk of severe upper gastrointestinal adverse effects may

2) such as the coxibs, but their use has been greatly Paracetamol

does

not

have

the

haematological

or

Bone modulating drugs such as calcitonin and

bone metastases (see p. 7 . 1 ) but have a slow onset of action

cause an initial transient increase in bone pain.

Ana lgesics Anti-i nflammatory Drugs and Anti pyretics 5 Caffeine has been used with the aim of enhancing the

27. British Pain Society. Opioids for persistent pain: good practice (issued

effects of non-opioid and opioid analgesics but is of

January 2010), Available at: http:/Jwww.britishpairuociety.org/book_

caffeine enhances the effect of ergotamine in the treatment

��.'?.!.�:..�r��.��f!.��!.��J� .��H�r.��······························

opioid_main.pdf (accessed 15/04/10)

debatable benefit. There are similar doubts about whether

of migraine (see Pharmacokinetics, p. 6 7 5 . 3 ) ; it may also

add to gastrointestinal adverse effects and in large doses can itself cause headache.

Corticosteroids have produced improvement, often

basis of postoperative analgesia after major surgery in the

.

collapse, depressed levels of consciousness, and addiction

procedures in neonates have been made by an international

because of fears of respiratory depression, cardiovascular

with potent opioid analgesics. Assessment of pain is also a it was widely believed that neonates were incapable of

by

raised

intracranial

pressure

and

added benefits of increasing well-being and appetite. Some

inhalational anaesthetics are used in subanaes­

thetic doses as inhalation analgesics for acute pain. In

particular, nitrous oxide is given with oxygen for pain relief in obstetrics and during dental and other procedures, and in

emergency management. Isoflurane, enflurane, and in

some countries methoxyflurane or trichloroethylene have

been used similarly.

Miscellaneous drugs. After the discovery that epidural

as fentanyl is advocated. together with infiltration of the site

with a local anaesthetic where time permits, for insertion of

substantial. in neuropathic pain. They can also relieve caused

absence of regional anaesthesia; a rapidly acting opioid such

Pain has often been undertreated in infants and children

refractory pain caused by bone metastases, and have the

headache

anaesthetics may be used for more painful procedures such as venepuncture if time permits. Opioids should be the

problem in children of all ages1-3 and it is not that long since

feeling pain.

Non-opioid analgesics are used in infants and children, either alone for minor pain or as an adjunct to

a chest drain."

frequently used but it lacks any anti-inilanunatory effect.

The

L

Child and Family Health, American Pain Society Task Force on Pain in acute pain in infants, children, and adolescents. 793-7.

either alone or with opioids or local anaesthetics, but their

moderate

such as clonidine and ketamine,

compared. It is given intravenously for rapid relief of severe

to

severe

pain

in

paediatric

patients,

and

analgesic properties when given by other routes, and

pain (for example after bums, fractures or other injuries), and is titrated to achieve a suitable analgesic dose.4-6•8•9

also appear to have

ketamine may be useful in reducing opioid requirements.

y

Some antiarrhythmics (including systemic lidocaine) ma

morphine may be given but its onset is slower and less

phenothiazines, as adjuvant analgesics is controversial;

alternative to intravenous morphlne.6 Continuous intra­

palliative care. See.below for discussions of the use of patient-controlled

doses has become popular for postoperative pain relie£.'·9

with extreme caution. The use of antipsychotics, such as the levomepromazine is sometimes used as an adjunct in

analgesia (below), and rubefacients and topical analgesics (p.

6 . 3 ) . Nerve blocks are discussed under Pain, on p. 1 98 1 . 1 . References. 1.

Sawynok J. Pharmacological rationale for the clinical use of caffeine.

Drugs 1995; 49: 37-50. 2.

Watson CP. The treatment of neuropathic pain: antidepressants and opioids.

3.

Clin J Pain 2000; 16 (suppl): S49-S55.

Curatolo M, Svetidc G. Drug combinations in pain treatment: a review of the published evidence and a method for finding the optimal combination.

4.

HJ.

McQuay

Best Pract Res Clin Anaesthesio/ 2002; 16:507-19. Bur J Pain 2002; 6

Neuropathic pain: evidence matters.

(suppl A): 11-18. 5.

Anonymous. Acute pain (Bandolier Extra, issued February 2003).

6.

Ballantyne JC, Mao J. Opioid therapy for chronic pain.

Available at: http://www.jr2.ox.ac.uk!bandolier/Extraforbando/APain. pdf (accessed 23/06/08)

N Engl J Med

2003; 349: 1943-53. 7.

Backonja M. Anticonvulsants for the treatment of neuropathic pain

Curr Pain Headache Rep 2003; 7:39-42.

syndromes. 8.

McQuay H. Pain and its control (issued 1st January, 2004). Available at:

predictable; some favour intranasal diamorphine as an

venous morphine infusion with or without initial loading

but titration of the infusion rate is necessary to achieve a balance

9.

The College of Emergency Medicine. Clinical Effectiveness Committee guideline for the management of pain in adults (2004). Available at:

Subcutaneous

(accessed 26/11/09)

et al. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 2004; 62: 218-25.

11. Quigley C. Opioid switching to improve pain relief and drug tolerability. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2004 (accessed 23/06/08).

et al. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg 2005; 101 (suppl): S30-S43.

12. Rathmell JP,

13. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence. 2nd ed, 2005. at:

Available

http://www.anzca.edu.au/resources/books-and­

publications/acutepain.pdf (accessed 23/06/08) 14. Eisenberg E,

et al. Efficacy and safety of opioid agonists in the treatment

of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials.

JAMA 2005; 293: 3043-

52. 15. Davis MP,

et al. Controversies in pharmacotherapy of pain management.

Lancet Oncol2005; 6:696-704. et al. Using opioids with persisting noncancer pain: a biopsychosodal perspective. Clin J Pain 2006; 22:137-46. 17. McQuay RJ, Moore RA. Dose-resporne in direct comparisons of different 16. Nicholas MK,

doses

of

aspirin,

ibuprofen and

paracetamol

(acetaminophen)

in

analgesic studies. Br J

Clin Pharmacol 2007; 63:271-8. 18. Knotkova H, Pappagallo M. Adjuvant analgesics. Anesthesiol Clin 2007; 25:775-86. 19. Tamches E,

et al. Acute pain in adults admitted to the emergency room: Swiss Med

development and implementation of abbreviated guidelines.

Wkly 2007; 137:223-7. 20. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute pain management: scientific evidence. Update to 2nd ed, December 2007. Available at: http://www.anzca.edu.au/resources/ books-and-publications/acutepain_update.pdf (accessed 23/06/08)

et al. Recent advances in the pharmacological management of pain. Drugs 2007; 67:2121-33. 22. Ghafoor VL, et al. Intrathecal drug therapy for long-term pain management. Am J Health-Syst Pharm 2007; 64: 2447-61. 23. Seidel S, et al. Antipsychotics for acute and chronic pain in adults. 21. Guindon J,

Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2008 (accessed 26/11/09). 24. Verdu B,

et al. Antidepressants for the treatment of chronic pain. Drugs

2008; 68: 2611-32. 25. British Pain Society. Intrathecal drug delivery for the management of pain and spasticity in adults; recommendations for best clinical practice (issued August 2008). Available at: http://www.britishpainsociety.org/ book_ittd_main.pdf (accessed 26/11/09) 26. Barber JB, Gibson SJ. Treatment of chronic non-malignant pain in the elderly: safety considerations.

Drug Safety 2009; 32:457-74.

analgesia

is

and

needed

infusions

in

of

respiratory

neonates,

morphine

depression

see

have

below).

also

been

therefore

probably

only

suitable

for

short-term

use.

Fentanyl has also been widely used for short-term analgesia in surgical procedures, 7-9•11•12 and other opioids such as

buprenorphine, hydromorphone, oxycodone, and tramadol

have been given.4 The use of codeine in children is restricted by its significantly increased risk of serious and life­

threatening adverse effects in ultrarapid metabolisers.

has been tried in children. Morphine has also been given to children by the epidural

route; 9 experience

with

the

intrathecal route is more limited. Other methods of opioid

drug delivery of possible value in paediatric analgesia

include transmucosal, 7•12 nasal, 6·8 and transdennaF·10

dosage.

Cancer pain in children may be treated using the

analgesic ladder scheme described under Cancer Pain (see p. 7. 1 ) .

Inhaled

useful

for

nitrous oxide and oxygen mixtures may be

preliminary procedures.6•8•9•11

pain

relief

and

short,

at:

painful

Local anaesthetics are especially suitable for the

management of acute pain in day-care situations. Single

Pediatrics 2001; 108:

http:llpediatrics.aappublications.org/cgi/

6.

Maurice SC,

1):

current practice and perspectives.

Morton NS. Management of postoperative pain in children.

The College of Emergency Medicine, Best practice guideline: manage­ ment of pain in children (issued July 2013). Available at: http://secure. collemergencymed.ac.uk/asp/document.asp?ID=4682

(accessed

ll/12/13) 7.

Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N

8.

Enal J Med 2002; 347: 1094-1103. Maurice SC, et al. Emergency analgesia in the paediatric population (part ll): phannacological methods of pain relief. Emerg Med J 2002; 19:101-5.

9.

Alder Hey Royal Liverpool Children's NHS Trust. Guidelines on the

management of pain in children. 1st ed, 1998. Available at: http:// painsourcebook.ca/pdfs/pps55.pdf (accessed 23/06/08) l0. Zempsky WT,

et al. Relief of pain and anxiety in pediatric patients in Pediatrics 2004; 1 14: 1348-56.

emergency medical systems.

1L Harvey AJ, Morton NS. Management of procedural pain in children.

Arch Dis Child Educ Pract Ed 2007; 92:ep20-ep26. 12. Krauss B, Green SM. Sedation and analgesia for procedures in children.

N Engl J Med 2000; 342: 938-45. 13. Howes

MC.

Ketamine

for

paediatric

sedation/analgesia

in

the

emergency department. Emerg Med J 2004; 2 1 : 275-80. 14. Stevens B,

et al. Sucrose for analgesia in newborn infants undergoing

painful procedures. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2004 (accessed 23/06/08). 15. American Academy of Pediatrics Committee on Fetus and Newborn and Section on Surgery, Canadian Paediatric Society Fetus and Newborn Committee. Prevention and management of pain in the neonate: an update. Pediatrics 2006; 1 18: 2231-41. Correction.

Patient-controlled analgesia using morphine (see below)

http://www .collemergencymed.ac.uk/asp/document.asp?ID=4193 10. Attal N,

care

used, 4 mostly for the relief of terminal cancer pain in children. Intramuscular injections are painful8•11 and

http://www.medidne.ox.ac.uk/bandolierlbooth/painpag/wisdom/C13. html (accessed 26/ll/09)

between

(particular

available

et al. Emergency analgesia in the paediatric population (part Emerg Med J 2002; 19:4-7. Arch Dis Child Educ Prad Ed 2007; 92:ep14-ep19. 5. Atkinson P, et al. Pain management and sedation for children in the emergency department. BMJ 2009; 339:1074-9.

Where intravenous access is not readily achievable, oral

be effective in chronic neuropathic pain, but must be used

Also

reprint/108/3/793.pdf (accessed 23/06/08) 3.

morphine is the standard against which the others are

American Academy of Pediatrics Committee on Psychosocial Aspects of Infants, Children, and Adolescents. The assessment and management of

The use of aspirin is greatly restricted by its association with

role, if any, in the management of pain is unclear. Some,

American Academy of Pediatrics and Canadian Paediatric Society. 2000; 105: 454-61. Also available at: http://aappolicy.aappublications.

NSAIDs such as ibuprofen are useful for minor pain!·6·8

opioids are still the mainstay of analgesia for

analgesic adjuvants (see Choice of 4.2) has also been advocated in some

org/cgilreprint/pediatrics;105/2/454.pdf (accessed 23/06/08) 2.

especially when associated with inflammation or trauma.

The

of

Prevention and management of pain and stress in the neonate. Pediatn'cs

4.

analgesia many other drugs have been tried by these routes,

use

children."

Reye's syndrome.

or intrathecal injection of opioids can produce effective

for painful

consensus group.I6

Analgesic, p.

opioid analgesics in severe pain!·' (they can reduce opioid

requirements,1•7 perhaps by up to 40%4). Paracetamol is

Similar recommendations

ibid. 2007; 1 19: 425.

Also available at: http://pediatrics.aappublications.org/cgi/reprint/118/ 5/223Lpdf (accessed 23/06/08) 16. Anand KJ; International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch

Pediatr Adolesc Med 2001; 155:173-80. Also available at:

http://archpedi.ama-assn.org/cgi/reprint/ 15 5/2/173. pdf

(accessed

23/06/08)

et al. The assessment and management of chronic pain in children. Paediatr Drugs 2002; 4: 737-46.

17. Chambliss CR,

Nerve blocks For a discussion of

the use

of

nerve

blocks in

management of pain, see under Pain, p. 1 98 1 . 1 .

the

������t�� Bupren­ orph i n e, .Chlqrhydrilte de; Bupr.,norphlnhydrochlorid: Buprenorphini Hydrochloripurn; CL- 1 12302; Hldrocloruro de .· . buprenorfina; NrH 8805; UM-952; 5ynpeHop¢;,�Ha

rt-lJ1poXI1opvJ.D.. (2.,!'1,1 NO.,HCI=504. l CAS � 53152-li-9. UN!i ·- �ot.'V/l./VIVV:J.l:JVI.

Pharmacopoeias. In Chin., Bur. (see p . vii ) . Jpn, and US. Ph. Em. 8: (Buprenorphine Hydrochloride ) . A white or almost white crystalline powder. Sparingly soluble in water; soluble in alcohol; practically insoluble in cyclohexane; freely soluble in methyl alcohoL Protect from light.

USP 36: (Buprenorphine Hydrochloride ) . pH of a 1 % solution in water i s between 4.0 and 6 . 0 . Store i n airtight containers. Protect from light.

Uses and Administration Buprenorphine is an opioid analgesic (p. I 08. 1 ) classified as an opioid agonist and antagonist. It is used for the relief of n1oderate to severe pain and as an adjunct to anaesthesia. Buprenorphine is also used in the treatment of opioid dependence. Buprenorphine has a relatively slow onset but prolonged duration of action. On intramuscular injection analgesia is apparent within 15 minutes and lasts up to 6 hours. A slower, more prolonged response is achieved after sublingual doses. The analgesic effects of buprenorphine after transdermal application may not be seen for at least 1 2 t o 2 4 hours o r u p t o 7 2 hours i n the case o f the once-weekly patch. Buprenorphine is usually given by intramuscular or intravenous injection or sublingually as the hydrochloride or as transdermal patches as the base. For all routes doses are expressed in terms of the base. Buprenorphine hydro­ chloride 1 07.8 micrograms is equivalent to about l OO micr� ograms of buprenorphine. Buprenorphine is given by all the above routes for opioid analgesia in moderate to severe pain. • The dose by intramuscular or slow intravenous injection is 300 to 600 micrograms repeated every 6 to 8 hours as required • By the sublingual route, doses of 200 to 400 micrograms may be repeated every 6 to 8 hours as required • For opioid treatment of chronic pain in patients aged 1 8 years and over transdermal patches delivering varying amounts of buprenorphine are available. Doses should be individually titrated for each patient according to previous opioid usage. During transfer to treatment With buprenorphine patches previous opioid analgesic therapy should be phased out gradually in order to allow for the gradual increase in plasma-buprenorphine concentrations. Depending on dose required up to 2 patches may be applied, however, this should be done at the same time to avoid confusion. Buprenorphine patches are not appropriate for acute pain. In the UK and USA, transdermal buprenorphine patches are available as follows: Transtec (Napp, UK) delivering buprenorphine in a range of 35 to 70 micrograms/hour. Initial dosages should not exceed 35 micrograms/hour in opioid�naive patients. For patients who have been receiving a strong opioid analgesic the initial dose should be based on the previous 24�hour opioid requirement. Use of a patch providing 35 micro­ grams/hour of buprenorphine is roughly equivalent to 30 to 60 mg daily of oral morphine sulfate. Patches should be replaced every 96 hours at the latest with the new patch being applied to a different site; use of the same area of the skin should be avoided for at least the next 2 applications. BuTrans (Napp. UK) and Butrans (Purdue. USA) delivering buprenorphine in a range of 5 to 20 micrograms/hour. UK licensed product information states that initial dosages should not exceed 5 microgra1ns/hour in all patients, whereas in the US,A, this dose is licensed for the initial treatment of opioid-naive patients or those who have been receiving a strong opioid analgesic whose daily dose is less than 30 mg of oral morphine or its equivalent. US licensed information recorrunends an

Beta-a mi nop ropion itrile/Buprenorph i ne 3 1 initial dose of 1 0 micrograms/hour for opioid-tolerant patients whose daily dose is between 30 and BO mg of oral morphine or its equivalent. In those requiring more than 80 mg daily of oral morphine or its equivalent the use of patches providing 20 micrograms/hour of buprenorphine may not provide adequate analgesia; however, applica­ tion of multiple patches to provide doses greater than 20 micrograms/hour is not licensed in the USA (see Adverse Effects and Treatment, below) . Patches should be replaced every 7 days with the new patch being applied to a different site; use of the same area of the skin should be avoided for the next 3 to 4 weeks. When used in balanced anaesthesia 300 micrograms may be given intramuscularly or 400 micrograms sublingually for premedication; 300 to 450 micrograms may be given intravenously as a perioperative analgesic supplement. For the treatment of opioid dependence in patients aged 16 years and over, the initial dose is 0.8 to 4 mg sublingually once daily. The dose may be increased as necessary but maintenance doses should not exceed 32 mg daily. Once the patient has been stabilised, the dosage should be reduced gradually to a lower maintenance dose; treatment may eventually be stopped if appropriate. For addicts who have not undergone opioid withdrawal before starting buprenorphine, the first dose of buprenorphine should not be given until the first signs of craving appear or until at least 4 (USA) or 6 (UK) hours after the last opioid use. In those already receiving methadone replacement, the dose of methadone should be reduced to a maximum of 3 0 mg daily before starting buprenorphine therapy. As a deterrent to abuse, combined sublingual preparations of buprenorphine hydrochloride and naloxone hydrochloride are available in some countries for the treatment of opioid dependence. Naloxone may also increase the analgesic effect of buprenorphine, see Administration with Bupren­ orphine, under Naloxone, p. 1 5 6 3 . 3 . F o r details of doses i n children, s e e below.

Action_

Buprenorphine is generally described as a mixed agonist-antagonist acting mainly as a partial agonist at ll opioid receptors, with some antagonist activity at K recep­ tors. It has also been shown to bind at j.t, 6, and K opioid binding sites and to have high affinity for the ll and 6 receptors and lesser affinity for the K receptor. 1 Bupren­ orphine, like fentanyl, has high lipid solubility, but has a lower intrinsic activity than fentanyl. Differences between buprenorphine and pure j.l opioid agonists such as fentanyl, including relatively slow onset of action, pro­ longed duration of action, resistance to antagonism by nal­ oxone, and lack of correlation between plasma concentra­ tions and analgesic effects, have been explained by differences in the way buprenorphine binds to opioid receptors. In a study in vitro buprenorphine had slow rates of association and dissociation from the opioid receptor when compared with fentanyU 1.

Bovill JG. Which potent opioid? Important criteria for selection.

2.

Boas RA. Villiger JW. Clinical actions of fentanyl and buprenorphine:

1 987;

33:

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520-30.

the significance of receptor binding.

Br J Anaesth

1985;

57:

1 92-6.

Administration in children.

Buprenorphine is used for the relief of moderate to severe pain in children. In the UK. those aged from 6 months to 12 years may be given 3 to 6 micrograms/kg by intramuscular or slow intravenous injec­ tion every 6 to 8 hours; up to 9 micrograms/kg may be given if required in refractory cases. In the USA, par­ enteral buprenorphine is licensed in children aged 2 years and over; usual doses of 2 to 6 micrograms/kg may be given intramuscularly or intravenously every 4 to 6 hours to those up to 12 years old. The sublingual route is licensed in the UK in children aged from 6 to 12 years and the following doses are given every 6 to 8 hours according to body-weight: • 16 to 2 5 kg: ! OO micrograms • 25 to 3 7 . 5 kg: 1 00 to 200 micrograms • 3 7 . 5 to 50 kg: 200 to 300 micrograms Older children requiring pain relief may be given the usual adult dose (see p . 3 0 . 3 ) for all the above routes. Buprenorphine is also used in the treatment of opioid dependence; adolescents aged 16 years and over may be given the usual adult dose (see p. 3 0 . 3 ) .

Opioid dependence.

Buprenorphine is used i n the treat­ ment of opioid dependence (p. 1 09 . 2 ) . Its agonist-antago­ nist properties may mean that it has a lower potential for dependence and a lower risk of respiratory depression in overdose than pure agonists such as methadone. Bupren­ orphine can be used as substitution therapy in patients with moderate opioid dependence for acute management of withdrawal and in maintenance treatment as an alter­ native to or with methadone. However, in patients depen­ dent on high doses of opioids buprenorphine may precipi­ tate withdrawal due to its partial antagonist properties; the daily opioid dose should be reduced gradually in such patients before beginning buprenorphine. Abuse of the preparation, as with other substitution therapies, may be a The symbol

problem. A combined sublingual preparation of bupren­ orphine hydrochloride and naloxone hydrochloride is available in some countries as a deterrent to abuse. References. 1.

Kakko J,

1 -year retention and social function after buprenorphine­

et al.

assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial.

2.

Fudala PJ,

Lancet 2003; 361: 662-8.

Office-based treatment of opiate addiction with a

et al.

sublingual-tablet formulation of buprenorphine and naloxone. 3.

Med 2003; 349: 949-58. Montoya ID, et al. Randomized trial

4.

Fiellin DA,

concurrent opiate and cocaine dependence.

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N Bngl J

of buprenorphine for treatment of

Clin Pharmacal Ther 2004;

34-48. Consensus statement on office-based treatment of

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opioid dependence using buprenorphine.

J Subst Abuse Treat 2004; 27:

1 5 3-9. 5.

Danaher PA, Welsh C . Managing opioid addiction with buprenorphine.

Am Pam Physician 2006; 73: 6.

addiction. 7.

1 5 73-8.

Sung S, Conry JM. Role of buprenorphine in the management of heroin Robinson

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Buprenorphine-containing treatments:

management of opioid addiction.

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CNS Drugs 2006; 2:0:

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NICE. Methadone and buprenorphine for the management o f opioid dependence: 2007 ) .

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Boothby L A , Doering P L . Buprenorphine f o r t h e treatment of opioid dependence.

1 0 . Mattick RP, methadone

Am J Health-Syst Pharm et al. Buprenorphine

2007;

266-72.

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maintenance versus placebo or

maintenance for opioid dependence. Available in The

Cochrane Database of Systematic Reviews; Issue Wiley;

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26106/08).

1 1 . Sullivan LE, Fiellin DA. Narrative review: buprenorphine f o r opioid­ dependent patients in office practice. 1 2 . Schottenfeld RS,

et al.

Ann Intern Med 2008; 148:

662-70.

Maintenance treatment with buprenorphine and

naltrexone for heroin dependence in Malaysia: a randomised, double­ blind, placebo-controlled trial. 13. Woody GE,

et al.

Lancet 2008; 371: 2 1 92-2200.

Extended vs short-term buprenorphine-naloxone for

treatment of opioid-addicted youth: a randomized trial.

300: 200 3-l l .

Correction.

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JAMA 2008;

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14. Orman JS, Keating GM. Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence. 15. Gowing L,

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Buprenorphine

Drugs 2009; 69: for

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577-607.

management

of opioid

withdrawal. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley;

2009

(accessed 3 0 / 1 0 / 0 9 ) .

Poin. ACUTE PAIN.

The BNF considers that buprenorphine may antagonise the analgesic effect of other opioids and is generally not recommended for the management of post­ operative pain. Nonetheless, it can be given intramuscu­ larly, intravenously, or sublingually for this purpose, although the intravenous route may be preferred for acute pain relief. The epidural route 1 and continuous subcuta­ neous infusion2 have also been used; an intranasal formu­ lation of buprenorphine has been investigated for the management of postoperative pain 1 Patient-controlled analgesia with intravenous3 and intramuscular4 bupren­ orphine is effective although its long half-life may limit such use. Buprenorphine had no adverse cardiovascular effects when given intravenously after open-heart surgery, ' suggesting that it was a suitable analgesic for patients with unstable circulation. Epidural analgesia with bupren­ orphine has also been used after cardiac surgery. 6 Buprenorphine was also considered suitable for the relief of pain in myocardial infarction? I.

Miwa Y,

et al. Epidural administered buprenorphine in the perioperative Can J Anaesth 1 996; 43: 907- 1 3 . et a!. Pain management after lumbar spinal fusion surgery using continuous subcutaneous infusion of buprenorphine. J Anesth 2005; 19: 1 99-2 03. Dingus D J , et al. Buprenorphine versus morphine for patient-controlled analgesia after cholecystectomy. Surg Gynewl Obstet 1 993; 177: 1-6. Harmer M, et al. Intramuscular on demand analgesia: double blind period.

2.

3. 4.

Kawamata T ,

controlled trial of pethidine, buprenorphine, morphine, and meptazinol.

6.

BMJ 1 983; 2.86: 680-2. Rosenfeldt FL, et al. Haem adynamic effects of buprenorphine after heart surgery. BMJ 1 978; 2.: 1 602-3. Mehta Y, et al. Lumbar versus thoracic epidural buprenorphine for

7.

Acta Anaesthesiol Scand 1 999; 43: Hayes MJ, et a l . Randomised

5.

postoperative analgesia following coronary artery bypass graft surgery. 388-9 3 . trial comparing buprenorphine and

diamorphine for chest pain in suspected myocardial infarction. 1 979;

2::

BMJ

300-2.

Buprenorphine may have a lower potential for p roducing dependence than pure agonists such as morphine. However, it has been subject to abuse (see under Precautions, p. 3 2 . 2 ) . Abrupt withdrawal of buprenorphine is said to produce only a mild abstinence syndrome, which may be delayed in onset. Buprenorphine is used for substitution therapy in the management of opioid dependence (see under Uses and Administration, above) .

Adverse Effects and Treatment As for Opioid Analgesics in general, p . 1 ! 0 . 1 . Acute hepatotoxicity, including elevated liver enzyme values, hepatitis with jaundice, hepatic failure, necrosis, and encephalopathy, and hepatorenal syndrome, has been reported in opioid-dependent addicts; these reactions have also occurred after the misuse of buprenorphine, particularly after high doses or intravenous use. Local reactions such as rash, erythema, and itching have been reported with the transderrnal patches. In isolated cases delayed local allergic reactions with marked signs of inflammation have occurred; the patches should be withdrawn in such cases. US licensed product information for Butrans (Purdue, USA) also warns that prolongation of the QT interval has occurred with transdermal bupren­ orphine when given at a dose of 40 micrograms/hour. Treatment of adverse effects is similar to that for other opioid analgesics (p. 1 ! 0 . 3 ) . The effects of buprenorphine are only partially reversed by naloxone (see Effects on the Respiratory System, p . 32. 1 ) but use of the latter is still recommended.

Incidence of adverse effects. Adverse effects reported 1 after parenteral buprenorphine in 8 1 87 patients were nausea ( 8 . 8 % ) , vomiting (7.4% ) , drowsiness (4. 3 % ) , sleeping ( 1 . 9 % ) , dizziness ( 1 .2 % ) , sweating (0.98 % ) , headache ( 0 . 5 5 % ) , confusion ( 0 . 5 3 % ) , lightheadedness ( 0 . 3 8 % ) , blurred vision (0.28 % ) , euphoria ( 0 . 2 7 % ) , dry mouth ( 0 . 1 ! % ) , depression ( 0 . 09 % ) , and hallucinations ( 0 . 09 % ) . Some studies2•3 have reported nausea, vomiting, and dizziness to be more troublesome with buprenorphine than with morphine. In a study" of sublingual buprenorphine, 50 of 1 4 1 cancer patients withdrew because of adverse effects, especially dizziness, nausea, vomiting, and drowsiness; constipation was not reported. A woman developed' a painless ulcer on the upper surface of her tongue after she had put sublingual buprenorphine tablets on rather than under her tongue. Shock occurred' in 2 patients 2 hours after receiving epidural buprenorphine 300 micrograms; treatment with naloxone was unsuccessful but symptoms disappeared spontaneously after 2 to 3 hours. In a multicentre study7 of transdermal buprenorphine, 252 of 1 2 2 3 patients with moderate to severe cancer pain or non-cancer pain withdrew due to adverse effects. The most commonly reported were nausea ( 1 1 %), vomiting ( 9 . 2 % ) , constipation ( 7 . 8 % ) , dizziness ( 7 . 5 % ) , drowsiness (4. 0 % ) , retching ( 3 . 7 % ) , generalised pruritus ( 2 . 0 % ) , and headache ( 1 . 6 % ) ; local adverse effects included pruritus ( 1 .4 % ) , dermatitis ( 1 . 3 % ) , and erythema ( 1 . 3 % ) . Another study" reported oedema, headache, nausea, palpitation, and difficulty concentrating as causes for therapy withdrawal in 4 out of 90 patients. l.

3.

4. 5.

CHRONIC PAIN.

l.

BOhme K. Buprenorphine in a transdennal therapeutic system-a new

2.

Evans HC, Easthope SE. Transdennal buprenorphine.

option.

Clin Rheumato/ 2002; 2.1

(suppl 1 ) : S l 3-S 1 6 .

Drugs

2003;

63:

1 999-2 0 1 0 . 3.

Sittl R. Transdermal buprenorphine i n the treatment o f chronic pain.

Expert Rev Neurother 2005; 5:

3 1 5-23.

4.

Sittl R. Transdennal buprenorphine in cancer pain and palliative care.

5.

Kress HG. Clinical update on the pharmacology, efficacy and safety of

Palliat Med 2006; 2:0

(suppl l ) : S25-S30.

transdermal buprenorphine. 6. 7.

Bur J Pain 2009; 13:

2 1 9-30.

Bcilint G. Buprenorphine treatment of patients with non-malignant musculoskeletal diseases.

Clin Rheumatol 2002; 2: 1

(suppl 1 ) : S l 7- S l 8 .

Hans G. Buprenorphine-a review of i t s role in neuropathic pain.

Opioid Manag

2007;

J

3: 1 9 5-206.

et al.

Sear JW,

et al.

Methodology of monitored release ·of a new

1 979;

71.

51:

BMJ

1 979;

t denotes a preparation no longer actively marketed

The symbol

Br J Anaesth

Kjaer M,

et al. A comparative study of intramuscular buprenorphine and morphine in the treatment of chronic pain of malignant origin. Br J Clin Pharmacol 1 982; 13: 487-92. Robbie DS. A trial of sublingual buprenorphine in cancer pain. Br J Clin Pharmacol l 979; 7 (suppl 3 ) : 3 1 5 S-3 1 7 S . Lockhart S P , Baron J H . Tongue ulceration after lingual buprenorphine. Christensen

1 346.

FR,

7.

Muriel C,

Andersen

LW.

Adverse

reaction

Br J Anaesth 1 982; 54: 476. et al. Effectiveness and tolerability

to

extradural

of the buprenorphine

transdermal system in patients with moderate to severe chronic pain: a

8.

multicenter,

open-label,

clinical study.

Clin Ther 2005; 27: 45 1-62.

uncontrolled,

prospective,

observational

Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: results of a phase placebo-controlled study.

ill,

multicenter, randomized. double-blind,

Clin Ther 2004; 26: 1 8 08-20.

Effects on the heort. For a report of myocardial infarction

associated with abuse of buprenorphine, see Abuse under Precautions, p . 32.2.

Effects on mental function.

Psychotomimetic effects have been relatively uncommon with buprenorphine. Halluci­ nations were reported' in only 7 of 8 1 47 patients (0.09 % ) given buprenorphine by injection. There have been reports of hallucinations after sublinguaF or epiduraP use. Harcus A W ,

et al.

Methodology of monitored release

preparation: buprenorphine. BMJ 1 979;

0::P.:�.�:�.�:.9.�1...'!Y�!.�.1r.':'�".'··············· ········ ·· ··········

1 63-5 .

buprenorphine.

l.

As for Opioid Analgesics, p. 1 09 . 1 .

2:

Buprenorphine for postoperative analgesia.

BMJ 1 984; 288: 6.

Transderrnal buprenorphine is used for chronic intractable cancer pain . 1 " 5 It has also been used successfully in chronic non-cancer pain including neuro­ pathic pain; 1•3•5·7 however, licensed product information states that this route is not suitable for the treatment of acute pain.

Harcus AW,

preparation: buprenorphine.

2.

2.

orphine. 3.

2. :

of a

new

1 63-5.

Paraskevaides E C . Near fatal auditory hallucinations after bupren­

BMJ 1 988; 2:96:

2 1 4.

MacEvilly M, O'Carroll C. Hallucinations after epidural buprenorphine.

BMJ 1 989; 2.98:

928-9.

® denotes a substance whose use may be restricted in certain sports (see p. viii)

32 Ana lgesics Anti-i nfl a m matory Drugs and Antipyretics Effects on the respiratory system. There have been vary­ ing reports on the occurrence of respiratory depression with buprenorphine. It may be subject to a 'ceiling effect' in which respiratory depression does not increase further above doses of about 3 micrograms/kg . 1 However, high doses of 30 or 40 micrograms/kg given as sole intravenous analgesic in balanced anaesthesia have been associated with severe respiratory depression. 2 Respiratory depression may be delayed in onset and more prolonged than with morphine and is only partially reversed by naloxone, possibly because buprenorphine is very firmly bound to opioid receptors. A study of sublingual buprenorphine for postoperative pain relief was abandoned when 3 of the first I6 patients showed signs of late-onset respiratory depression after the second dose of bupren­ orphine; the respiratory depression did not respond to naloxone. ' Successful reversal has been shown in healthy subjects with buprenorphine-induced respiratory depres­ sion given large doses of naloxone 5 or I 0 mg, but not with I mg; reversal was gradual in onset and decreased the duration of the normally prolonged respiratory depression.• Other studies found that lower doses of naloxone 2 to 4 mg given over 30 minutes, 5•6 or bolus doses of 2 to 3 mg followed by a continuous infusion of 4 mg/hour, 6 were effective in reversing buprenorphine-induced respiratory depression. The authors of both these studies suggested that a longer duration of naloxone infusion may be needed for reversal of respiratory depression caused by high doses of buprenorphine. The respiratory depressant and analgesic effects of buprenorphine were decreased by the concomitant use of naloxone.7 It should be noted that a combined sublingual preparation of buprenorphine hydrochloride and naloxone hydrochloride is available in some countries for the treatment of opioid dependence. 1.

Dahan A,

Comparison of the respiratory effects of intravenous

et al.

buprenorphine and fentanyl in humans and rats.

Br J Anaesth 2005; 94:

825-34. 2.

Schmidt JF, respiratory

3.

et al.

Postoperative pain relief with naloxone: severe

depression

and pain

Anaesthesia

1 98 5 ; 40: 5 8 3-6.

ThOrn S·E,

et al.

buprenorphine. TJ.

after

high

dose

buprenorphine.

Prolonged respiratory depression caused by sublingual

Lancet

Naloxone

1 988; i: 1 79-80.

4.

Gal

5.

Dahan A . Opioid-induced respiratory effects: new data o n bupren­

depression.

reversal of

Clin Pharmacol Ther

buprenorphine-induced

respiratory

1 989; 45: 66-7 1 .

orphine.

6. 7.

PalliatMed 2006; ZO (suppl 1 ) : s3-s8. van Dorp E. et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology 2006; 105: 5 1-7. Lehmann KA. et al. Influence of naloxone on the postoperative analgesic and respiratory effects of buprenorphine. Bur J Clin Pharmacol 1 988; 34: 343-52.

Overdosage.

A small case series reported1 acute bupren­ orphine intoxication in 5 children, aged from I5 to 22 months, after accidental ingestion of sublingual tablets; of these, 4 had ingested a combined preparation containing naloxone (Suboxone; Reckitt Benckiser, USA ) . Symptoms included drowsiness and miosis; decreased respiratory rates were reported in 4. All 5 children required hospital admission; 4 were treated with naloxone and I needed mechanical ventilation. Accidental poisoning has also been reported' in a 9-month-old infant who ingested Sub­ axone; his symptoms were reversed by naloxone. A retro­ spective review' of buprenorphine overdoses in children under 6 years of age reported by US poison centres to a national surveillance system from November 2002 to December 2005 concluded that overdosage is generally well tolerated. Out of 86 reports, 54 children developed symptoms of toxidty. Such symptoms included: drowsi­ ness or lethargy ( 5 5 % ) , vomiting ( 2 I % ) , miosis ( 2 1 % ) , respiratory depression ( 7 % ) , agitation or irritability ( 5 % ) , pallor ( 3 % ) , and coma ( 2 % ) . There were no fatalities, and significant CNS and respiratory depression occurred in 7 % . Suboxone preparations were the most commonly ingested products. The authors considered that any child who has ingested more than 2 mg and any aged under 2 years who has had more than a lick or taste should be referred to the emergency department. During the years I 980 to 2002, buprenorphine was mentioned in 43 cases of adult fatalities in the UK.4 Of these, 27 deaths were confirmed to have involved buprenorphine including 7 cases where it was taken alone. In those deaths where multiple drugs were involved sedatives or benzo­ diazepines were detected in 2 3 cases and other opioids were found in I7 cases; alcohol had also been taken in IO cases. The authors also found an increase in buprenorphine­ related fatalities since 1 999 when the high-dose formulation became available. I.

2. 3.

Geib

A-J,

et al.

Adverse

buprenorphine exposure.

effects

Pediatrics

in

children

after unintentional

2006; 1 18: 1 746-5 1 .

Cho C S , e t al. Exploratory buprenorphine ingestion i n a n infant. Ann Emers Med 2006; 48: 1 09 . Hayes BD, et a l . Toxicity of buprenorphine overdoses in children. Abstract: Pediatrics 2008; 121: 807-8. Full version: http:l/pediatrics. aappublications.org/cgi/reprintf 1 2 1 /4/e782 (accessed 22/07/08)

4.

Schifano F,

et al.

Buprenorphine mortality, seizures and presoiption

data in the UK.. 1 980-2002.

Hum Psychopharmacol 2005; ZO:

All cross-references refer to entries in Volume A

343-8.

Precautions As for Opioid Analgesics in general. p. 1 1 0. 3 . Buprenorphine has opioid antagonist actions and may precipitate withdrawal symptoms if given to patients physically dependent on opioids. Respiratory depression, if it occurs, is relatively slow in onset and of prolonged duration; it may be only partially reversed by naloxone. Licensed product information states that baseline liver function levels should be established before starting buprenorphine therapy, and periodic monitoring of liver function should be performed throughout therapy in patients being treated for opioid dependence. It should be used with caution in all patients with pre-existing hepatic impairment. Absorption of buprenorphine from transdermal patches may be increased as the temperature tises and patients should therefore avoid exposing the patch to external heat; similarly, patients with fever may require monitoring because of increased absorption. It may take up to 30 hours for plasma concentrations of buprenorphine to decrease by 50% after removal of a patch; patients who have had adverse effects should be monitored during this period. US licensed product information for Butrans (Purdue, USA) recommends that transdermal buprenorphine should be avoided in patients with a personal or family history of QT interval prolongation and used with caution in those with hypokalaemia or unstable cardiac disease such as atrial fibrillation, congestive heart failure, or myocardial ischaemia.

Abuse.

A 22-year-old man had chest pains on each of two occasions after he had inhaled crushed buprenorphine tablets. 1 An ECG taken after the second episode suggested that the patient had suffered a myocardial infarction. Intravenous injection of crushed sublingual tablets was associated with rhabdomyolysis and sciatic neuropathy in 2 patients.2 A case series' of 4 patients reported severe limb and digit complications, such as ischaemia and gan­ grene, from parenteral abuse of sublingual buprenorphine tablets; intra-arterial injection in 2 cases resulted in ampu­ tation of the affected digits or limb. The use of adulterants in illicit preparations may also cause adverse effects: 4 patients on substitution treatment developed candida endophthalmitis after intravenously injecting sublingual buprenorphine diluted with lemon j uice.4 Hepatotoxicity has been seen in opioid-dependent addicts after buprenorphine abuse (see Adverse Effects and Treatment, p. 3 ! . 3 ) . I.

2.

3. 4.

Cracowski J-L, orphine.

e t al. Myocardial infarction Ann Intern Med 1 999; 130: 5 3 7 .

associated with bupren­

Seet R C S , Lim ECH. Intravenous u s e of buprenorphine tablets associated with rhabdomyolysis and compressive sciatic neuropathy. Ann Emery Med 2006; 47: 396-7. Lao HW, et al. Severe upper limb complications from parenteral abuse of Subutex. Ann Acad Med Singapore 2005; 34: 5 75-8. Cassoux N, et al. Presumed ocular candidiasis in drug misusers after intravenous use of oral high dose buprenorphine (Subutex). Br J Ophthalmol 2002; 86: 940-- 1 .

Breost feeding. From a study1 of a breast-feeding mother who was receiving sublingual buprenorphine 4 mg daily, it was estimated that at the age of 4 weeks the total amount ingested by the infant during a 24-hour period was 3 . 2 8 micrograms for buprenorphine and 330 nanograrns for norbuprenorphine. Another study2 found that bupren­ orphine, also taken sublingually, was present in the breast milk of a breast-feeding mother with a maternal milk-to­ plasma ratio of about one. The authors of both studies considered the amount absorbed through breast feeding to be low. Some licensed product information state that bupren­ orphine, regardiess of route, should not be given to mothers who are breast feeding. However, the BNF permits breast feeding and recommends that breast-fed infants should be monitored for opioid-induced adverse effects. Studies in rats have shown that it may inhibit lactation. L

2.

Marquet P,

et al. Buprenorphine withdrawal syndrome in a newborn. Clin Pharmacol Ther 1 997; 62: 569-7 1 . Johnson RE, e t al. Buprenorphine treatment o f pregnant opioid­ dependent women: maternal and neonatal outcomes. Dru9 Alcohol Depend 2 0 0 1 ; 63: 97-1 0 3 .

Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies buprenorphine as not porphyrinogenic; it may be used as a drug of first choice and no precautions are needed.1 L

The Drug Database f o r Acute Porphyria. Available a t : http:l/www. drugs-porphyria.org (accessed 2 2 / l 0/ 1 1 )

Pregnancy. An infant born t o a mother who was being treated with sublingual buprenorphine 4 mg daily for diamorphine addiction suffered a minor withdrawal syndrome 2 days after birth. 1 The infant rapidly recovered without any treatment. No further signs of withdrawal occurred when breast feeding was abruptly stopped at the

age of 8 weeks. In another report2 of 1 5 opioid-dependent mothers who had received buprenorphine maintenance sublingually during their pregnancies, withdrawal symp­ toms were either absent or mild in I2 of the neonates. The remaining 3 neonates required treatment with mor­ phine. There appeared to be no correlation between the buprenorphine dose and the degree of withdrawal symp­ toms. A literature review' found that of about 309 infants born to opioid-dependent mothers maintained on bupren­ orphine (sublingual dose range: 0.4 to 2 4 mg daily) , I 9 3 developed neonatal abstinence syndrome; of these, I49 required treatment. More than 40% of treated cases were confounded by misuse of other drugs. Onset of symptoms occurred within the first 12 to 48 hours and peaked within about 72 to 96 hours; duration of symptoms was about I 2 0 to 1 68 hours although in some infants, it was reported to last for 6 to I 0 weeks. The 6 7 pregnancies of 66 women using sublingual buprenorphine have been followed in a prospective study.4 The incidences of premature birth, caesarean section, and low Apgar scores in buprenorphine-exposed neonates were no greater than those seen in the general population although the mean birth-weight of the exposed neonates was significantly lower. In the exposed group, 9 1 % of neonates needed intensive care treatment: 76% had neonatal abstinence syndrome and 57% needed opioid replacement therapy. There were also 2 cases of sudden infant deaths in the exposed group, which was considered to be higher than that generally expected. 1. 2. 3.

Marquet P,

et al. Buprenorphine withdrawal syndrome in a newborn. Clin Pharmacol Ther 1 997; 6Z: 569-7 1 . Fischer G , e t al. Treatment o f opioid-dependent pregnant women with buprenorphine. Addiction 2000; 95: 2 3 9-44. Johnson RE, et al. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Druo Alcohol Depend 2003; 70 (suppl 2 ) : S87-S 1 0 1 .

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Kahila H ,

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A prospective study o n buprenorphine u s e during

pregnancy: effects on maternal and neonatal outcome.

Gynecol Scand 2007; 86:

Acta Obstet

1 85-90.

Interactions For interactions associated with opioid analgesics, see p. 1 1 ! . 2. Buprenorphine is metabolised by the cytochrome P450 isoenzyme CYP3A4; consequently, use with other drugs that induce or inhibit this isoenzyme may result in changes in plasma concentrations of buprenorphine and, possibly adverse effects. Some manufacturers state that dosage adjustment of buprenorphine may be necessary when used with such drugs. The UK licensed product information for one sublingual formulation (Subutex; Schering-Plough) recommends that the dose of buprenorphine should be halved when starting treatment with the potent CYP3A4 inhibitor, ketoconazole. There have been reports of respiratory and cardiovas­ cular collapse in patients given therapeutic doses of intravenous buprenorphine and diazepam. Use with other potentially hepatotoxic drugs may increase the risk of liver damage.

Anolgesics.

There is a risk that, with opioid agonist­ antagonists such as buprenorphine, their antagonistic effects might impair more effective analgesic therapy. This appeared to happen in 2 cancer patients both of whom were given sublingual buprenorphine that was later sub­ stituted by morphine.1 Conventional doses of morphine were inadequate and in one patient raising the dose of morphine proved fatal. 1.

Overweg-van Kints J, Stricker BHC. Falende pijnbestrijding tijdens sublinguaal gebruik van buprenorfine.

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Antivirals.

Various IllY-protease inhibitors and NNRTis can inhibit or induce cytochrome P450 isoenzymes, and most are also substrates for CYP3A4; thus, they have the potential to interact with buprenorphine. A pharmacoki­ netic study1 found that usual doses of neljinavir, ritonavir, and lopinavir-ritonavir given to HN-negative patients tak­ ing buprenorphine with naloxone for opiate dependence did not produce any clinically significant interactions: rito­ navir increased the area under the concentration-time curve (AUC ) of buprenorphine by about 5 7 % , although no adverse effects were seen. Another pharmacokinetic study' in a similar group of patients also found no clini­ cally significant interactions between buprenorphine with naloxone and delavirdine or efavirenz: delavirdine increased the AUC of buprenorphine fourfold, and efavirenz decreased it by about 5 0 % , but no adverse effects were seen. However, a small case series' of 3 opioid-dependent patients reported symptoms of buprenorphine toxicity, such as dizziness, daytime somnolence, and decreased mental functioning, with concomitant atazanavir and tito­ navir therapy.

Bu prenorp h i ne/Butorphanol Tartrate 33 Buprenorphine does not appear to significantly affect the pharmacokinetics of antiretrovirals. 1•2 1.

McCance-Katz EF,

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McCance-Katz EF,

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1-The

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IT-The

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Clin Pharmacokinet 2005;

44: 6 6 1 -80.

BUCCAL ROUTE.

Absorption of sublingual buprenorphine is relatively slow. In a I O-hour study1 plasma concentrations after 400 or 800 micrograms given sublingually peaked at about 200 minutes (range 90 to 360 ntinutes) and buprenorphine was still detected in plasma at the end of the study. Systentic availability was about 5 5 % (range I6 to 94% ) and absorption was more or less complete 5 hours after a dose. However, the authors of a subsequent study2 considered that this was an overestimation, possibly due to methodological flaws. The later study results indicated that the bioavailability of sub­ lingual buprenorphine is about 30% and that sublingual holding times between 3 and 5 minutes are bioequivalent. Another single-dose study' found that the bioavailability of sublingual buprenorphine was 5 0 % less from a tablet than from a liquid formulation. Later studies4•5 noted that the bioavailability of buprenorphine from a sublingual tablet relative to a sublingual liquid formulation was about 70% after daily dosing for 7 days. One of these stu­ dies• also found that the bioavailability of sublingual buprenorphine from a tablet formulation containing nal­ oxone was higher than from a singie-ingredient tablet for­ mulation and similar to that seen with liquid formula­ tions. 1.

Bullingham RES,

2.

Mendelson J,

et al.

3.

et al. Pharmacokinetics of intravenous buprenorphine in children. Br J Clin Pharmacol 1 989; lB: 202-4. Barrett DA. et al. The pharmacokinetics and physiological effect of buprenorphine infusion in premature neonates. Br J Clin Pharmacol 1 9 9 3 ; 36: 2 1 5-19.

Renal impairment. Buprenorphine clearance appears to occur mainly by hepatic extraction and metabolism and would not be expected to be related to renal function, whereas metabolites are excreted in urine. In a study, buprenorphine kinetics were sintilar in anaesthetised healthy patients to those in patients with renal impair­ ment, with a mean elintination half-life of 398 and 239 ntinutes, respectively. ' Plasma concentrations of the metabolites norbuprenorphine and buprenorphine-3 -glu­ curonide were increased about 4 times and I5 times, respectively in patients with renal impairment, 1 but signif­ icant pharmacological activity was unlikely since norbu­ prenorphine has little analgesic activity compared with the parent compound and buprenorphine- 3-glucuronide has none. l.

Hand CW,

et al.

Buprenorphine disposition in patients with renal

impairment: single and continuous dosing, with special reference to metabolites.

Br J Anaesth 1 990; 64:

276-82.

���!?.�.��.!��.�� ........................................................................... .

Proprielary Preparations (details are given in Volume B ) Single-ingredient Preparations. Arg.: Restiva; Austral.: Norspan;

Suboxone; Subutex; Temgesic; Austria: Suboxone; Subutex; Temgesic; Transtec; Triquisic; Belg.: Suboxone; Subutex; Temgesic; Transtec; Braz.: Temgesic; Canad.: BuTrans; Subox­ one; Cht1e: Transtec; China: Sha Fei (ill $ ); Shumeifen (iff � it); Cz.: Norspan; Ravata; Suboxone; Subutex; Temgesic; Transtec; Trapamaphin; Denm.: Buprenotex; Norspan; Norvip­ ren; Suboxone; Subutex; Temgesic; Transtec; Fin. : Norspan; Subutext; Temgesic; Fr. : Suboxone; Subutex; Temgesic; Ger.: Cras; Norspan; Suboxone; Subutex; Temgesic; Transtec; Gr.: Prenorvine; Suboxone; Subutex; Hong Kong: Suboxone; Subu­ text; Temgesic; Hung. : Buprent; Suboxone; Transtec; India: Addnok; Bunogesic; Buprigesic; Buprinor; Norphin; Pentorel; Tidigesic; Indon. : Suboxone; Subutex; Irl. : BuTrans; Centra­ dolt; Suboxone; Subutex; Temgesic; Transtec; Israel: BuTrans; Nopant; SBT; Subutex; Ital. : Suboxone; Subutex; Temgesic; Transtec; Jpn: Norspan; Malaysia: Suboxone; Mex.: Brospina; Temgesic; Transtec; Neth. : BuTrans; Suboxone; Subutext; Temgesic; Transtec; Norw.: Norspan; Suboxone; Subutex; Temgesic; NZ: Norspan; Suboxone; Temgesic; Philipp.: Nor­ span; Pol.: Bunondol; Suboxone; Transtec; Port. : Buprex; Nor­ spant; Suboxone; Subutex; Transtec; Trapamafin; Triquisic; Rus.: Bupranal (.6ynp8Hll.li ) ; Nopan (HonaH); Transtec (TpaHCTeK); S.Afr. : Subutex; Temgesic; Singapore: Temgesic; Spain: Buprex; Suboxone; Transtec; Swed. : Buprenotex; Nor­ span; Suboxone; Subutex; Temgesic; Switz.: Subutex; Temgesic; Transtec; Thai.: Buprinet; Turk.: Suboxone; UK: BuTrans; Hapoctasin; Suboxone; Subutex; Temgesic; Tephine; Transtec; USA: Buprenex; Butrans; Suboxone; Subutext.

Multi-ingredient Preparations. USA: Zubsolv. Phannacopaeial Preparations

BP 20 14: Buprenorphine Injection; Buprenorphine Sublingual Tablets; Buprenorphine Transderroal Patches.

et a l .

Br J Clin Pharmacol 1 982;

Compton P,

Relative bioavailability of different buprenorphine

et al.

Drug Alcolwl Depend 2004;

Pharmacokinetics, bioavailability and opioid effects of

liquid versus tablet buprenorphine.

Children.

Drug Alcohol Depend 2006; Bl: 25-3 1 .

The terminal elintination hall-life of bupren­ orphine was only about I hour in small children aged 4 to 7 years given 3 micrograms/kg intravenously as premedi­ cation, but could not be estimated reliably because of the rapid decline in plasma-buprenorphine concentrations. ' Clearance values did, however, appear higher than in adults; steady-state volume of distribution was similar. Premature neonates (gestational age 27 to 32 weeks) given a similar dose followed by an infusion of 720 nano­ grams/kg per hour had a considerably lower clearance rate and had a mean elimination hall-life of 20 hours. 2 Although this dosing regimen appeared t o be safe, seda­ tion was judged to be inadequate in 4 of the I2 neonates studied. It was suggested that as buprenorphine given by infusion ntight not produce consistent sedation and

BD,

et al.

Double-blind

comparison

of

intravenous

labor. 2.

Am J Obstet Gynecol 1994; 171: 993-8. Gillis JC, et al. Transnasal butorphanol: a review of its pharmacodynamic

and pharmacokinetic properties, and therapeutic potential in acute pain management. 3.

Commiskey

Drugs 1 995; 50: 1 57-75.

s. et al.

Butorphanol: effects of a prototypical agonist�

antagonist analgesic on

109-16.

K

�opioid receptors.

J Pharmacol Sd 2005; 98:

Administration in hepatic or renal impairment.

The dosage of butorphanol may need to be adjusted in patients with hepatic or renal impairment. When given by injec­ tion the initial dose for pain should be hall the usual initi­ a! dose (see above ) . Subsequent doses should be deter­ ntined by the patient's response; a dosage interval of at least 6 hours has been recommended. For nasal use the initial dose should be limited to I mg followed by I mg after 90 to I20 minutes if necessary; subsequent doses if required should generally be given at intervals of not less than 6 hours.

Headache. Butorphanol has been advocated for use as a nasal spray in the treattnent of ntigraine, but there have been problems with abuse and dependence ( see p. 34. I ) and its place in therapy, if any, still remains to be estab­ lished. See also Antintigraine Drugs, under Interactions, p. 34.2.

3.

74: 37-43.

5.

Atkinson

butorphanol (Stadol) and fentanyl (Sublimaze) for analgesia during

Freitag

FG.

The

acute

treatment

of

migraine

with

transnasal

(TNB). Headache Q 1993; 4 (suppl 3): 22-8. et al. Transnasal butorphanol in the treatment of acute migraine. Headache 1 99 5 ; 35: 65-9. Melanson SW, et al. Transnasal butorphanol in the emergency department management of migraine headache. Am J Emera Med 1 997; 15: 57-6 1 .

butorphanol

et a!. Bioavailability of sublingual buprenorphine. J Clin Pharmacol 1 997; 3 7 : 3 1 -7 . Nath RP, et al. Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 1 999; 39: Strain E C ,

1.

1.

665-7 3 .

formulations under chronic dosing conditions.

References.

2.

6 1 9-2 3 . 4.

1 5 minutes of intramuscular injection or a n intranasal dose and may last for 3 to 4 hours after parenteral doses or for 4 to 5 hours after intranasal doses. For the relief of moderate to severe pain, butorphanol tartrate is given in doses of I to 4 mg (usually 2 mg) by intramuscular injection or in doses of 0.5 to 2 mg (usually I mg) by intravenous injection every 3 to 4 hours. It may also be given as a nasal spray, in usual doses of I mg (I spray in I nostril), repeated after 60 to 90 minutes, if necessary. This sequence may be repeated after 3 to 4 hours as needed. An initial dose of 2 mg ( I spray in each nostril) may be given for severe pain, but should not be repeated until 3 to 4 hours later. In obstetric analeesia I to 2 mg may be given by intramuscular or intravenous injection during early labour in women at term. This dose may be repeated after 4 hours if necessary but an alternative analgesic should be used if delivery is expected within 4 hours. In anaesthesia, 2 mg may be given intramuscularly for premedication 60 to 90 ntinutes before surgery. For use in balanced anaesthesia, a usual dose is 2 mg given intravenously shortly before induction and/or 0.5 to I mg given intravenously in increments during anaesthesia. The total dose needed varies but most patients require 4 to I 2 . 5 mg. Dosage adjustment may be needed in the elderly. When given by injection the initial dose of butorphanol for pain should be half the usual initial adult dose. Subsequent doses should be determined by the patient's response; a dosage interval of at least 6 hours has been recommended. For nasal use the initial dose should be lintited to I mg followed by I mg after 90 to I 2 0 minutes if necessary; subsequent doses if required should generally be given at intervals of not less than 6 hours . Similar recommendations have also been made for patients with hepatic or renal impairment, see below.

References.

Sublingual buprenorphine used postoperatively:

ten hour plasma drug concentration analysis.

13:

Olkkola KT.

2006; 43 (suppl 4 ) : 5 2 3 5-5246.

Bruce RD, Altice FL. Three case reports of a clinical pharmacokinetic

After intramuscular injection, buprenorphine rapidly reaches peak plasma concentrations. Absorption also takes place through the buccal mucosa after sublingual doses and peak plasma concentrations occur after 90 minutes. Transdermal application results in absorption through the skin; the ntinimum effective concentration is reached in I 2 t o 24 hours and peak plasma concentrations occur after about 60 hours. However, there is a lack of correlation between plasma concentrations and analgesic activity. Buprenorphine is about 96% bound to plasma proteins. Elimination of buprenorphine is bi- or triphasic; metabolism takes place in the liver by oxidation via the cytochrome P450 isoenzyme CYP3A4 to the pharmacolo­ gically active metabolite N-dealkylbuprenorphine (norbu­ prenorphine ) , and by conjugation to glucuronide metab­ olites. Buprenorphine is subject to considerable first-pass metabolism after oral doses. However, when given by the usual routes buprenorphine is excreted mainly unchanged in the faeces; there is some evidence for enterohepatic recirculation. Plasma elintination hall-lives have ranged from 1 . 2 to 7 . 2 hours after intravenous injection; elimination hall-lives after sublingual or transdermal use are longer and may range from 2 0 to 3 6 hours or more. Metabolites are excreted in the urine, but very little unchanged drug is excreted in this way. Buprenorphine crosses the placenta and small amounts are distributed into breast milk. 1.

2.

Interactions between buprenorphine and protease

interaction with buprenorphine and atazanavir plus ritonavir. 2006; 20:

1.

nonnudeoside reverse-transcriptase inhibitors

efavirenz and delavirdine. antiretrovirals:

analgesia in premature neonates, it could not be recom­ mended for use in neonatal care.

Interactions between buprenorphine and

Pharmacopoeias. In

us.

USP 36: (Butorphanol Tartrate) . A white powder. Its solutions are slightly acidic. Sparingly soluble in water; insoluble in alcohol, in chloroform, in ether, in ethyl acetate, and in hexane; slightly soluble in methyl alcohol; soluble in dilute acids. Store in airtight containers at a temperature of 25 degrees, excursions permitted between I5 degrees and 30 degrees.

Uses and Administration Butorphanol tartrate, a phenanthrene derivative, is an opioid analgesic (p. I 08 . I ) with opioid agonist and antagonist properties; it is pharmacologically sintilar to pentazocine (p. 1 2 0. 3 ) . Butorphanol is used for the relief of moderate to severe pain, including the pain of labour, and as an adjunct to anaesthesia. Onset of analgesia occurs within

The sytnbol t denotes a preparation no longer actively marketed

Hoffert MJ,

Pruritus. Results from a small study1 o f 6 patients with severe opioid-induced pruritus unresponsive to diphen­ hydrantine, and from a case series of 5 patients with intractable pruritus from other causes,> suggest that intra­ nasal butorphanol may be an effective treattnent. Doses have ranged from I mg every other day to 2 mg every 4 to 6 hours. 1.

Dunteman E,

et al. Transnasal butorphanol for the treatment

of opioid�

induced pruritus unresponsive to antihistamines. J Pain Symptom Manage 1 996; 2.

ll: 2 5 5-60.

Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus.

J Am Acad Dermato1 2006; 54:

527-3 1 .

e:e:�.�f!.�.::.9.�1...�!!.�.�:.9.��.'.. ................................

. As for Opioid Analgesics, p. 1 0 9 . 1 . Butorphanol may have a lower potential for producing dependence than pure agonists such as morphine. However, it has been subject to abuse (see under Precautions, p. 34. I ) . Abruptly stopping chronic butorphanol has produced a less severe withdrawal syndrome than with morphine.

34 Ana lgesics Anti-i nfla m matory Drugs and Antipyretics

Adverse Effects and Treatment As for Opioid Analgesics in general, p. 1 1 0 . 1 , and for Pentazocine, p. 1 2 1 . 1 . Headache, and feelings o f floating may also occur. Hallucinations and other psychotomimetic effects are rare and have been reported less frequently than with pentazocine. In addition insomnia and nasal congestion may occur frequently when butorphanol is given intranasally. Because butorphanol has opioid agonist and antagonist activity, naloxone is the recommended antagonist for the treatment of overdosage.

Effects on the respiratory system. Butorphanol

2 mg pro­ duces a similar degree of respiratory depression to mor­ phine I 0 mg, but a ceiling effect is apparent with higher doses of butorphanol. l It has been reported to be a less potent respiratory depressant than fentanyl,2 but more potent than nalbuphine.3 1,

Nagashima H,

et al.

Respiratory and drculatory effects of intravenous

butorphanol and morphine. 2.

Clin Pharmacol Ther

1 976; 19: 7 3 8-45.

Dryden GE. Voluntary respiratory effects of butorphanol and fentanyl following barbiturate induction: a double-blind study.

J Clin Pharmacal

1 986; 26 : 203-7. 3.

Zucker JR,

et al.

Respiratory effects of nalbuphine and butorphanol in

anesthetized patients.

Anesth Analg

1 987; 66: 879-8 1 .

Precautions As for Opioid Analgesics in general, p. 1 1 0 . 3 . Although cardiovascular effects may be less than with pentazocine, butorphanol should generally be avoided after myocardial infarction. Butorphanol may precipitate withdrawal symptoms if given to patients physically dependent on opioids. The dosage regimen of butorphanol may need to be adjusted in the elderly and in patients with hepatic or renal impairment.

Abuse.

A WHO expert committee considered in 2006 that the likelihood of butorphanol abuse was low and was not great enough to warrant international control . 1 Abuse had been reported infrequently and only in a few countries. The committee also commented that, pharmacologically, intranasal preparations of butorphanol do not appear to differ in their abuse potential from parenteral prepara­ tions; however, other factors such as availability and usage patterns may affect the likelihood of abuse. Indeed, US licensed product information states that there have been more reports of abuse with intranasal preparations than with injectable ones. Cases of butorphanol abuse have been published2•3 including a report of fibrous myopathy associated with chronic intramuscular abuse. 1.

Antimigraine drugs. No pharrnacokinetic interactions were reported when butorphanol nasal spray and subcuta­ neous sumatriptan were used within a minute of each other in healthy subj e cts . 1 However, another study2 in healthy subjects found that the AUC and peak plasma concentration of intranasal butorphanol were reduced by about 29% and 38%, respectively when given I minute after intranasal sumatriptan. No such effect was noted when administration was separated by 30 minutes. It was suggested that sumatriptan may reduce butorphanol absorption by inducing transient nasal vasoconstriction. 1,

Srinivas NR,

et al.

Lack

of pharmacokinetic interaction between

butorphanol tartrate nasal spray and sumatriptan succinate, 2.

Pharmacol 1995; 3S: 432-7. Vachharajani NN, et al. A pharmacokinetic butorphanol

and

sumatriptan

nasal

J Clin

sprays

in

healthy

importance of the timing of butorphanol administration.

subjects:

WHO Tech Rep Ser 942

Pharmacokinetics of butorphanol tartrate administered

from single-dose intranasal sprayer.

Am J Health-Syst Pharm

2004; 61:

2 6 1 -6. 2.

Davis GA,

et al.

Bioavailability of intranasal butorphanol administered

from a single-dose sprayer. 3.

Wermeling D P ,

et al.

Am J Health-Syst Pharm 2005; 62:

48- 5 3 .

Pharmacokinetics, bioequivalence, a n d spray

weight reproducibility of intranasal butorphanol after administration with 2 different nasal spray pumps.

J Clin Pharmacol 2005; 45:

969-7 3 .

�-��!?.�.��-���-�� ........................................................................... .

Proprielary Preparations (details are given in Volume B ) Single-ingredient Preparations. China: Nuo Yang (*'�Pi);

India: Butodol; Butrum; Mex.: Stadol; Philipp. : Stadolt; Rus.: Stadol (Cr8110JI ); USA: Stadol.

Pharmacopoeial Preparations

USP 36: Butorphanol Tartrate Injection; Butorphanol Tartrate

Nasal Solution.

Canakinumab

3,

Loder E . Post-marketing experience with an opioid nasal spray for

Rheumatol l 9 9 1 ;

(BAN, USAN, riNNJ

J

18: 1 9 3 4-5.

migraine: lessons for the future.

Cephalalgia

2006; 26: 89-97.

Breost feeding.

No adverse effects have been seen in breast-fed infants whose mothers were given butorphanol, and the American Academy of Pediatrics considers1 that it is therefore usually compatible with breast feeding. In a study2 of 12 women, butorphanol was detected in breast milk after both intramuscular and oral doses. However, the milk-to-plasma ratio after a 2-mg intramus­ cular dose (0.7) was significantly less than that after an 8-mg oral dose ( I . 9 ) . Although the mothers were not breast feeding at the time of the study, the authors concluded that the potential for any adverse effects on nursing infants after maternal butorphanol use would be minimal. 1.

American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. 2010]

Correction.

ibid.;

Pediatrics

1029.

2 0 0 1 ; 108: 776-89. [Retired May

Also

available

at:

http://aappolicy.

aappublications.org/cgi/content/full/pediatrics % 3 b 1 08/3/776 (accessed 26/06/08) 2.

KA, et al. Human perinatal Obstet Gynecol 1 980; 138: 797-800.

Pittman

distribution of butorphanol.

Am J

Pregnancy. Two instances of sinusoidal fetal heart rate pattern were noted out of 1 88 consecutive cases of butor­ phanol use in active-phase labour. ' Visual hallucinations and paranoid delusions developed in a woman on receiv­ ing a 1 -mg intravenous injection of butorphanol early in labour; the psychosis had resolved 40 hours after the injection and was not noted on follow-up 2 weeks later -' 1. 2.

Welt SL Sinusoidal fetal heart rate and butorphanol administration.

J Obstet Gynecol 1 985; 1 52 : 362-3. A, et al. Acute psychosis Neuropsychiatr Clin Neurosci 1 998; 10:

Davis

Am

associated with butorphanol.

J

2 36-7.

Interactions For interactions associated with opioid analgesics, see p. 1 1 1 . 2 . All cross-references refer t o entries i n Volume A

et al.

Use of canakinumab in the cryopyrin-assodated

N Engl J Med 2009; 360:

2 4 1 6--2 5 .

Canakinumab in C A P S Study Group. Sustained

patients with cryopyrin-associated periodic syndrome treated with

3.

Administration. INTRANASAL ROUTE. References. et a!.

RJ, et al.

Kone-Paut I,

withdrawal study.

Butorphanol is absorbed from the gastrointestinal tract but it undergoes extensive first-pass metabolism. Peak plasma concentrations occur 0 . 5 to I hour after intramuscular and intranasal doses and I to I. 5 hours after oral doses. Butorphanol has a plasma elimination half-life of about 4 . 5 hours. About 80% is bound to plasma proteins. Butorphanol is extensively metabolised in the liver through hydroxylation, N-dealkylation, and conjugation; only 5% being excreted unchanged. Excretion is mainly in the urine; about 1 5 % of a parenteral dose is excreted in the bile. It crosses the placenta and is distributed into breast milk.

Davis GA,

Lachmann

periodic syndrome.

canakinumab: results of a double-blind placebo-controlled randomized

Pharmacokinetics

1.

·

remission of symptoms and improved health-related quality of life in

2002; 22: 282-7.

2006. Also available at: http://libdoc.who.

Wagner JM, Cohen S . Fibrous myopathy from butorphanol injections.

1. 2.

Cephalalgia

int/trs/WHO_TRS_942_eng.pdf (accessed 26/06/08) 2.

References.

interaction study between

WHO. WHO expert committee on drug dependence: thirty-fourth report.

every 8 weeks. A second dose of 1 5 0 mg may be given 7 days after the initial dose if the response has been unsatisfactory; if this produces a full response after 7 days, the dose should be maintained at 300 mg every 8 weeks. If the response has been unsatisfactory, a third dose of 300 mg may b e given 7 days after the second dose and if this produces a fuil response after 7 days, the dose should be maintained at 600 mg every 8 weeks. For details of use and dosage in children, including use in juvenile idiopathic arthritis, see Administration in Children, below.

Schlesinger N,

Arthritis Res Ther 2 0 1 1 ; 13: R202. et al. Canakinumab for acute gouty arthritis

with

treatment

limited

multicentre, extensions. 4.

Ruperta

options:

results

from

two

in patients

randomised,

active-controlled, double-blind trials and their initial

Ann Rheum Dis 2 0 1 2 ; 71: 1 8 3 9-48. et al. PRINTO. PRCSG. Two

N,

randomized

canakinumab in systemic juvenile idiopathic arthritis.

trials

of

N Engl J Med

2 0 1 2; 367: 2 3 9 6--2406.

Administration in children.

Canakinumab may be used in children for the treatment of cryopyrio-associated periodic syndromes ( CAPS ) including familial cold auto-inflamm­ atory syndrome (FCAS) and Muckle-Wells syndrome (MWS ) . It is given by subcutaneous injection as a single dose, according to age and body-weight. In the UK, the following regimen is used in children aged 2 years or older: • � 2 years, weighing � 7. 5 kg and < 15 kg: 4 mg/kg initially, followed by a usual maintenance dose of 4 mg/kg every 8 weeks; a second dose of 4 mg/kg may be given 7 days after the initial dose if the response has been " unsatisfactory, and if this produces a full response after 7 days, the dose should be maintained at 8 mg/kg every 8 weeks • � 4 years, weighing � 1 5 kg and ,;;; 40 kg: 2 mg/kg initially, followed by a usual maintenance dose of 2 mg/kg every 8 weeks; a second dose of 2 mg/kg may be given 7 days after the initial dose if the response has been unsatisfactory, and if this produces a full response after 7 days, the dose should be maintained at 4 mg/kg every 8 weeks. If the response has been unsatisfactory, a third dose of 4 mg/kg may be given 7 days after the second dose and if this produces a full response after 7 days, the dose should be maintained at 8 mg/kg every 8 weeks • � 4 years, weighing > 40 kg: the usual adult dose (see Uses and Administration, above) may be given Similar initial doses are used in the USA in children aged 4 years and over, and weighing at least 1 5 kg; a dose of 3 mg/kg has been suggested for those with an inadequate response. Canakinumab is also licensed for the treatment of active systemic juvenile idiopathic arthritis (p. 1 2 . 1 ) in children aged 2 years or older. The recommended dose in those weighing 7 . 5 kg or more is 4 mg/kg (maximum of 300 mg) given as a single subcutaneous injection every 4 weeks.

Adverse Effects and Precautions Uses and Administration Canakinumab is a recombinant human monoclonal interleukin - 1 � antibody used for the symptomatic treatment of frequent gouty arthritis attacks (defined as at least 3 attacks in the previous 12 months) when the use of NSAIDs and colclticine are contra-indicated, not tolerated, or produce an inadequate response, and repeated courses of corticosteroids are inappropriate. Canakinumab may be used for the treatment of juvenile idiopathic arthritis. It is also used in the management of cryopyrin -associated periodic syndromes ( CAPS ) including familial cold auto­ inflammatory syndrome ( F C A S ) and Muckle-Wells syndrome (MWS ) , which are rare inherited auto-inflamm­ atory disorders. For the treatment of gouty arthritis attacks, canakinu­ mab should be used as on -demand therapy; hyperuricaemia should be managed with appropriate urate-lowering therapy (see Gout and Hyperuricaemia, p. 600. 1 ) . The recommended dose is 1 5 0 mg given by subcutaneous injection as a single dose as soon as possible after the onset of an attack. Patients who do not respond to initial treatment should not be re-treated with canakinumab. Those who respond may be given another dose at least 1 2 weeks after the initial dose. For the treatment of CAPS, canakinumab is given by subcutaneous injection as a single dose; patients with a body-weight greater than 40 kg may be given an initial dose of 1 5 0 mg, followed by a usual maintenance dose of I S O mg

The adverse effects reported most commonly with canakinumab are headache, nasopharyngitis, nausea, diarrhoea, respiratory-tract infections including influenza, and vertigo. Injection site reactions have also occurred. Canakinumab has been associated with an increased incidence of serious infections and it should therefore be given with caution to patients with active infections, a history of recurring infections, or underlying conditions that may predispose them to developing infections. Canakinu­ mab treatment should not be started or continued in patients with severe infections that require treatment. Patients should be screened for active and latent tuberculosis infection before starting canakinumab treat­ ment. Patients should be up to date with appropriate inununisation schedules, including pneumococcal vaccine and inactivated influenza, before starting treatment with canakinumab; live vaccines should not be given at the same time as canakinumab unless the benefits clearly outweigh the risks ( see also Interactions, p. 3 5 . 1 ) . Treatment with canakinumab should not b e started in patients with neutropenia, and it is recommended that neutrophil counts should be taken before starting treatment, I to 2 months later, and periodically thereafter. Patients who have vertigo during treatment with canakinumab should avoid driving or operating machinery.

Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAP O S ) and the Porphyria Centre Sweden, classifies canakinumab as possibly porphyrinogenic; it should be used only when no

Ca naki n u ma b/Ca psa icin 35 safer alternative is available and precautions should be considered in vulnerable patients. ' l.

The Drug Database for Acute Porphyria. Available at: http:lfwww. drugs-porphyria.org (accessed

06110/ 1 1 )

Interactions There are no formal interaction studies with canakinumab; however, it is recommended that live vaccines should not be given at the same time as canakinumab as its effect on vaccine efficacy or the risk of infection transmission is unknown. If use together is unavoidable, live vaccines should not be given until at least 3 months after the last, and before the next, dose of canakinumab. The use of TNF inhibitors with canakinumab may increase the risk of serious infections and neutropenia; such combinations are not recommended. A sintilar effect may also occur when used with other interleukin - 1 antagonists. During inflammation the expression of cytochrome P450 isoenzymes is suppressed by cytokines such as interleukin1 f3, and cytochrome P450 expression may therefore be normalised when treatment with a cytokine inhibitor such as canakinumab is started. This becomes clinically significant for cytochrome P450 isoenzyme substrates that have narrow therapeutic ratios where the dose has to be individually adjusted (e.g. warfarin) . Therefore when starting or stopping therapy with canalcinumab, patients being treated with such drugs should be monitored as doses of these drugs may need to be adjusted.

Pharmacokinetics Peak serum concentrations occur about 7 days after a single subcutaneous injection of canakinumab; the mean terminal half-life is about 26 days. The absolute bioavailability was estimated to be 6 6 % .

Although not a counter-irritant itself, capsaicin has been included in rubefacient preparations for the relief of muscular and rheumatic pain. A high-concentration transdermal patch containing cap­ saicin 8% (equivalent to 1 79 mg in total) is available for the treatment of peripheral neuropathic pain in non-diabetic patients, either as monotherapy or as an adjunct. The treatment area and surrounding 1 to 2 em should be pretreated with a topical anaesthetic before applying the patch, for example, topical lidocaine 4% left for 60 minutes. Up to a maximum of 4 patches may be applied to the most painful areas of the skin and left in place for 30 minutes on the feet (e.g. in IDV-associated neuropathy) or for 60 minutes on other locations (e.g. in postherpetic neuralgia) . Treatment may b e repeated every 90 days i f necessary. A long-acting topical solution has been investigated for painful conditions such as postoperative, musculoskeletal, and trauma-induced neuropathic pain including interdigital neuroma.

Action.

The action of capsaicin and related compounds (vrutilloids) are complex and still being investigated. Cap­ saicin has been found to produce burning pain'·' by acti­ vating specific vanilloid receptors such as TRPV1 (transient receptor potential channel, vanilloid subfantily member I ) which are also stimulated b y heat and acids. TRPVI is expressed by nerves and other tissues such as the kerati­ nocytes of the epidermis, bladder urothelium and smooth muscle, and liver. The analgesic effect of capsaicin has been suggested to be due to both depletion of substance P from local sensory C­ type nerve fibres•·• and to the desensitisation of vanilloid receptors. 1 - 3 •9 Since the effect of capsaicin does not rely on vasodilatation in the skin it is therefore not considered to be a traditional counter-irritant. 1.

References. 1.

Szallasi

A,

Blumberg

mechanisms.

Chakraborty A.

et al. Phannacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin- 1 fl monoclonal antibody. Clin Pharmacokinet 2012; 5 1 : e l --e l 8 .

2.

receptor TRPVl : an update.

.

Proprielary Preparations (details are given in Volume B ) Single-ingredient Preparations. Austral.: natis; Austria: llaris;

Braz. : llaris; Canad. : Ilaris; Cz.: Ilaris; Denm.: Ilaris; Fr.: Ilaris; Ger.: llatis; Gr.: llatis; Irl. : llatis; Israel: naris; Ita/. : narts; Jpn: llatis; Neth.: naris; Norw.: Ilaris; NZ: llatis; Pol.: narts; Port.: llatis; Spain: naris; Swed. : narts; Switz. : naris; Turk. : naris; UK: llatis; USA: llaris.

Vanilloid

(capsaicin)

receptors

and

Bur J Biochem 2004; 271:

1 8 1 4- 1 9 .

3.

Wang Y. The functional regulation of TRPVl a n d i t s role in pain

4.

Rumsfield JA, West D P . Topical capsaicin i n dermatologic and peripheral

sensitization.

P.��P.�.��.���.�� ...........................................................................

PM.

Pharmacol Rev 1 999; 51: 1 5 9-2 1 1 .

Cortright DN, Szallasi A . Biochemical pharmacology o f the vanilloid

Neurochem Res 2008; 33: 2008--12.

pain disorders.

5.

DICP Ann Pharmacother

1 9 9 1 ; 2:5:

381-7 .

Cordell GA, Araujo O E . Capsaicin: identification, nomenclature, and pharmacotherapy.

6.

Winter J,

Ann Pharmacother 1993; 27: 330-6. et al. Capsaicin and pain mechanisms. Br J Anaesth 1 995; 75:

1 5 7-68. 7.

Del Bianco E,

et al. The effects of repeated dermal application of capsaicin

to the human skin on pain and vasodilatation induced by intradermal

Andersson K-E,

et al. Intravesical vanilloids and neurogenic incontinence: ten Urol Int 2004; 72: 145-9. et al. Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence. Curr Opin Urol 2009; 19: 380-94. 1 1 . Yamaguchi 0, et al. Neurogenic Bladder Society. Clinical guidelines for overactive bladder. Int J Urol 2009; 16: 126-42. 12. Bultitude MI. Capsaicin in treatment of loin pain/haematuria syndrome. Lancet 1 995; 345: 92 1-2. 1 3 . Uzoh CC, et al. The use of capsaicin in loin pain-haematuria syndrome. BJU Int 2009; 103: 2 3 6-9. years experience.

Neuropathic pain. Capsaicin has been tried topically in various types of pain including neuropathic pain, which does not generally respond to conventional systemic anal­ gesics. Topical capsaicin crerun (in a usual strength of 0.075 % ) is used in the management of diabetic neuro­ pathy (p. 8.2) and postherpetic neuralgia (p. 1 0 . 3 ) . A high-concentration transdermal capsaicin patch 8% is also available for the treatment of peripheral neuropathic pain in non-diabetic patients. A systematic review' suggested that capsaicin, given as either a repeated dose of the cream or a single application of the patch, was of benefit in neuropathic pain, although limited data and inconsis­ tent definition of outcomes meant that estimates of benefit and harm were not robust. Other types of pain syndrome for which capsaicin has been tried include reflex sympa­ thetic dystrophy (see Complex Regional Pain Syndrome, p. 8 . 1 ) , postmastectomy neuroma, amputation stump pain, chronic neck pain, and the pain of oral mucositis.' See also Rheumatic Disorders, below, for use in musculoskeletal pain. I.

Derry S,

et al. Topical capsaicin

Chichester: John Wiley;

2.

for chronic neuropathic pain in adults.

Available in The Cochrane Database of Systematic Reviews; Issue Hautkappe M ,

e t al.

2009

Review o f the effectiveness o f capsaidn for painful

cutaneous disorders and neural dysfunction.

Clin J Pain

1 998; 14:

Pruritus. Substance P is a possible mediator of itch sensa­ tions and since capsaicin acts as a depletor of substance P it has been tried in the relief of pruritus (p. 1 687. 3 ) asso­ ciated with various diseases and haemodialysis. 1·8 It has also been used to provide relief from pruritus induced by hetastarch9 and for the itch and pain associated with PUVA therapy.10• 1 1 However, a systematic review12 in 2 0 1 0 considered that there was currently no convincing evidence that topical capsaicin was effective for the treat­ ment of pruritus in any medical condition. l.

Leibsohn E . Treatment of notalgia paresthetica with capsaicin.

3.

Hautmann G,

Tominaga M, Julius D . Capsaicin receptor in the pain pathway.

Jpn J

Pharmacol 2000; 83: 20-4.

In the USA. capsaicin cream is licensed in children, for details see above.

Breneman DL,

et al. Topical capsaicin for treatment J Am Acad Dermatol 1 992; 26: 91-4.

of hemodialysis­

related pruritus.

4.

Aclminis1ration in children.

97-

106.

2.

Drugs 1 997; 53: 909-14.

4.

(accessed 29/0 1 1 1 0) .

Br J Clin Pharmacol 1 996; 41:

1-6.

9.

Lazzeri M,

10.

Fusco BM, Giacovazzo M. Peppers and pain: the promise of capsaicin.

injection of add and hypertonic solutions.

8.

9.

1 992; 49: 3 3 5-6. et al. Aquagenic pruritus. Br J Dermatol 1994; 1 3 1 : 920- l .

POlster-Holst R , Brasch J. Effect of topically applied capsaicin o n pruritus

in patients with atopic dermatitis.

5.

Cutis

PUVA and capsaicin treatments.

Hautkappe M ,

e t al.

J Dermatol Treat 1 996; 7: 1 3- 1 5 .

Review o f the effectiveness o f capsaicin for painful

cutaneous disorders and neural dysfunction.

Clin J Pain 1 998; 14: 97-

106.

Headache.

Prevention of attacks of cluster headache (p. 670. 1 ) by repeated application of capsaicin to the nasal mucosa has been reported.' The Z-isomer (zucapsaicin; civamide) has also been found to be modestly effective. 2 Repeated nasal application of capsaicin has also been found to be effective in chronic migraine' (p. 670. 3 ) .

Do not confuse capsrucm with caps1cm, which is capsicum oleoresin (see Capsicum, p. 2469. 3 ) .

NOTE.

Pharmacopoeias. I n US. USP 3 6 : (Capsaicin ) . An off-white powder. M.p. 57 degrees to 66 degrees. Practically insoluble in cold water; soluble in alcohol. in chloroform, and in benzene; slightly soluble in carbon disulfide. Store in a cool place in airtight containers. Protect from light.

Uses and Administration Capsaicin is the active principle of the dried ripe fruits of Capsicum spp. It is used as a topical analgesic (p. 6 . 3 ) in peripheral neuropathic pain including postherpetic neur­ algia after the lesions have healed and diabetic neuropathy (see Neuropathic Pain, below), and in osteoarthritis and rheumatoid arthritis (see Rheumatic Disorders, below ) . Capsaicin is usually applied sparingly 3 or 4 times daily (and not more often than every 4 hours) as a 0.02 5 % or 0 . 0 7 5 % cream; in the UK these creruns are not licensed for use in children, but in the USA they may be used in children over 2 years of age. A more concentrated crerun containing 0 .2 5 % capsaicin is available in some countries. Capsaicin cream should be rubbed well into the skin until little or no residue is left on the surface. Therapeutic response may not be evident for 1 to 2 weeks for arthritic disorders, or 2 to 4 weeks for neuralgias (or even longer if the head or neck are involved ) . For the management of painful diabetic neuropathy, UK licensed product informa­ tion recommends that capsaicin should only be used under specialist supervision and that treatment should be reviewed after the first 8 weeks and regularly re-evaluated thereafter.

I.

Fusco BM,

capsaicin in cluster headache.

crossover study.

Gut 2003; 52: 1 323-6.

Makhlough A. Topical capsaicin therapy for uremic pruritus in patients on hemodialysis.

9.

Szeimies R-M,

Iran J Kidney Dis 2 0 1 0; 4: 137-40. et al. Successful treatment of hydrox:yethyl starch­ Br J Dermatol l 994; 131: 380-2.

induced pruritus with topical capsaicin.

10.

Burrows NP, Norris PG. Treatment of PUVA-induced skin pain with capsaicin.

Saper J R ,

headaches.

Stander s.

idiopathic intractable pruritus ani: a randomised, placebo controlled.

8.

Preventative effect o f repeated nasal applications of

e t al.

Pain 1 994; 59: 321-5. et al. Intranasal dvamide f o r t h e treatment of episodic cluster Arch Neural 2002; 59: 990-4. 3. Fusco BM, et al. Repeated intranasal capsaicin applications to treat chronic migraine. Br J Anaesth 2003; 90: 8 1 2 .

2.

et al. Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol 2001; 44: 471-8. 7. Lysy J, et al. Topical capsaicin-a novel and effective treatment for 6.

Br J Dermato/ 1 994; 131:

1 997; 137: 1 52 . 12. Gooding S M , e t a l . treatment of pruritus.

Micturition disorders.

Intravesical instillation of capsaicin or its analogue resiniferatoxin have been tried for painful bladder disorders and to treat bladder detrusor hyperre­ flexia . ' ·• Results have been variable, and they are consid­ ered to be of limited use.10·" Instillation into the ureter has also been tried in the management of the loin pain/ haematuria syndrome12 but pain relief appears to be at best short-term and its use is associated with significant adverse effects." I.

Lazzeri M,

2.

de seze M,

et al.

Intravesical capsaicin for treatment of severe bladder

pain: a randomized placebo controlled study.

J Urol (Baltimore) 1 996;

156: 947-52.

et al.

Capsaicin and neurogenic detrusor hyperreflexia: a

double-blind placebo-controlled study in

20 patients with spinal cord Neurourol Urodyn 1 998; 17: 5 1 3-2 3 . e t al. Intravesical capsaicin i n patients with detrusor hyper­ reflexia: a placebo-controlled cross-over study. Scand J Urol Nephrol 1 999; 33: 104-1 0. 4. de seze M, et al. Intravesical instillation of capsaicin in urology: a review of the literature. Bur Urol 1 999; 36: 267-77. 5 . de Seze .M,. et al. Capsai'cine intravesicale et hyperreflexie du detrusor: experience de 100 instillations sur une pertode de cinq ans. Ann Readapt Med Phys 2001; 44: 5 1 4-24. 6. Szallasi A. Fowler CJ. Mter a decade of intravesical vanilloid therapy: still more questions than answers. Lancet Neural 2002; I: 1 67-72. 7. El-Mahrouky AS, et al. The effect of intravesical capsaicin and resiniferatoxin in neurogenic bladder dysfunction. Adv Bxp Med Bioi 2003; 539: 3 5 9-79. 8 . de seze M, et al. Intravesical capsaicin versus resiniferatoxin for the lesions.

3.

The symbol t denotes a preparation no longer actively marketed

Petersen T ,

treatment of detrusor hyperreflexia in spinal cord injured patients: a double-blind. randomized, controlled study.

2 5 1-5.

J Urol (Baltimore) 2004; 171:

584-5.

1 1 . Kirby B, Rogers S. Treatment of PUVA itch with capsaicin.

Br J Dermatol

Systematic review of topical capsaicin in the

Int J Dermatol 2 0 1 0; 49: 858-6 5 .

Psoriasis. Since substance P h a s b e e n implicated i n the pathophysiology of several inflammatory dermatological processes, capsaicin, a substance P depletor, has been tried with some benefit in some skin disorders including psor­ iasis . 1 · 3 The usual management of psoriasis is discussed on p. 1 688. 1 . 1.

Bernstein JE,

2.

Ellis CN,

et al. Effects of topically applied capsaicin on moderate and J Am Acad Dermatol 1 986; 15: 504-7. et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1 993; 29: 438-42. 3. Hautkappe M, et al. Review of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. Clin J Pain 1 998; 14: 97106. severe psoriasis vulgaris.

Rheumatic disorders. Topical capsaicin is used for the temporary relief of the pain of arthritis. From the results of a meta-analysis' of randomised, double-blind, placebo­ controlled studies and later studies''' it appears that cap­ saicin is effective in easing the pain of osteoarthritis (p. 1 2 . 3 ) . Based on these results, the Arthritis Research Crunpaign in the UK4 considered topical capsaicin to be safe and can be effective in reducing pain and tenderness in the affected j oints. Published evidence' for efficacy in rheumatoid arthritis (p. 1 3 . 2 ) appears to be limited. A review of use in both neuropathic and musculoskeletal chronic pain concluded that its benefits were at best mod­ erate, but noted that in a minority of patients unrespon-

36 sive to, or intolerant of, other treatments it might be use­ ful. 6 Capsaicin may be a useful therapy for pain associated with primary fibromyalgia4,7 (see Soft Tissue Rheumatism, p, 1 4 , 2 ) , which responds poorly to conventional treat­ ment. l.

Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin.

2.

Eur J Clin Pharmacol Altman RD, et a!.

1 994; 46: 5 1 7-22. Capsaicin cream 0 . 0 2 5 %

osteoarthritis: a double-blind study.

as monotherapy for

Semin Arthritis Rheum

1 994; 23

(suppl 3 ) : 25-3 3 . 3.

McCleane G. The analgesic efficacy o f topical capsaicin i s enhanced by

4.

Arthritis Research Campaign. Complementary and alternative medi­

glyceryl trinitrate in painful osteoarthritis: a randomized, double blind, placebo controlled study.

Eur J Pain

2000; 4: 3 5 5-60.

cines for the treatment of rheumatoid arthritis, osteoarthritis and fibromyalgia

(issued

February

2009 ) .

Available

at:

http:/lwww.

anhritisresearchuk.org/pdf/Complementary % 2 0and%20alternative% 20medicines_ l l 0 1 2 0 1 0 1 543 3 1 .pdf (accessed 28/07 / 1 0 ) 5.

Deal CL_

e t a l . Treatment o f arthritis with topical capsaicin: a double­ Clin Ther 1 9 9 1 ; 13: 383-95. Mason L, eta!. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 2004; 328: 9 9 1 -4. McCarty DJ, et al. Treatment of pain due to fibromyalgia with topical capsaicin: a pilot study. Semin Arthritis Rheum 1 994; 23 (suppl 3 ) : 41-7 . blind trial.

6. 7,

P; Doublecapt; No Pain-HP; Qutenza; R-Gelt; Rid-a-Pain HP; Theragent; Zostrix.

Multi-ingredient Preparations.

Arg.: Atomo Desinflamante C; Rati Salil Crema; Rati Salil Flex; Canad. : Menthacin; Rub A535 Extra Strength Arthritis; Tiger Balm Patch Warm; Cz. : Cap­ sicolle; Fr. : Capsaine; Capsict; Gr.: Ponostop; Hong Kong: Salo­ methylf; Hung. : Inno Rheuma Forte; Nicoflex; Salonpas Lini­ ment; India: Accept; Acent; Aho; Arflur; Arthrill; Axane; Capsidal; Diclomax Power Gel; Diplofen; Diptase; Divexx; Dofec Plus; Dolowin; Mahadol; Myolaxin·D; Nam; Nelsid; Niclofen; Nimulid Nugel; Nise Gel; Onspot; Opinac; Indon.: Flexozin; Nostren; Ital. : Perfluxi Cremagel; Remystick; Pol.: Capsigel N; Neo-Capsiderm; Rus.: Nicoflex (Hmw¢neKc); Switz. : DUL-X warm; Isola Capsicum N Plus; UK: NatraFlex; Ukr.: Nizer (Hafuep)t; USA: Aspercreme Max; Bio-Therm Pain Relieving Lotion; Capzasin Quick Relief; Dendracin Neurodend­ traxcin; Exoten-C; Gold Bond Foot Pain Relieving; Gold Bond Pain Relieving Foot Roll-On; Heet; Icy Hot PM; LidoPro; Medi­ Derm; Medrox; Menthacin; New Terocin; Pain Doctor; Ultracin; Ziks; Zostrix Hot & Cold Therapy System.

Carprofen (BAN, USAN, r/NN) C-S/20; Carprclfene; C�rptofeno, Carprpfenum; Karp'rofeen!; lrsane.c); Heppylor (Xeiiilllop) .

Pharmacopoeial Preparations

BP 20 14: Choline Salicylate Ear Drops;

Choline Salicylate

Oromucosal GeL

Clofexamide (riNNJ

(\NPc246; GofexarnidaiC16fexamicturn;·· KnoeKtaMwt1.

2c(4-(hrorophenow}-Nc(2cdietfJyl�rninoethyl)acetaO")ide.. .

C:,,.Hcr0N20;,=284.8 ,-::45 "- .1223-36·5: UN/1 -� 07TP4J77HI'.

Profile

Clofexamide has been used topically as the hydtochloride in preparations for musculoskeletal, joint, and soft-tissue disorders.

dol Compuesto; Prestoflam; Yuredol; Venez. : Dologinex; Dorixi­ na Flex; Migradorixina; Plidan Compuesto.

Codeine

!BANI

Co(jein; Codefna; Codeine: . CodH: . . · . . . . .· . · . . •.•· ·... . . , · •. .. . . • . .·... ··. . . . · . ·.·•··• • 7,8-Didehyctro-4.S·epoxy-3·f11ethoxy- 1 7-rnethylmorpfli(lah, 6:�1 monohy .•. . de; Co�aMOf)-'

lWlna>:JlOf)IAR

out; Slam; Sleeper; Sleepers; Slime; Slow; Sludge; Smack; Snotty; Snow; Spider; Spider blue; Stuff; Stunna; Sugar; Suidde; Sweet dreams; Sweet Jesus; Sweet stuff; Synthe; Tang; Tar; Taste; Tecata; Tecate; Thailandaise; Thanie; The beast; The fake throwdown; The Jack Bauer; The Loud­ House Permadillo; The Nax; The witch; Thing; Thunder; Tiger; Tigre; Tigre Blanco; Tigre del Norte; Tits; TNT; T.N.T.; Tongs; Tootsie roll; Top drool; Train; Trash; Twin towers; Twists; Vidrio; Whack; Whicked; White; White Bitch; White boy; White dragon; White dynamite; White girl; White horse; White junk; White lady; White nurse; White Pony; White stuff; White Tiger; Wicked; Wings; Witch; Witch hazel; WTC; Zoquete.

All cross-references refer to entries in Volume A

1.

Davey EA, Murray JB. Hydrolysis of diamorphine in aqueous solutions.

2.

Davey EA, Murray JB. Determination of diamorphine in the presence of

Pharm J 1 969; 203: 737. its degradation products using gas liquid chromatography.

Pharm J 1 9 7 1 ;

207: 167. 3.

et al. Stability o f diamorphine Pharm J 1 9 8 1 ; 226: 682-3.

Pharmacopoeias. In Br. and Swiss. Swiss also includes the

4.

Twycross RG. Stability of diamorphine in chloroform water.

anhydrous form.

5.

Beaumont IM. Stability of diamorphine in chloroform water.

BP 20 I4: (Diamorphine Hydrochloride ) . A white or almost

6.

Jones

white crystalline powder, odourless when freshly prepared but develops an odour characteristic of acetic acid on storage. Freely soluble in water and in chloroform; soluble in alcohol; practically insoluble in ether. Protect from light.

Cooper H,

in chloroform water mixture.

Pharm J

1 9 8 1 ; 227: 2 1 8. 1 9 8 1 ; 227: 4 1 . VA, e t a!.

Diamorphine

subcutaneous infusion.

7.

Omar O A ,

8.

Kleinberg ML,

et al. et al.

Pharm J

solution

for

Br J Clin Pharmacol 1 987; 23: 6 5 1 P .

Diamorphine

subcutaneous infusion.

stability i n aqueous stability i n aqueous

solution

for

J Phann Pharmacol l 989; 41: 275-7.

Stability of heroin hydrochloride in infusion devices

and containers for intravenous administration.

Am J Hosp Pharm 1 990;

47: 377-8 1 .

lncompatibilily.

Street names. The following terms have been used as 'street names' (see p. vii) or slang names for various forms of diamorphine: 57 Chevy; A Sidani; AlP; Al Capone; Amelia; Antifreeze; Aries; Aunt Hazel; Auntie Hazel; Aunty Hazel; Bacalhau; Bad bundle; Bad seed; Ball; Ballot; Bart Simpson; Batman; Beast; Big Bad Boy; Big bag; Big doodig; Big H; Big Harry; Bin laden; Bindle; Birdie powder; Black; Black Dragon; Black eagle; Black Girl; Black pearl; Black stuff; Black tar; Black tootsie roll; Blanche; Blanco; Blast; Bleue; Block busters; Blow; Blows; Blue bag; Blue hero; Blue star; Bobby Brown; B omb; B omba; Bombe; B ombido; Bombita; Bombitas; Bombs away; Bone; Bonita; Boy; Bozo; Brad; Brain damage; Brea; Brick gum; Broja; Brother; Brown; Brown crystal; Brown rhine; Brown sugar; Brown tape; Bugger; Bull dog; Bundle; Burra; Butu; Caballo; Caca; Calbo; Capital H; Caps; Captain Jack; Carga; Carne; Cavalo; Chang; Chapopote; Charley; Chatarra; Cheese; Cheevah; Cheva; Cheval; Chi; Chiba; Chick; Chicken; Chicle; Chieva; China cat; China white; Chinche; Chinese H; Chinese red; Chinese Rocks; Chinoise; Chip; Chiva; Choco!an; Chaco­ fan; Chueva; Chunks; Climax; Cocofan; Coffee; Cotics; Cotton Candy; Courage pills; Crank; Crap; Crop; Crown crap; Cura; Dead on arrival; Dead president; Deuce; Diesel; Diggidy; Dirt; D OA; Dog food; Dogee; Dogie; Doogie; Doojee; Dookey Rocks; Dooley; Doosey; Dope; Downtown; Dr. Feelgood; Dragon; Dreck; DT; Dugee; Dugie; Duji; Dujra; Dujre; Dust; Dyno; Dyno·pure; Eggs; Eight; Eighth; Elephant; Estuffa; Fachiva; Ferry dust; Fix; Flea powder; Foil; Foo foo stuff; Foolish powder; Furra; Galloping horse; Gallup; Gamot; Garbage; Gato; Gear; George; George smack; Ghost; Girl; Glacines; Glass; Goat; Gold; Golden Brown; Golden girl; Golpe; Goma; Good; Good H; Good Horse; Good and plenty; Goods; Goop; Grape Jolly Rancher; Gravy; Grey shields; H; H22; H -bomb; H Caps; Hache; Hair; Hairpiece; Hairy; Hammer; Hard candy; Hard stuff; Harriet Tubman; Harry; Harry Jones; Hayron; Hazel; Heaven; Heaven dust; Heavy stuff; Helen; Hell dust; Henry; Hera; Hero; Hero of the underworld; Heroa; Heroina; Heron; Herone; Hessle; Him; Holy terror; Hombre; Homebake; Homicide; Hong�yen; Hood; Hop; Horning; Horse; Horsebite; Hot dope; Hot heroin; HRN; Isda; Jack; Jee gee; Jerry Springer; Jesus; Jive; Jive doo jee; Joharito; Jojee; Jones; Joy; Joy dust; Joy flakes; Joy powder; Judas; Junco; Junk; Kabayo; Kaka Water; Karachi; Kermit the Frog; La Buena; La Chiva; Lady H; Layne; LBJ; Lemonade; Life saver; Little bomb; Man; Manteca; Matsakow; Mayo; Mexican Black Tar; Mexican brown; Mexican Dirt; Mexican horse; Mexican mud; Mister Brownstone; Mojo; Money talks; Monkey; Montego; Morse Code Features; Morotgara; Mortal combat; Mother pearl; Mr. Brownstone; Mud; Murotugora; Muzzle; Nanoo; Nice and easy; Nickel bag; Nickel deck; Nixon; Noddy Brown; Noise; Nose; Nose drops; Number 3; Number 4; Number 8; Nurse; Oddy Noddy; Of course my horse; Ogoy; Oil; Old garbage; Old navy; Old Steve; One way; Orange line; Outfit; Pack; Pakistanaise; Pako; Pangonadalot; Parachute; P-dope; Peg; Pepper; Perfect high; P·funk; Pluto; Po; Poeira; Poison; Polvo; Poppy; Poudre; Powder; Predator; Primo; Produto; Pulborn; Pure; Quill; Race horse Charlie; Racehorse Charlie; Ragweed; Rain; Rambo; Rane; Raw; Raw fusion; Raw hide; Raw Opportunities; Ready rock; Red chicken; Red devil; Red eagle; Red rock; Red rum; Reindeer dust; Rhine; Ring of Turd; Rob Flaherty; Rock; Rocks; Rush hour; Sack; Salt; Scag; Scat; Scate; Schmack; Schmeck; Schmeek; Scott; Scramble; Second to none; Shit; Shmeck; Shmeek; Shmek; Shoot; Silk; Skag; Skid; Skunk; Slack-dad-eat-your-heart-

maintained for a minimum of 2 days. When stored in glass syringes both strengths of diamorphine hydrochloride were stable for I 5 days at 4 degrees and at room temperature the I mg/mL solution was stable for a minimum of 7 days and the 2 0 mg/mL solution was stable for a minimum of 1 2 days. There were no substantial changes in physical appearance or pH.

Diamorphine hydrochloride is incompati­ ble with mineral acids and alkalis and with chlorocresol . 1 The BNF notes that cyclizine may precipitate from mixtures with diamorphine hydrochloride at concentra­ tions of cyclizine greater than 10 mg/mL, or in the presence of sodium chloride 0 . 9 % , or as the concentration of diamorphine relative to cyclizine increases; mixtures of diamorphine and cyclizine are also liable to precipitate after 24 hours. It also considers that mixtures of diamorphine and haloperidol are liable to precipitate after 24 hours if the haloperidol concentration is above 2 mg/mL. Under some conditions mixtures of metoclopramide and diamorphine may become discoloured and should be discarded. 1.

McEwan JS, Macmorran GH. The compatibility of some bactericides.

Phann 1 1947; 158: 260-2.

Stabilily. Diamorphine is relatively unstable in aqueous solution and is hydrolysed to 6 - 0-monoacetylmorphine and then morphine to a significant extent at room tem­ perature; 3- 0-monoacetylmorphine is only occasionally detected. The rate of decomposition is at a minimum at about pH 4 . u I n a study of the stability of aqueous solutions o f diamorphine i n chloroform water it w a s concluded that such solutions should be used within 3 weeks of preparation when stored at room temperature. 3 Another study4 noted that the degradation products of diamorphine were not devoid of analgesic activity. Using a more sensitive analytical method it was reported that although the pH range of maximum stability of diamorphine in aqueous solution was 3.8 to 4.4, the addition of buffers reduced stability -' Simple unbuffered chloroform water gave maximum stability, the shelf· life of such a solution being 4 weeks at room temperature. The BP 2 0 1 4 recommends that solutions for injection be prepared immediately before use by dissolving Diamorphine Hydrochloride for Injection in Water for Inj ections. This may pose a problem with solutions for subcutaneous infusion when concentrated solutions may remain in infusion pump reservoirs for some time. 6 Investigation of 9 concentrations of diamorphine stored at 4 different temperatures for 8 weeks7 revealed instability under conditions of concentration, time, and temperature prevalent during subcutaneous infusion. Degradation of diamorphine occurred at all concentrations (0. 98 to 2 5 0 mg/mL) at teinperatures of 4 degrees and above; the effect of temperature was significant at 2 1 degrees and 37 degrees. The percentage fall in diamorphine concentration was directly related to initial concentratio� and was accompanied by a corresponding increase in 6 - 0 monoacetylmorphine and, t o a lesser extent, morphine; other possible breakdown products such as 3 - 0-mono­ acetylmorphine were not present in detectable quantities. Diamorphine degradation was associated with a fall in pH and the development of a strong acetic acid-like odour. Precipitation and a white turbidity was seen in solutions of 1 5 . 6 mg/ml and above after incubation for 2 weeks at 2 I degrees and 3 7 degrees. It has been noted that solutions for infusion are generally freshly prepared and used within 24 hours, but that signs of precipitation should be watched for, especially when using longer-term infusions and high concentrations of diamorphine.7 In another stability study8 diamorphine hydrochloride in concentrations of both I and 20 mg/mL in sodium chloride 0 . 9 % was stable for a minimum of 1 5 days at room temperature (23 degrees to 25 degrees) and 4 degrees when stored in a PVC container. In one type of disposable infusion device (Infusor) similar solutions were stable for I 5 days even at 31 degrees. In another infusion device (Intermate 200) diamorphine was stable for a minimum of 1 5 days at both concentrations and all temperatures except for the I mg/mL solution kept at 3 I degrees when stability was only

Uses and Administration Diamorphine hydrochloride is an acetylated morphine derivative and is a more potent opioid analgesic (p. 1 08. I ) than morphine (p. 9 3 . 2 ) . Diamorphine is used for the relief of severe pain especially in palliative care. It is also used similarly to morphine for the relief of dyspnoea due to pulmonary oedema resulting from left ventricular failure. Diamorphine has a powerful cough suppressant effect and has been given as Diamorphine Linctus (BPC I 9 7 3 ) to control cough associated with terminal lung cancer although morphine is now preferred. In the treatment of acute pain usual doses of diamorphine hydrochloride by subcutaneous or intramus­ cular injection are 5 to 1 0 mg every 4 hours. Doses equivalent to one-quarter to one-half of the corresponding intramuscular dose may be given by slow intravenous injection. For the pain of myocardial infarction doses of 5 mg are given by slow intravenous injection at a rate of 1 to 2 mglminute with a further dose of 2 . 5 to 5 mg if required; doses may be reduced by one-half for elderly or frail patients. Doses of 2 . 5 to 5 mg may be given intravenously at the same rate for acute pulmonary oedema. For chronic pain 5 to l 0 mg may be given by subcutaneous or intramuscular injection every 4 hours; the dose may be increased according to needs. Similar doses may be given orally, although it is converted to morphine by first-pass metabolism (see Pharmacokinetics, p. 48. 2 ) . Diamorphine hydrochloride may a l s o be given by continuous subcutaneous or intravenous infusion or intraspinally. For details of doses in children, see below.

Action. Because of its abuse potential, supply of diamor­ phine is carefully controlled and in many countries it is not available for clinical use; morphine can provide equivalent analgesia by dose adjustment. There has been much debate regarding the relative merits of analgesia with diamorphine or morphine. Many now regard oral morphine to be the opioid analgesic of choice although diamorphine hydrochloride may be preferred for injection because it is more soluble in water thus allowing the use of smaller dose volumes. Diamorphine hydrochloride may also be preferred to morphine salts for intraspinal use because it is more lipid-soluble. As a guide to relative potency: • diamorphine hydrochloride 5 mg given intramuscularly is equivalent to about 10 mg given orally, which in turn is equivalent to about I 5 mg of oral morphine sulfate • when either drug is given by subcutaneous infusion, diamorphine hydrochloride I 0 mg every 24 hours is equivalent to about I 5 mg every 24 hours of morphine sulfate Administration in children.

In the treatment of acute or chronic pain in children, the BNFC suggests the following doses of diamorphine hydrochloride according to age or body-weight, and adjusted according to response: by continuous intravenous infusion: • neonates with spontaneous respiration may be given 2 . 5 to 7 micrograms/kg per hour • ventilated neonates may be given 50 micrograms/kg initially by intravenous injection over 30 minutes followed by I 5 micrograms/kg per hour by contin­ uous intravenous infusion • I month to I2 years: I 2 . 5 to 25 micrograms/kg per hour by intravenous injection: • l to 3 months: 20 micrograms/kg every 6 hours • 3 to 6 months: 2 5 to 5 0 micrograms/kg every 6 hours • 6 to 12 months: 75 micrograms/kg every 4 hours

Diamorph ine Hyd roch loride 47 •

1 to 12 years: 75 to 1 0 0 micrograms/kg (maximum of 5 mg) every 4 hours

orally: •

1 month to 12 years: 1 0 0 to 200 micrograms/kg (maximum of 1 0 mg ) every 4 hours In a study1 of the effects of diamorphine in 34 premature infants (gestational age 26 to 40 weeks) , a loading dose of 5 0 micrograms/kg given as an intravenous infusion over 30 minutes followed by a continuous infusion at a rate of 15 micrograms/kg per hour was considered to be safe and resulted in plasma concentrations of morphine comparable with those that usually produce adequate analgesia in children and adults; the duration of the infusion ranged from 14 to 149 hours . Small but significant reductions in heart rate and mean blood pressure were noted but these were not associated with any clinical deterioration. The fall in respiration rate reflected the desired intention to encourage synchronisation of the infants' breathing with the ventilator. The authors concluded that intravenous diamorphine could be given safely to neonates and would provide adequate analgesia. A later study' indicated that the use of a 200 micrograms/kg loading dose conferred no benefit over a 5 0 micrograms/kg dose and might produce undesirable physiological effects. In a comparative study' with morphine (200 micrograms/kg loading dose over 2 hours, followed by maintenance infusion of 25 micro­ grams/kg per hour) in ventilated preterm neonates requiring sedation, diamorphine ( 1 2 0 micrograms/kg over 2 hours and then 15 micrograms/kg per hour) was as effective as morphine in producing sedation and also had a faster onset of action. The small but significant drop in blood pressure noted during morphine infusions was not seen with diamorphine infusions. The subcutaneous route appeared to be as effective and safe as the intravenous route for infusions in children for postoperative pain relief after elective abdominal surgery. 4 The dose of diamorphine used in both groups of children was 1 mg/kg given at a rate of 20 micrograms/kg per hour. Intranasal diamorphine has been investigated in adults and children, and appears to be effective and well tolerated; because it does not require a needle it may offer particular advantages in children. 5 Guidelines' for analgesia in children in Accident and Emergency departments in the UK recommend the use of intranasal diamorphine as an alternative to, or before treatment with, intravenous morphine for severe pain such as that associated with large bums, long bone fracture or dislocation, appendicitis, or sickle-cell crisis. In the UK, an intranasal spray containing the equivalent of 720 or 1 600 micrograms of diamorphine per actuation is licensed for the treatment of acute severe nociceptive pain in children and adolescents aged 2 to 1 5 years in a hospital setting. The preparation and dose given are dependent on the child's body-weight; children weighing under 30 kg should receive the nasal spray delivering 720 micrograms per actuation in the following doses: • 12 to < 1 8 kg: 2 sprays ( 1 .44 mg) • 18 to < 24 kg: 3 sprays (2. 1 6 mg) • 24 to < 30 kg: 4 sprays (2.88 mg) Heavier children should receive the nasal spray delivering 1 600 micrograms per actuation as follows: • 30 to < 40 kg: 2 sprays ( 3 . 2 mg) • 40 to 5 0 kg: 3 sprays (4.8 mg) 1.

Elias-Jones AC,

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Barker DP,

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regimens of diamorphine in ventilated newborn infants.

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diamorphine for sedation of pretenn neonates. 4.

Neonatal Ed 1 998; 79: P34-P39. et al. Comparison of iv

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Br J Anaesth

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T h e College of Emergency Medicine. B e s t practice guideline: manage� ment of pain in children (July 2 0 1 3 ) . Available at: http:/lsecure. collemergencymed . a c . u k / a s p { document.asp?ID=4682

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Opioid dependence. The treatment of opioid dependence is discussed on p. 1 0 9 . 2 . Many opiate misusers have expressed a preference for withdrawal using diamorphine rather than methadone. In a comparative study stabilisa­ tion was achieved using either diamorphine or methadone 1 mg/mL oral solutions;' patients could not identify which they had been given. Whenever signs of physical with­ drawal were seen 10 mL of either solution was given and the total amount over the first 24 hours taken as the patient's daily requirement. The mean dose of diamor­ phine required for stabilisation was 55 mg compared with 36 mg for methadone. Some centres have given diamor­ phine in the form of reefers. Diamorphine has also been prescribed with methadone in the management of addicts.' A systematic review' that included this study failed to produce conclusive results about the efficacy of diamorphine (alone or with methadone) in maintenance treatment; however, since the studies were not directly

comparable, continued evaluation in clinical studies is required. Oral tablets• and intravenous injection'·' of diamorphine have also been tried in severely dependent, treatment-resistant patients. Breast feeding has been used to treat diamorphine dependence in the offspring of dependent mothers but this is no longer considered to be the best method and some authorities recommend that breast feeding should be stopped. 1.

Ghodse AIL

et al.

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Bur J Anaesthesio l 2 000;

et al. Postoperative analgesia by continuous extradural infusion of bupivacaine and diamorphine. Br J Anaesth 1 988; 60: 845-50. 8. Madej TH, et al. Hypoxaemia and pain relief after lower abdominal surgery: comparison of extradural and patient�controlled analgesia. Br J Anaesth 1 992; 69: 554-7. 9 . Reay BA, et al. Low-dose intrathecal diamorphine analgesia following major orthopaedic surgery. Br J Anaesth 1 989; 62: 248-52. 10. Kestin IG, et al. Analgesia for labour and delivery using incremental diamorphine and bupivacaine via a 32�gauge intrathecal catheter. Br J Anaesth 1 992; 68: 244-7. I I . Vaughan DJA. et al. Choice of opioid for initiation of combined spinal epidural analgesia in labour-fentanyl or diamorphine. Br J Anaesth

Lee A.

2 0 0 1 ; 86: 567-9. 12. Hallworth SP, for

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Br J Anaesth 1 999; 82.: 228-32. Cowan CM, et al. Comparison of intrathecal

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Br J Anaesth 2002; 89: 452-8. et al. Minimum dose of intrathecal

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Controlled trial of prescribed heroin in the treatment of

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Pain. ACUTE PAIN. Rapid pain relief may be obtained with the intravenous injection of diamorphine. Other routes include the intraspinal route for which diamorphine is well suited because of its lipid solubility and pharmacoki­ netics. Epidural doses of diamorphine have ranged from 0 . 5 to 1 0 mg . ' Analgesia was significantly more prolonged and more intense after epidural rather than intramuscular injection of diamorphine 5 mg in women who had had caesarean section;' itching was reported by 5 0 % of patients undergoing epidural analgesia. Epidural diamor­ phine alone' or with bupivacaine4 has been used for analgesia during labour; addition of adrenaline appeared to improve the quality and duration of analgesia with diamorphine.' In another study addition of diamorphine to bupivacaine produced a high incidence of pruritus and drowsiness.' A study' of patient-controlled analgesia for postoperative pain found that although epidural diamor­ phine, used alone or with bupivacaine, reduced the analgesic dose requirement, there was little clinical advan­ tage over the subcutaneous route. Continuous epidural infusion of diamorphine 500 micro­ grams/hour in 0 . 1 2 5 % bupivacaine provided postoperative analgesia superior to that with either drug alone in patients undergoing major abdominal gynaecological surgery." A similar infusion produced analgesia superior to that with either epidural bolus injection or patient-controlled intra­ venous diamorphine in patients undergoing total abdo­ minal hysterectomy.• However, more patients receiving the continuous epidural infusion were hypoxaemic than in the other 2 groups. Diamorphine has also been given intrathecally for postoperative analgesia and should be effective at lower doses than with the epidural route because of greater CSF concentrations. Diamorphine 2 5 0 or 500 micrograms given intrathecally with bupivacaine spinal anaesthesia both provided greater postoperative analgesia than bupivacaine alone! but the incidence of adverse effects, especially nausea, vomiting, and urinary retention, was still high with either dose and routine use of this technique was not recommended. Intrathecal diamorphine with bupivacaine has also been used for analgesia during labour1 0· " and caesarean section.12·1 6 In a study12 in patients undergoing caesarean section, intrathecal diamorphine 2 5 0 micrograms showed comparable postoperative analgesia with a 5 -mg epidural dose and was associated with less postoperative nausea and vomiting. Other studies 1 3 • 1 5 found that intrathecal diamorphine reduced supplemental analgesic requirements during and after caesarean section when compared with intrathecal fentanyl. Intrathecal diamor­ phine 400 micrograms was considered by some14 to be the lowest dose required to reduce intraoperative analgesic supplementation to below 5 % ; however, lower doses of 300 micrograms have been used in practice. 1 6 Diamorphine has been extensively used by cardiologists in the UK for the management of pain in acute left ventricular failure, unstable angina, and myocardial infarction. It has been theorised that diamorphine may offer benefits over morphine because its stimulatory effects at opioid o receptors on the myocardium may reduce the extent of myocardial damage. l 1 Evidence to support this theory is, however, lacking.

D, et al.

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Obstet Anesth 2007; 16: 1 7-2 1 . 1 7 . Poullis M . Diamorphine and Briti sh cardiology: s o w e are right!

lnt J Heart

1999; 82: 645-6.

CHRONIC PAIN.

Patients with chronic opioid-sensitive pain are often treated with diamorphine given by continuous subcutaneous infusion using a small battery-operated syringe driver. The following technique has been desctibed. 1 Diamorphine hydrochloride 1 g could be dis­ solved in 1 . 6 mL of water to give a solution with a volume of 2 . 4 mL (4 1 5 mg/mL) , but the maximum suggested con­ centration was 2 5 0 mg/mL. If the analgesic requirement was unknown the following protocol was recommended: • Start inj ections every 4 hours of 2 . 5 or 5 mg diamorphine, or, if the patient has already been taking opioids, a dose that is equivalent to the last dose • If this is unsatisfactory increase this dose in 5 0 °/o increments until the patient repons even a little pain relief • Calculate the 24-hour requirement by multiplying by six, and stan the infusion at this level • Increase the 24-hour dosage in the pump by 5 0 % increments until the pain is controlled. Note that requirements may vary from less than 20 mg to more than 5 g per 24 hours When starting an infusion it is important not to allow any breakthrough pain. This may be achieved either by starting the infusion more than 2 hours before the previous oral dose wears off or by giving a loading dose injection of the 4hourly requirement. Although generally free from complications, sterile abscess formation was reported in 2 patients with advanced cancer receiving diamorphine by continuous subcutaneous infusions. 2 The intraspinal' and intraventricular' routes have also been used successfully in patients with intractable pain. Topical application of diamorphine has also been tried'·' for the control of pressure ulcer pain in a small number of palliative care patients. I.

2.

Dover SB. Syringe driver in terminal care. Hoskin PJ,

et al.

BMJ

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spinal analgesia practice i n palliative care.

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�P.I!.'!.�:��I!..9.�9...�it.h..�r.9.��.t.. ................................

.

As for Opioid Analgesics, p. 1 09. 1 . Diamorphine i s subject to abuse (see under Adverse Effects, Treatment, and Precautions, below) . Diamorphine is used for substitution therapy in the management of opioid dependence (see under Uses and Adrululstration, above ) .

�9.-:.:r.s.: .���!�!. . !r.:9.�:���.. 9.�9.. �r.::?�!�?.'!.S. ....

1 9 9 1 ; 66:

. . . A s for Opioid Analgesics i n general, p. 1 1 0. 1 . Pulmonary oedema after overdosage i s a common cause of fatalities among diamorphine addicts. Nausea and hypotension are claimed to be less common than with morphine. There are many repons of adverse effects associated with the abuse of diamorphine, usually obtained illicitly in an adulterated form.

et al. Epidural diamorphine and bupivacaine in labour. Anaesthesia 1 989; 44: 400-3. Bailey CR, et a]. Diamorphine-bupivacaine mixture compared with plain bupivacaine for analgesia. Br J Anaesth 1 994; 72: 58-6 1 .

Abuse. Most of the repons of adverse effects with diamor­ phine involve its abuse. In addition to the central effects, there are effects caused by the adruinistration methods

1.

Morgan M . The rational use of intrathecal and extradural opioids.

2.

Macrae DJ,

caesarean section.

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Anaesth

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diamorphine, extradural phenoperidine and im diamorphine following

Br J Anaesth et al. Extradural

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Br J Anaesth

242--6. 4. 5.

The symbol t denotes a preparation no longer actively marketed

McGrady EM..

The symbol

® denotes a substance whose use may be restricted in certain sports (see p. viii)

48 and by the adulterants.L2 Thus in many instances it is dif­ ficult to identify the factor causing the toxicity. Most body systems are involved including the immune system,3 kid­ neys,4·5 liver,6 respiratory system, ?- 1 1 and the nervous sys­ tem.t2-17 Other aspects of the illicit use of diamorphine include fatal overdose18 and smuggling by swallowing packages of drug19•20 or other methods of internal bodily concealment. l.

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Hendrickse RG,

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2005. JWM:WR 2005; 54: 793-6. Correction. ibid.; 852. Husby G , et al. Smooth muscle antibody i n heroin addicts. Ann Intern Med 1 975; 83: 801-5. Cunningham EE, et al. Heroin-associated nephropathy. lAMA 1983; 250: 2935-6. do Sameiro Faria M, et at. Nephropathy associated with heroin abuse in Caucasian patients. Nephrol Dial Transplant 2003; 18: 2308- 1 3 . Weller IVD, et al. Clinical, biochemical, serological, histological and ultrastructural features of liver disease in drug abusers. Gut 1 984; 25: 4 1 7-2 3. Anderson K. Bronchospasm a n d intravenous street heroin. Lancet 1 986; i: 1208. Cygan J, et al. lnhaled heroin-induced status asthmaticus: five cases and a review of the literature. Chest 2000; 117: 272-5 . Boto de los Bueis A, et al. Bronchial hyperreactivity in patients who inhale heroin mixed with cocaine vaporized on aluminium foil. Chest 2002; 121: 1223-30. April

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Although generally free from complica­ tions, sterile abscess formation was reported in 2 patients with advanced cancer receiving diamorphine by continu­ ous subcutaneous infusions. 1 Acute dysphoric reactions have been reported after the use of epidural diamorphine.2 1.

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Hypersensitivity. Anaphylaxis occurred in a patient given intrathecal dian1orphine and bupivacaine for surgical anaesthesia;1 the authors noted that the patient received patient-controlled analgesia with morphine shortly after the reaction without problem. Subsequent skin prick tests identified diamorphine as the likely causative agent. l.

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INHALATIONAL ROUTE.

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INTRASPINAL ROUTE. Diamorphine is much more lipid-soluble and has a more rapid onset and shorter durati9n of action than morphine. Although deacetylation to morphine occurs rapidly in the blood it occurs only slowly in the CSF after intraspinal injection of diamorphine 1 After intrathecal injection diamorphine was removed from the CSF much more rapidly than morphine 2 Peak plasma concentrations of morphine after epidural diamorphine injection were significantly higher and were achieved sig­ nificantly faster than after epidural injection of morphine. 3

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Morgan M. The rational use of intrathecal and extradural opioids.

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Children.

Loading doses of either 5 0 micrograms/kg or 200 micrograms/kg of diamorphine were given as an intra­ venous infusion over 30 minutes to 19 ventilated neonates followed by a continuous infusion of 1 5 micrograms/kg per hour, and the pharmacokinetics of the products of diamorphine metabolism (morphine, morphine-6-glucuro­ nide, and morphine- 3-glucuronide) studied. 1 Although the overall elimination of morphine was reduced com­ pared with adults, the relative contributions of the various metabolic routes of morphine remained similar between neonates and adults. Data from this study did not indicate any advantage for the higher loading dose (see also under Uses and Administration, p. 46. 3 ) . Barrett DA,

e t al.

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glucuronide pharmacokinetics in newborn infants receiving diamor­ phine infusions.

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A literature review1 found that intranasal diamorphine had a similar pharma­ cokinetic profile to that of intramuscular diamorphine. It is rapidly absorbed, as a dry powder, via the nasal mucosa although this is not as complete as by intramuscular inj ec­ tion; intranasal absorption appeared to be dose dependent. The pharmacokinetics of inhaled diamorphine fumes ("chasing the dragon" ) have been studied2 in diamorphine addicts receiving substitution therapy with diamorphine and methadone. Absorption through the lungs occurred very rapidly and was virtually complete immediately after inhalation; bioavailability was estimated to be about 5 3 % .

2.

Breast feeding. The American Academy of Pediatrics has stated1 that, when used as a drug of abuse by breast-feed­ ing mothers, diamorphine has caused adverse effects in the infant, notably tremors, restlessness, vomiting, and poor feeding. However, the BNF considers that diamor­ phine when given in therapeutic doses to a breast-feeding mother is unlikely to affect the breast-fed infant. See also Opioid Dependence under Uses and Adminis­ tration, p. 47. 1 . 1.

Administration.

Br J

Anaesth 1 994; 72: 728.

Boerner U, et a!. The metabolism of morphine and heroin in man. Dmg Metab Rev 1975; 4: 39-73. lnturrisi C E , et al. T h e pharmacokinetics of heroin in patients with chronic pain. N Eng! J Med 1 984; 310: 1 2 1 3-17. Moore RA, et al. Opiate metabolism a n d excretion. Baillieres Clin Anaesthesiol 1 987; 1: 829-58. Barrett DA. et al. Morphine kinetics after diamorphine infusion in premature neonates. Br J Clin Phannacol 1 9 9 1 ; 32: 3 1-7. Girardin F, et al. Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts. Clin Phannacol Ther 2003; 74: 341-52. Halbsguth U, et a!. Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to

J Toxicol Clin Toxicol 2003; 41: 887-9 1 . et a!. Acute heroin-related neuropathy. J Peripher Nerv Syst

Administration.

3 35-8.

Diamorphine hydrochloride is well absorbed from the gastrointestinal tract, although this may be erratic. and after subcutaneous or intramuscular injection. On injection it is rapidly hydrolysed to the active metabolite 6- 0-mono­ acetylmorphine ( 6-acetylmorphine) in the blood and then to morphine (p. 9 5 . 3 ) . Oral doses are subject to extensive first�pass metabolism to morphine; neither diamorphine nor 6-acetylmorphine has been detected in the blood after giving diamorphine by this route. B oth diamorphine and 6acetylmorphine readily cross the blood-brain barrier. Morphine glucuronides are the main excretion products in the urine. A small amount is excreted in the faeces.

A fatal case of spongiform leukoencephalopathy linked to

2006; 1 1 : 304-9. 1 8 . Kintz P, et at. Toxicological data after heroin overdose. Hum Toxicol 1 989; 8: 487-9. 19. Stewart A, et al. Body packing-a case report and review of the literature. Postgrad Med J I 990; 66: 659-6 1 . 2 0 . Traub SJ, e t al. Pediatric "body packing". Arch Pediatr Adolesc Med 2003; 157: 174-7.

An Esp Pediatr 2001; 55:

Interactions

"chasing the dragon".

17.

of heroin addiction during

For interactions associated with opioid analgesics, see p. 1 1 1 .2 .

Heroin inhalation and progressive spongiform

N Eng! J Med 1 997; 336: 589-90.

et al. Maternal and fetal effects 1 Reprod Med 1 990; 35: 1 5 9-62 .

pregnancy.

1 979; 94: 292-5. Lifschitz MH, et al.

830

cases.

J Pediatr

Fetal and postnatal growth of children born to

narcotic-dependent women.

J Pediatr 1983; 102: 686-9 1 .

HM . Babies born in a district general hospital t o mothers taking

4.

Klenka

5.

heroin. BM.l I 986; 293: 745-6. Gregg JEM, et al. Inhaling heroin BMJ 1 988; 296: 754.

during pregnancy: effects on the baby.

All cross-references refer to entries in Volume A

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations, Switz.: Diaphin; UK: Ayendi. Pharmacopoeial Preparations

BP 20 14: Bupivacaine and Diamorphine Injection; Diamorphine

Injection; BPC 1973: Diamorphine Linctus.

Diclofenac Diethylamine (BANMJ

· b1ciof���c · ·· Dieth%tam(nor'iium: · . .· f.?i$k1ter\aco pietli�rhina; l)iM()fe!'\ Hyc!rol4VJ1Ct({lelfa'K '?nQJJaM14H . . . .·. .·· ·• · · 1.3 . Q2, C6tlnN0�1

(AS --- u 9f)23-66-'4. ATC ,.c-0}1,4)(.18. ArC: \let'-:; QOUAX(B. i.)NII ·---·· )(f>F8EK�i!Z.(L . (,,,Hqcto:N

Diclofenac Potassium (BANM, USAN, riNNMJ CGP-458408; . . Didpfenac,KaH�rn; [)JQ!ofenac • •Pot;Jsslq u�; ..

Di(lofena�o potasico; Qi,:lofena�um kafit:um; ()i�19ffitiaakk\, kali0m; Riklofena� . .. f)raselna st'i); . ··. Dlklofen;Jk !?Qtasyum; Qi�IQfenakkallum; Dlk!ofemik-kalium; Dikiofenako kaiio drusk?; Kalif Qidofenatum; Kan�i! ,!l�KIJb�K�JP$€HaK · Sc>c!ium [2-(2,6,dichloroanllino)phenyt]acerar�; .

c,.H100,NN\102o;3 ! 8J CAS 7 I$�ON% ATC�DI IAXIB. ATCV�t - 0[)1 1AX18. UNit- OT§1;!62910.

DICL is a code approved by the BP 2 0 1 4 for use on single unit doses of eye drops containing diclofenac sodium where the individual container may be too small to bear all the appropriate labelling information.

NOTE.

Pharmacopoeias. In Chin., Bur. (see p . vii) , Jpn, US, and Viet.

Ph. Eur. 8: (Diclofenac Sodium ) . A white to slightly yellowish, slightly hygroscopic, crystalline powder. Spar­ ingly soluble in water; soluble in alcohol; slightly soluble in acetone; freely soluble in methyl alcohol. Store in airtight containers. Protect from light.

USP 36: (Diclofenac Sodium ) . A white to off-white, hygroscopic, crystalline powder. Sparingly soluble in water; soluble in alcohol; practically insoluble in chloroform and in ether; freely soluble in methyl alcohol. pH of a I % solution in water is between 7.0 and 8 . 5 . Store in airtight containers. Protect from light.

Diclofenac 49

Uses and Administration Diclofenac, a phenylacetic add derivative, is an NSAID (p. 1 0 2 . 3 ) . It is used mainly as the sodium salt for the relief of pain and inflammation in various conditions: musculo­ skeletal and j oint disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis; peri-articular disorders such as bursitis and tendinitis; soft-tissue disorders such as sprains and strains; and other painful conditions such as renal colic, acute gout, dysmenorrhoea, migraine, and after some surgical procedures. It has also been used in some countries for the management of actinic keratoses and fever. Eye drops of diclofenac sodium are used for the prevention of intra-operative miosis during cataract extraction, for the treatment of inflammation after surgery or laser treatment of the eye, for pain in corneal epithelial defects after surgery or accidental trauma, and for the relief of ocular signs and symptoms of seasonal allergic conjunctivitis. The usual oral or rectal dose of diclofenac sodium is 7 S to 1 SO mg daily in divided doses. In the UK the maximum dose regardless of route or indication is 1 SO mg daily; however, in the USA a maximum oral dose of 200 mg daily is allowed in the treatment of rheumatoid arthritis. Modified-release preparations of diclofenac sodium are available for oral use. Diclofenac has also been given in equivalent oral doses as the free add in dispersible preparations for short-term treatment up to 3 months long. Diclofenac is also given orally as the potassium salt. Doses of the potassium salt are similar to those for diclofenac sodium. Diclofenac potassium is also used in the treatment of migraine in an initial dose of SO mg taken at the first signs of an attack; an additional dose of S O mg may be taken after 2 hours if symptoms persist. If necessary further doses of SO mg may be taken every 4 to 6 hours to a maximum daily dose of 200 mg. Diclofenac sodium may also b e given by deep intramuscular injection into the gluteal muscle in a dose of 7 S mg once daily or, if required in severe conditions, 75 mg twice daily. Diclofenac sodium may also be given as a continuous or intermittent intravenous infusion in glucose S% or sodium chloride 0. 9% (both previously buffered with sodium bicarbonate) or as a bolus intravenous injection. For the treatment of postoperative pain a dose of 7S mg may be given over 30 to 120 minutes or as a bolus injection. The dose may be repeated once after 4 to 6 hours if necessary. To prevent postoperative pain, an initial dose of 2S to SO mg diclofenac sodium may be given after surgery over 1 5 to 60 minutes followed by S mg/hour to a maximum of 1 S O mg daily. Alternatively, the initial dose may be given as a bolus injection over S to 60 seconds followed by additional injections up to the maximum daily dosage; this may be repeated after 4 to 6 hours if necessary although the total dose should not exceed the maximum daily dose of 1 5 0 mg. The maximum period recommended for parenteral use is 2 days. Diclofenac sodium is also used intramuscularly in renal colic in a dose of 7S mg repeated once after 30 minutes if necessary. For dosage details in children, see below. Diclofenac sodium is used as a 0. 1 % ophthalmic solution in various situations: • for the prevention of intra-operative miosis during cataract surgery, it is instilled in the appropriate eye 4 times during the 2 hours before surgery • for the treatment of postoperative inflammation after cataract surgery, it is instilled 4 times daily for up to 2 8 days starting 24 hours after surgery • for the control of post-photorefractive keratectomy pain, it is instilled twice in the hour before surgery, then one drop twice at S-minute intervals immediately after the procedure, and then every 2 to S hours while awake for up to 24 hours • for pain control after accidental trauma, one drop is instilled 4 times daily for up to 2 days • in the treatment of inflanunation and discomfort after strabismus surgery, one drop is instilled 4 times daily for the first week; this is reduced to 3 times daily in the second week, twice daily in the third week, and as required for the fourth week • for the control of inflammation after argon laser trabeculoplasty, one drop is instilled 4 times during the 2 hours before the procedure followed by one drop 4 times daily for up to 7 days after the procedure • for the treatment of pain and discomfort after radial keratotomy, one drop is instilled before surgery followed by one drop immediately after surgery and then one drop 4 times daily for up to 2 days • to relieve symptoms of seasonal allergic conjunctivitis, one drop is instilled 4 times daily as necessary Diclofenac diethylamine is used topically as a gel containing the equivalent of 1 % of diclofenac sodium for the local symptomatic relief of pain and inflanunation; it is applied to the affected site 3 or 4 times daily; treatment should be reviewed after 14 days or after 28 days if used for osteoarthritis. A topical spray containing diclofenac sodium

4% is also available; 4 or S sprays ( 3 2 or 40 mg of diclofenac sodium) may be applied 3 times daily, up to a maximum of 1S sprays ( 1 2 0 mg of diclofenac sodium) daily; treatment should be reviewed after 7 or 8 days. A topical solution of diclofenac sodium 1 . 6 % is available for the treatment of osteoarthritis in superficial joints such as the wrist or knee; it is applied in small aliquots to achieve a total of 20 or 40 drops, depending on the size of the joint, and repeated four times daily. Diclofenac is also used in the management of actinic keratoses; it is applied twice daily as diclofenac sodium gel 3% for 60 to 90 days but the optimum therapeutic effect may not be seen until 30 days after the end of treatment. Diclofenac epolamine is also used topically as a plaster containing the equivalent of 1 % of diclofenac sodium for local symptomatic pain relief in ankle sprain and epicondylitis. In the treatment of ankle sprain, 1 plaster is applied once daily for a maximum of 3 days and for epicondylitis, 1 plaster is applied twice daily for a maxiroum of 14 days. Diclofenac is available as a combination preparation with misoprostol (p. 2 1 40. 3 ) for patients at risk of NSAID­ induced peptic ulceration.

live, than 28 days of treatment with fluorouracil S % cream (to lesions o n the other side ) . 6 1.

Rivers JK, McLean Dl. An open study t o assess the efficacy and safety of topical 3 % diclofenac in a 2 . 5 % hyaluronic add gel for the treatment of actinic keratoses.

2.

TOPICAL. References to the use of plasters providing sus­ tained topical release of diclofenac epolamine, J . 6 and reviews of the use of a topical solution of diclofenac with dimethyl sulfoxide to treat osteoarthritis.7•8 The latter was found to be effective and better tolerated than oral use.

1.

Galeazzi M, Marcolongo R. A placebo-controlled study of t h e efficacy and tolerability of a nonsteroidal anti-inflammatory drug, DHEP plaster, in

inflammatory

peri-and extra-articular rheumatological

diseases.

Drugs Exp Clin Res 1993; 19: 107- 1 5 . 2.

Dreiser RL, Tisne-Camus M . DHEP plasters a s a topical treatment of knee

3.

Res 1993; 19: 1 1 7-2 3 . Affaitati G , et a!. Effects

osteoarthritis-a double-blind placebo-controlled study.

Drugs Exp Clin

o f topical diclofenac (DHEP plaster) o n skin,

subcutis and muscle pain thresholds in subjects without spontaneous pain.

4.

Drugs Exp Clin Res 2001; 27: 69-76.

Jenoure P-J. :Evaluation d'un anti-inflammatoire non sterordien topique

5.

Med 2004; 33: 10-13. Briihlmann P, et al.

Presse

Short-term treatment with topical diclofenac

epolamine plaster in patients with symptomatic knee osteoarthritis: pooled analysis of two randornised clinical studies.

Curr Med Res Opin

6.

2006; ll: 2429-38. et a[. Topical diclofenac patch for postoperative wound pain in laparoscopic gynecologic surgery: a randomized study. J Minim Invasive Gynecol 2006; 13: 1 9 5-200.

7.

Towheed TE . Pennsaid therapy for osteoarthritis of the knee:

a

systematic review and metaanalysis of randomized controlled trials.

J

Alessandri F,

1 239-42.

Topical treatment of actinic keratoses with 3 . 0 %

2 . 5 % hyaluronan gel. Br J Dermatol 2002; 146: 94-100. 3 . Ulrich C, et al. Treatment of multiple actinic keratoses with topical diclofenac 3% gel in organ transplant recipients: a series of six cases. Br J Dermatol 2 007; IS6 (suppl 3 ) : 40-2. 4. Pirard D. et al. Three percent didofenac in 2 . 5 % hyaluronan gel in the treatment of actinic keratoses: a meta-analysis of the recent studies. Arch Dermatol Res 2005; 297: 1 8 5-9. 5 . McEwan LE, Smith JG. Topical diclofenac/hyaluronic add gel in the treatment of solar keratoses. Australas J Dermato/ 1997; 38: 187-9. 6 . Smith SR, et al. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouradl cream in the treatment of actinic keratoses of the face and scalp.

Poin. Reviews. I.

McCormack PL. Scott

2.

Derry P,

postoperative pain.

et al.

U.

J Drugs Dermatol 2006; 5: 1 5 6-9.

Didofenac sodium injection (Dyloject ) : in

Drugs 2008; 68: 1 2 3-30.

Correction.

ibid.; 80 1 .

Single dose oral diclofenac for acute postoperative pain in

adults. Available in The Cochrane Database of Systematic Reviews; Issue

2. 3.

Chichester: John Wiley;

Standing JF,

e t al.

(accessed

2009

09/09/0 9 ) .

Diclofenac for acute pain i n children. Available i n The

Cochrane Database of Systematic Reviews; Issue

2009

(accessed

4.

Chichester: John

18/031 1 0 ) .

Adverse Effects and Treatment As for NSAIDs in general, p . 1 04. 3. There may be pain and, occasionally, tissue damage at the site of injection when diclofenac is given intramuscu­ larly. Diclofenac suppositories can cause local irtitation. Transient burning and stinging may occur with didofenac ophthalmic solution; more serious corneal adverse effects have also occurred ( see Effects on the Eyes, p . S O. ! ) . Topical preparations of diclofenac, such as plasters and gel, may cause application site reactions.

Incidence of adverse effects. A review of worldwide clini­ cal studies with diclofenac1 has reponed the incidence of drug-associated adverse effects to be about 1 2 % ; about 1 6 % of patients who had adverse effects stopped treat­ ment (a figure corresponding to about 2% of the entire patient sample) . The most . frequently reported adverse effects were gastrointestinal and were reported in 7 . 6 % of patients. CNS-related adverse effects were reported in 0 . 7 % of patients and allergy or local reactions in 0.4 % . This and other reviews2 have shown that adverse effects associated with diclofenac are usually mild and transient and appear to be unrelated to the dose given. The incidence of adverse effects in children is similar to that in adults. 3 I.

2. 3.

Willkens RF. Worldwide clinical safety experience with didofenac.

Semin Arthn'tis Rheum 1 985; 15 (suppl 1 ) : 1 05-10. Small RB. Didofenac sodium. Clin Pharm 1 989; 8: 545-8. Standing JF, et al. Prospective observational study of adverse drug reactions to diclofenac in children. Br J Clin Pharmarol 2009; 68: 243-5 1 .

Effects on the blood.

Results of a large survey undertaken to assess the relation between agranulocytosis, aplastic anaemia, and drug exposure indicated that diclofenac was significantly associated with aplastic anaemia, providing an estimated tenfold increase in risk. ! There are reports of other haematological abnormalities including haemolytic anaemia, 2•3 thrombocytopenia, 4•5 neutropenia, 5 and agranulocytosis• occurting in patients given diclofenac. Localised spontaneous bleeding, 7 bruising, 8 inhibition of platelet aggregation, 7 and prolonged bleeding time8 have been reported. I.

The International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia: a first report of their relation to drug use with special reference to analgesics. JAMA

2. 3.

dans le traitement de la douleur et de !'inflammation: exemple de Flector Tissugel 1% dispositif local bioadhesif de diclofenac epolamine.

Arch Dermatol 1 997; 133:

diclofenac i n

Wiley;

Administration. IN CHILDREN. In children aged 1 to 12 years the licensed UK oral or rectal dose of diclofenac sodium for juvenile idiopathic arthritis is 1 to 3 mg/kg daily in divided doses. In children aged 6 to 12 years diclofenac sodium may also be given rectally for the treatment of acute post­ operative pain, either alone or as an adjunct to opiate therapy; a usual dose is 1 to 2 mg/kg daily in divided doses for a maximum of 4 days. The parenteral route is not licensed for use in children although it has been used (see below ) . The BNFC suggests slightly different doses o f diclofenac sodium: in the management of rheumatic disease, including juvenile idiopathic arthritis, in children from 6 months to 1 8 years o f age, i t recommends a n oral dose o f 3 t o S mg/kg daily, in 2 or 3 divided doses. For relief of mild to moderate pain and inflammation in, for example, soft-tissue disorders, the recommended oral or rectal dose in children from 6 months to 1 8 years of age is 0 . 3 to 1 mg/kg given three times daily; children 2 to 1 8 years of age may be given a similar dose once or twice daily by intravenous infusion or deep intramuscular (gluteal) injection for up to 2 days for postoperative pain. Rectal doses may also be given for postoperative pain to children from 6 months to 1 8 years of age, according to body-weight, for a maximum of 4 days: those weighing 8 to 12 kg may be given 1 2 . S mg twice daily and heavier children 1 mg/kg three times daily. Regardless of route or indication, a maximum daily dose of 1 SO mg should not be exceeded. Diclofenac potassium has also been used in children aged over 14 years for the treatment of rheumatic disease, musculoskeletal disorders, and postoperative pain; it is given in an oral dose of 75 to 1 0 0 mg daily in 2 or 3 divided doses.

JK.. et al.

Rivers

1 986; 256: 1 749-57. et al. Autoimmune hemolytic anemia induced by didofenac. Ann Pharmacother 1995; 29: 787. Ahrens N, et al. Misdiagnosis in patients with diclofenac-induced hemolysis: new cases and a concise review. Am J Hematol 2006; 81: 1 2 8-L6pez A,

31.

4.

George S , Rahi AHS. Thrombocytopenia associated with diclofenac therapy.

5.

Am J Health-Syst Pharm 1995; 52: 420- 1 .

Kim HI.. Kovacs M J . Diclofenac-associated thrombocytopenia and neutropenia.

6.

Ann Pharmacother 1 995;

Colomina P , Garda

s.

29: 7 1 3- 1 5 .

Agranulocytosis caused b y diclofenac.

DICP Ann

Pharmacother 1 989; 23: 507. 7. 8.

Price AJ, Obeid D . Spontaneous non-gastrointestinal bleeding associated with diclofenac.

Lancet 1 989; ii: 1 520.

Kbazan U,

Didofenac sodium and bruising.

et al. 1 12: 472-3.

Ann Intern Med 1 990;

RJzeumatol 2006; 33: 567-73. 8.

Moen MD. Topical diclofenac solution.

Aclinic keroloses.

Drugs 2009; 69: 2621-32.

Diclofenac sodium 3% in hyaluronic add gel is used1·3 in the treatment of actioic keratoses (see Basal Cell and Squamous C ell Carcinoma, p . 7 1 4.2), and a meta-analysis4 found it to be of benefit, despite previous concerns that the preparation may not be significantly more effective than hyaluronic acid gel alone. 5 An open­ label comparison involving 3 0 patients with multiple acti­ nic keratoses suggested that 90 days of treatment with diclofenac sodium 3 % gel (to lesions on one side of the face and scalp) was better tolerated, but slightly less effec-

The symbol t denotes a preparation no longer actively marketed

Effecls on the cardiovascular system. For a discussion of the cardiovascular effects of NSAIDs, including diclofenac, see p . 1 0 S . l .

Effects o n electrolytes. A syndrome resembling the syndrome of inappropriate antidiuretic hormone secretion has been reported in elderly women given diclofenac. l·2 Also the UK CSM had received a report of fatal hyponatr­ aemia in another elderly woman. 2 I.

Petersson I,

et al.

Water intoxication associated with non-steroidal

anti-inflammatory drug therapy.

2.

Cheung

NT, et al.

Acta Med Scand 1 987; lll: 221-3.

Syndrome of inappropriate secretion of antidiuretic

hormone induced by diclofenac.

BMJ 1 993; 306: 186.

50 Effects on the eyes. A patient who had been taking oral diclofenac for several years and had increasingly com­ plained of dry, gritty eyes noticed that eye irritation disap­ peared within 3 days when diclofenac had to be stopped because of gastrointestinal effects. 1 Ocular diclofenac and related drugs have been hnplicated in reports of corneal toxicity. Ulceration of the conjunctiva or cornea, corneal or scleral melts, and perforations have been reported in patients using diclofenac eye drops, particularly after cataract surgery. 2•5 Keratitis and perfora­ tions were also reported with ketorolac eye drops,4 although less frequently. For mention of corneal melting with bromfenac, see p . 3 0 . 1 . L

Reid ALA, Henderson R . Diclofenac and dry, irritable eyes.

2.

Lin JC,

US:

et al.

Surg

2000;

I.

J Cataract Refract

2. ulceration, and perforation associated with

topical nonsteroidal anti-inflammatory drugs.

Ophthalmology

29:

Szczeklik A,

et a!.

BMJ 1 977; 2:

3.

205-10.

CSM/MCA. Avoid a l l NSAIDs i n aspirin-sensitive patients.

Current

8. Also available at: http:!!www.mhra.gov.uk/home/

Carson J,

2.

Deakin M,

Small bowel perforation associated with an excessive

et

dose of slow release diclofenac sodium.

BMJ 1 988; 297: 488-9.

Gentric A, Pennec YL. Diclofenac-induced pseudomembranous colitis. 1 26-7.

Lancet 1 992; 340:

Effects on the kidneys.

Renal papillary necrosis1 and nephrotic syndrome2-4 have been reported in patients tak­ ing diclofenac. See also Effects on Electrolytes, p. 4 9 . 3 . I.

Scott S J ,

2.

Beun GDM,

e t al. Renal papillary necrosis associated with diclofenac BMJ 1 986; 292: 1 050. et al. Isolated minimal change nephropathy associated with diclofenac. BMJ 1 987; 295: 1 82-3 . 3 . Yinnon AM, et al. Nephrotic syndrome associated with diclofenac sodium. BMJ 1 987; 295: 5 5 6 . sodium.

AA, et al. Diclofenac hepatitis. BMJ 1 982; 284:

1.

Dunk

Breen EG,

3.

Schapira D,

et a!. Fatal hepatitis

Porphyrio.

The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies diclofenac as prob­ ably porphyrinogenic; it should be prescribed only for compelling reasons and precautions should be considered in all patients. 1 1.

Gut

1 986;

Veterinary use.

Veterinary use o f diclofenac i n cattle in South Asia has been associated with severe decline in the numbers of vultures, to whom the residues are highly toxic if they consume the carcasses.L2 Meloxicam (p. 8 6 . 3 ) h a s been suggested as an alternative. l.

Diclofenac-induced hepatotoxicity.

Ryley NG,

5.

Helfgott SM,

2.

27:

Purcell P,

Bhogaraju A.

et al. Diclofenac hepatitis. Gut 1 9 9 1 ; 32: 1 3 8 1 - 5 . et al. Diclofenac-assodated hepatitis. South Med J

1 999;

2004; 271

Sharp D . Meloxicam to prevent rabies?

Greaves RRSH,

92:

and

non-generic

prescribing,

fulminant liver failure. 9.

Diggory P,

et al.

liver

transplantation

Deterioration in renal function has been attributed to the use of diclofenac with ciclosporin. 1 Increased concentrations o f diclofenac were also noted with ciclosporin;2 licensed product information for ciclos­ porin recommends that the dosage of diclofenac should be reduced by about one-half when the two are given together.

for

7 1-3.

Renal and hepatic impairment in association with

et al.

didofenac administration. 10. Banks AT,

leading to

Eur J Gastroenterol Hepatol 2 0 0 1 ; 13: Postgrad Med J 1989; 64:

507-8.

Diclofenac-associated hepatotoxicity: analysis of 180

cases reported to the Food and Drug Administration as adverse reactions.

Hepatolo.qy

1 99 5 ;

22:

820-7.

Effects on the skin.

Self-limiting skin reactions such as rash or pruritus may occur in patients given diclofenac. More serious skin reactions attributed to diclofenac include bullous dermatitis1 and erythema multiforme .2·3 Local irritation and necrosis have occurred on intramuscu­ lar injection of didofenac.4-7 l.

Gabrielsen T0,

et al.

Drug-induced bullous dermatosis with linear IgA

deposits along the basement membrane.

Acta Derm Venereol (Stockh)

1 9 8 1 ; 6 1 : 439-4 1 . 2.

Morris BAP, Remtulla S S . Erythema multiforrne major following use of diclofenac.

Can Med Assoc J 1 985; 133:

665.

All cross-references refer to entries in Volume A

1. 1

Branthwaite JP, Nicholls A. Cyclosporin and didoft:nac interaction in rheumatoid arthritis.

2.

Kovarik J M ,

et al.

Lancet

1 9 9 1 ; 337: 2 5 2 .

Cyclosporine a n d nonsteroidal antiinflammatory

drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid anhritis.

J Clin Pharmacol l 997; 37: 336-43.

Corticosteroids. Concomitant use of ophthalmic prepara­ tions containing diclofenac with those containing corticos­ teroids in patients with significant pre-existing corneal inflammation may increase the risk of developing corneal complications.

Br J Clin Pharmacol

Colestyramine appears substantially to reduce the bioavailability of diclofenac when the two drugs are given together; 1 colestipol produces a similar but smaller effect. l.

al-Balla SR,

The effects of cholestyramine and colestipol on the

et al.

absorption of diclofenac in man. Int J C!in

Pharmacol Ther

1 994;

32: 44 1 -

5.

Misoprostol.

The plasma concentration of diclofenac was reduced when it was given as a I 00-mg dose daily in the form of a modified-release preparation to subjects receiv­ ing misoprostol 800 micrograms daily. 1 Use together was also associated with an increase in the incidence and severity of gastrointestinal effects. Studies by the manufac­ turer2 had failed to find any significant pharmacokinetic interactions between diclofenac and misoprostol when given in a formulation containing diclofenac 50 mg and misoprostol 200 micrograms. 1.

Dammann HG,

et al.

Differential effects of misoprostol and raoitidine on

the pharmacokinetics of diclofenac and gastrointestinal symptoms.

Clin Pharmacol 1 993; 36: 2.

Karim A.

Br J

345-9.

Pharmacokinetics

of

didofenac

and

administered alone or as a combination product.

misoprostol

Drugs

when

1 99 3 ; 45 (suppl

I ) : 7-14.

Parasympathomimetics. Licensed product information for acetylcholine chloride ophthalmic preparations has stated that there have been reports that acetylcholine and carbachol have been ineffective when used in patients treated with topical (ophthahnic) NSA!Ds .

Pharmacokinetics Diclolenac is rapidly absorbed when given as an oral solution, sugar�coated tablets, rectal suppository, or by intramuscular injection. It is absorbed more slowly when given as enteric-coated tablets, especially when this dosage form is given with food. Although diclofenac given orally is almost completely absorbed, it is subject to first-pass metabolism so that about 50% of the drug reaches the systemic circulation in the unchanged form. Diclofenac is also absorbed percutaneously. At therapeutic concentra­ tions it is more than 9 9 % bound to plasma proteins. Diclofenac penetrates synovial fluid where concentrations may persist even when plasma concentrations fall; small amounts are distributed into breast milk. The terminal plasma half-life is about I to 2 hours. Diclofenac is metabolised to 4' -hydroxydiclofenac, 5 -hydroxydiclofenac, 3'-hydroxydiclofenac, and 4', 5 -dihydroxydiclofenac. It is then excreted in the form of glucuronide and sulfate conjugates, mainly in the urine (about 6 0 % ) but also in the bile (about 3 5 % ) ; less than I % is excreted as unchanged diclofenac. References. l.

Fowler PD,

et al. Plasma and

synovial fluid concentrations of diclofenac

sodium and its major hydroxylated treatment of rheumatoid arthritis. 2.

Maggi CA.

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metabolites

during long-term

Eur J Clin Pharmacol 1 983; 25: 389-94.

Comparative bioavailability of diclofenac hydro­

xyethylpyrrolidine vs diclofenac sodium in man.

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Davies NM, Anderson KE . Clinical pharmacokinetics of diclofenac:

4.

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r t at.

Clin Pharmacokinet l 997; 33:

1 84-2 1 3 .

Influence o f age and cytochrome P450 2 C 9 genotype disposition

of

diclofenac

and

celecoxib.

Clin 42: 283-92. et al. Bioavailability of diclofenac potassium at low doses. Br J Clin Pharmacol 2005; 59: 80-4. 6. Standing JF, et al. Population pharmacokinetics of oral diclofenac for acute pain in children. Br J Clin Pharmacol 2008; 66: 846-5 3 . 7 . Miyatake S, e t al. Randomized clinical comparisons o f didofenac '5 .

Hinz B,

concentration in the soft tissues and blood plasma between topical and

Ciclosporin.

Inadvertent diclofenac rechallenge from generic

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Short-term sucralfate administration alters potassium

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therapeutic insights and pitfalls.

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Lipid regulating drugs.

Lancet 2006; 367: 887-8.

For interactions associated with NSAIDs, see p . 1 0 7 . 3 . Diclofenac should n o t be given intravenously t o patients already receiving other NSAIDs or anticoagulants including low-dose heparin.

264: 2660-2. 6.

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diclofenac absorption in healthy male volunteers.

1 997; 43:

Didoknac poisoning is widespread in declining vulture

Interactions

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et al. Diclofcnac associated hepatitis. Gut 1 989; 30: A708. et al. Diclofenac-associated hepatotoxicity . .lAMA 1 990;

7.

et a!.

(suppl 6 ) : S458-S460.

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Shult7: S,

populations across the Indian subcontinent.

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1 605-6.

associated with diclofenac.

BMJ 1 983; 286:

Breast feeding. Diclofenac is distributed into breast milk although the BNF considers the amount to be too small to be harmful to breast-fed infants.

Effects on the liver. Elevations of serum aminotransferase activity and clinical hepatitis, 1 -8 including fatal fulminant hepatitis2•5 have occurred in patients taking diclofenac. There has also been a case report of hepatorenal damage attributed to diclofenac.9 Analysis10 of 1 80 of the cases of diclofenac-associated hepatic injury received by the FDA between November 1 988 and June 1 9 9 1 suggested an increased risk of hepatotoxicity in female patients and those taking diclofenac for osteoarthritis. Hepatotoxicity had been detected within 6 months of starting diclofenac in 8 5 % of the patients. The biochemical pattern of injury was hepatocellular or mixed hepatocellular in 6 6 % of patients and cholestatic injury was found in 8% of patients. Signs of hypersensitivity were uncommon and it was considered that the mechanism of hepatic injury was likely to be a metabolic idiosyncratic reaction rather than due to intrinsic toxicity of diclofenac. 2.

Anaphylactic shock induced by didofenac.

Precautions

1 990; 323: 1 3 5 .

therapy.

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As for NSAIDs in general, p. I 07 . I . Systemic diclofenac i s contra�indicated in patients with moderate to severe heart failure (NYHA class II to IV) , ischaemic heart disease, peripheral arterial disease, o r cerebrovascular disease . I t should be used with caution in patients with significant risk factors for cardiovascular events such as hypertension, hyperlipidaemia, diabetes mellitus, and smoking. Systemic diclofenac is also contra-indicated in patients with severe hepatic or renal impairment. In addition, u s e of intravenous diclofenac i s contra-indicated in patients with moderate or severe renal impairment, hypovolaemia, or dehydration; it should also not be given intravenously to patients with a history of haemorrhagic diathesis, cerebrovascular bleeding (includ­ ing suspected), or asthma nor in patients undergoing surgery with a high risk of haemorrhage. Ophthalmic preparations containing diclofenac should not be used by patients who wear soft contact lenses.

Colonic ulceration and bleeding during diclofenac

et al.

Dux S, 1861.

Effects on the gastrointestinal tract. The most frequent adverse effects reported in patients given diclofenac sys­ temically are gastrointestinal in nature. Typical reactions include epigastric pain, nausea, vomiting, and diarrhoea. Rarely peptic ulcer and gastrointestinal bleeding have occurred. Diclofenac has also been implicated as the causa­ tive agent in colonic ulceration, 1 small bowel perforation,2 and pseudomembranous colitis.3 Diclofenac suppositories may cause local reactions such as itching, burning, or exacerbation of haemorrhoids. 1.

I.

2 3 1 -2 .

idcplg?IdcService=GET_FILE&dDocName:=CON20244 S S &Revision S ­

Flach AJ. Corneal melts associated with topically applied nonsteroidal

Trans Am Ophthalmol Soc 2 00 1 ; 99:

BMJ

Gastrointestinal drugs. A decrease in the plasma concen­ tration of diclofenac has been reported1 when given after sucralfate.

Asthmatic attacks induced in aspirin-sensitive patients

by diclofenac and naproxen.

electionMethod=LatestReleased (accessed 0 1 / 1 1 / 07)

anti-inflammatory drugs.

3.

1 99 5 ;

Ezzedine K, et a!. Nkolau syndrome following diclofenac administration. Br J Dermatol 2004; 150: 38 5-7. Mutalik S, Belgaumkar V. Nicolau syndrome: a report of 2 cases. J Drugs Dermatol 2006; 5: 377-8.

Problems 1 993; 19:

200 1 ; 108:

936-44. 5.

Hiirk6nen M, Ekblom-Kullberg S. Reversible deterioration of renal function after didofenac in patient receiving triamterene.

293: 6�8-9.

Ann Pharmacother

Aspirin-sensitive asthmatic patients have developed reactions (rhinorrhoea, tightness of chest, wheezing, dyspnoea) when challenged with diclofenac in doses of 10 to 25 mg1 and the UK CSM has received a report of an aspirin-sensitive patient who died from acute asthma 4 hours after a single 2 5 -mg dose of diclofenac 2 Anaphylactic shock has been reported 3

200 1 ;

Guidera

27: 622-3 1 . AC, et a!. Keratitis,

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1058.

Pillans PI, O'Connor N. Tissue necrosis a n d necrotising fasciitis after intramuscular administration of didofenac.

Hypersensitivity.

Corneal complications associated with topical

ophthalmic use of nonsteroidal antiinflammatory drugs. 4.

6. 7.

Med J Aust

Arch Ophthalmol

Ann Intern Med 1 992; ll7:

Diuretics. Deterioration in renal function has been attribu­ ted to the use of diclofenac with triamterene. 1

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Stricker BHC, van Kasteren B J . Didofenac-inducedisolated myonecrosis and the Nicolau syndrome.

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Young J. Erythema multiforrne-like eruption as a result of 'Solaraze' treatment.

1 9 94; 160: 308. anti-inflammatory drugs after ocular surgery.

3.

3. 4.

oral applications.

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1 2 5-9.

Prepa a ons . . . . . . . .r. . . .ti. . . . . . . . . . .

. ...

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Arg. : Ainedif; Aldoron NF; Algi­

cler; Algioxib; Anaflex; ATM 1 0 1 ; Atomo Desinflamante Geldic; Banoclus; Befol; Blokium Prostt; Blokium; Calmoflex; Curin­ flam VL; Curinflam; DFN; Diastone; Diclac; Diclofilab; Dicloge­ sic; Diclogrand; Diclolabsa; Diclolam; Diclomar; Diclonex; Dicloreumol; Difenac Forte; Difenac; Dilamt; Dioxaflex Protect; Dioxaflex; Disipan; Distec; Dolo Tomanil; Dolofenac; Doland� tor; Dolvan; Doxtran; Excelentia Analgesico; Faboflemt; Flexin; Flexiplen; Flogolisin; Fluxpiren; Gel Antiinflamatorio; Gentisa� lyl; Iglodine; Imanol; Ingecloft; Kamoxt; Kinalgin; Klonafenac; Levedad; Lorbifenac; Metaflex NF; Miocalmt; Nalgiflex; Natura Fenac; Norviken; Oxa; Oxaprost; Pronix; Quer-Out; Rati Salil D; Reumosan; Rodinac; Salicrem Forte; Silfox; Tomanil; Vesa-

Diclofenac/Difl unisal 5 1 lion; Viartril NF; Vimultisa; Virobron Gel; Virobron NF; Val­ forte; Voltaren Colirio; Voltaren Migrat; Voltaren; Xedenol; Austral.: Arthrotec; Clonact; Dencorub Anti-Inflammatory; Diclact; Diclohexalt; Dinact; Fenac; Imflac; Solaraze; Viclofen; Voltaren Ophtha; Voltaren; Voltfast; Austria: Algefit; Arthrotec; Dedolor; Deflamat; DidacHexal; Didobene; Diclomelan; Didos­ tad; Diclosyl; Dolostrip; Dolpasse; Flector; Solaraze; Tratul; Vol­ tadol; Voltaren; Belg.: Arthrotec; Cataflam; Dicloabak; Dido­ fastt; Diclofemedt; Diclotopt; Docdidofet; Flector; Kinespir; Motifene; Polyflam; Voltapatch; Voltaren; Braz.: Artren; Bella­ reo; Benevran; Biofenac; Cataflam; Cataflex; Cataflexym; Cina­ flan; Cinatil; Clofenak; Clofenid; Deltaflogin; Deltaren; Didac; Dido P; Dicloflogil; Didogenom; Diclonaco; Diclonax; Diclonil; Diclosodicot; Diclostir; Dicloton; Dioxaflex; Dnaren; Dorflan; Dorgen; Dryltac; Fenaflan; Fenaren; Fenburilt; Fisioren; Fla­ dont; Flamatrat P; Flanakint; Flanaren; Flodin Duo; Flogan; Flogiren; Flotac; Infladex; Inflamax; Kindarent; Maxilerg; Neo­ coflan; Neotaflan; Neotaren; Olfent; Ortoflant; Poltax; Proben­ xi!; Prodofenacot; Sodix; Still; Tekaflex; Vendrex; Volflanil; Voltaflan; Voltaflex; Voltaren Colirio; Voltaren; Voltrix; Zotac; Canad.: Apo-Diclo; Arthrotec; Novo-Difenact; Nu-Diclo; Penn­ said; Pro-Dido; Voltaren Ophtha; Voltaren; Chile: 3A O!teno; Amofen; Artren; Autdol; Cataflam; Deflamat; Diclac; Diclota­ ren; Dicogel; Elitiran; Exflamt; Flamesan; Flector; Flotac; Klafe­ nac; Lertus; Merpal; Oftic; Pirexyl; Piroflam; Pro Lertus; Sipirac; Turbogesic; Voltaren; China: Aofen (�:Jf); Apo-Diclo (�»{); Arthrotec (�Wi5/:); Bi Si Fu ($Wi�l! ) ; Chen Jing (!ili:ll< ) ; De Fu Ka (�!i-F); Di Fu Xin (il!lt!i'/iX); Di Pu (il!l-lf); Diclac (il!l:l'I:Jf5/: ) ; Difene ( l\ll :Jf ); Difnal (ii!! Jil #l); Digen (il!li!R); Fei Ya Ning ( '!11 !Il'"r ); Fei Yan (��l!r)t; Fen Di Ning (:Jfil!l'J'); Fen Na Ke (:Jf Jl�5/:); Fendi (:Jfil!l); Gede (:11\ � ); Ji Sorig Cats); Jiu Ning (0. 'J'); Kaflan (t!i'ft!ll'il!); Kang Tai (}�!'�); Lai Bi Xin ( * lt>Wi); Li Shu (:ll. ff ); Lu Lin (/l11;\l; ); Luck (!f-liT); Luo Pu Jia (i!t-lffi); Novolten (iil\'il!T); Olfen (��:Jf); Pu Ta Ning (-lfft!l'J'); Rui Pei En (JW>i!!6l. ) ; Shi Xiang ({±�); Si Fu Xin (I.!PJ1./iX); Tian Jun Li (:le'l't:f!J); Tian Xin Li Do (:le>Wi:f!J!ili); Tong Du Ding ( [ll] tf: IIJ); Voltaren (t!i'ft!l;ll; ) ; Voren (��-i1f ) ; Xi Shu ( fdlt); Xin Pu Fen (fiX J'l':Jf) ; Yi Er Song (i/(�f'c ); Yi Ke ( i/(;fiif ) ; Yi Ke Lin (l§[\\i ;\l; ); Yi Lin (i/(;\l;); Yingtaiqing (:i€::t:1i'); Zhi Qing (�il't); Cz. : Almira!; Apo-Diclo; Didoabak; Didofent; Didoreum; DIKY; Dobnina; Dorosant; Flector; Monoflam; Myogit; Naklofen; Olfen; Rewo­ dinat; Uniclophen; Uno; Veral; Voltaren; Denm.: Alterflex; Arthrotec; Diclodan; Diclon; Diclopax; Dicuno; Difenet; Eeze; Fenacopt; Fenacta; Flectort; Instantin; Modifenact; Solaraze; Voltaren; Fin.: Arthrotec; Diclomex; Dicuno; Eeze; Flectort; Motifene; Solaraze; Voltaren; Fr.: Artotec; Compralfene; Dicloced; Dispadol; Flector; Solaraze; Tendo!; Tevalgiesprayt; VoltarenActigo; Voltarendolo; Voltarene; Voltarenophta; Vol­ terenplast; Xenid; Ger.: Allvorant; Arthotec; Didabeta; Didact; Dido-Dividot; Dido·Purent; Dido-saart; Dido; Didodoct; Didofenbeta; Dilen; Dolgit·Didot; Effekton; Flector; Jutafe­ nact; Monoflam; Optalidon Zahnschmerz mit Didofenact; Rewodinat; Sandoz Schmerzgelt; Solaraze; Voltaren Ophtha; Voltaren; Gr. : Actisuny; Anthraxiton; Arthrotec; Batafil; Cata­ flam; Clonac; Contralg; Counterflame; Declofon; Delimon; Denaclof; DicloDuo; Diclofast; Diclojet; Diclophlogont; Diclo­ plast; Dicloral; Difend; Dinaclon; Evinopon; Eyeclof; Fenoclof; Figrel; Flefatrnin; Iilflaforte; Javipren; Linobol; Minlflam; Opto· bet; Pengon; Pennsaid; Relipain; Rheumavek; Ruvominox; Sfi­ nac; Topalgon; Urigon; Vilacril; Vilonit; Voltaren; VurdOn; Hong Kong: Almira!; Apo-Dido; Artharent; Arthrotec; Astont; Cataflam; Clofec; Clofenac; Curinflam; Dido-Denk; Diclofen; Diclogesict; Dicofen; Difenac; Difenolt; Doroxan; Erdon; Euro­ fenac; Fenac; Fenadium; Flector; Flogofenact; Grofenact; Infla­ nac; Lesflam; Olfen; Painofft; Panaflex; Remafen; Remethan; Ren; Rhemofenaxt; Ruvominox; Syn!enact; Takst; Tapain; Uniren; Vartelon; Vidofenact; Voltaren Ophtha; Voltaren; Vol· tont; Votalent; Zolterol; Hung.: Cataflam; Didac; Didomel; Flamerilt; Flector; Fortedol; Voltaren Ophta; Voltaren; India: Ado max; Adgel; Adiflam; Agile- K; Agile; Ale!en; Antiflam; Argesic; Ark; Anndic; Artilov; B-Nac; Beconac; Bestodek; Bid­ nac; Bionac; Bioran; Cadmax; Cannact; Capsigyl-D; Caredec; Clopar; Cofenac; Combinac; D-Nova; Dacron; Deedo; Defcin; Delbitol; Delta-K; Demo; Dersy; Devona; Diclam; Diclasia; Diclo-DT; Dido-K; Dicloact; Dicloat; Diclobit; Diclodol; Dido­ dyne; Didofam; Didofast; Didofen; Didoflaro; Didoflaroe; Diclolab; Dicloma; Diclomax; Diclomol; Diclomol; Diclomove; Diclonac; Diclonet; Didonij; Diclonip; Diclonova; Dicloran; Diclostar; Diclotal; Didovar; Diclowin; D iclozed; Dicnac; Dic­ nacx; Dico; Dicol; Dicoliv; Dicos; Dicron; Dicven; Difenac; Dife­ nic; Difin; Difisal; Dlkiofen; Dikonb; Dikpa; Dikul; Dilofen; Dilo­ na; Dion; Disoral; Divexx; Divon; DLF; Dofec; Doflex; Dolact; Dolocide K; Dolocide Plus; Dolzy; DS- 1 5; Dynapar; E-Nac; E­ Par; Emflam; Emflam; Esgipyrin DS; Exflam; Penac; Fenbest; Fendase; Pengel; Pensaid; Pensaide; Fento; Pineact; Plamese; Plexigesic-K; Plexigesic; Gic; Haloran; I -Gesic; Imflamol; Inac; Indofen; Intragesic; J onac; Justin; K-Fenac; Knac; Lafen; Lee­ max; Lipcy; Lofen; Lofy; Lysoflaro; Mifenac; Mindol; Mishanac; Misonac; Mobiaid; Mobyle; Nac Gel; Nac; Nado; Nal-M; Neo­ dol; Nifdec; Noctel; Novofen; Novoflam; NSAID Eye; Nudido; Nufenac; Nupatch; Odonac; Onafen; Ontac; Oronac; Osteoflam; Oxalgin·D; Oxalgin-SR; Oxalgin; Oxynal; Painkair; Panama; Parafortan; Profenac; Reactine; Relaxyl; Relaxyl; Solunact; Tro­ magesic; Tromax; Voveran; Indon. : Abdiflamt; Aclonac; Alflam; Araclof; Atranac; Berifent; Cataflam; Catanac; Defla­ mat; Dicloflam; Diclomect; Diflam; Divoltar; Eflagen; Elithris; Exaflam; Penarent; Fenavel; Flamar; Flamenact; Flamic; Inflam; Kadiflam; Kaditic; Kaflam; Kamaflam; Klotaren; Lafla­ nac; Linac; Matsunaflam; Merflam; Nacoflar; Nadifen; Neurofe­ nac; Nichoflam; Nilaren; Potazent; Prostanact; Provoltar; Reclofen; Renadinac; Renvoi; Scanaflam; Scantaren; Tirmaclo;

Troflam; Valto; Volmatik; Voltadex; Voltaren Ophtha; Voltaren; Voren; X-Flam; Xepathritis; Yariflam; Zegren; Irl. : Arthrotec; Cataflam; Didac; Dido; Didomaxt; Didomelt; Difene; Flector; Kyflam; Solaraze; Voltarol Oplttha; Voltarol; Voltfast; Israel: Abitren; Arthrotec; Betaren; Cataflam; Demofenac; Dicloftil; Didoplast; Didorengel; Olfen; Physicare Gel; Swiss Relief; Vol­ taren Ophtha; Voltaren; Ital. : Algosenac; Artrotec; Dealgic; Deflamat; Didocular; Diclofan; Didoftil; Didoral; Didor�um; Diclotears; Diep Grat; Dolaut; Doroxan; Dropflam; Fenadol; Fender; Flector; Plogofenac; Itami; Leviogel; Misofenac; Nadi­ clopht; Novapirina; Pennsaid; Solaraze; Topfanst; Traulen; Vol­ tadol; Voltadvance; Voltaren; Voltfast; Zeroflog; Jpn: Anavan; Malaysia: Altnlral; Analpan; Cataflam; Clofec; Clofenact; Dif­ nal; Doroxan; Fenac; Inflanac; Lesflam; Neo-Pyr�zont; Olfen; Panaflex Extra; Remafent; Remethan; Rhemofenax; Uniren; Vokam; Voltaren; Voren; Zolterol; Mex.: 3A Ofteno; Alsidex­ tent; Ariflam; Artrenac Pro; Artrenac; Artrene; Artrotec; Ata­ lak; Calaffier; Catafast; Cataflam; Clo-Far; Clofenix; Clonodi­ fent; Coral; Deflox; Didafena; Diclac; Diclopisa; Dicloran; Diclosol; Dioxaflex; Diqfanol; Dirret; Docril; Dofent; Doflatem; Dolaren; Dolflam; Dolofenac; Doltarac; Evadol; Fenagel; Penal­ gin; Fervex; Flamydol; Flamygel; Flankol; Flogoken; Flotac; Fortical; Fustarent; Galedol; Hipo Sport; Lertus; Lifenac; Liro� ken; Lodyfen; Lonatec; Lufac-Z; Mafena; Manacon; Merxil; Metradnt; Musol; Nediclon; Neo-Dolaren; Pharma:flam; Practi­ ser; Precifenac; Selectofen; Solo!; Still; Vicmafent; Volfenac; Voltaren; Neth.: Arthrotec; Cataflam; Dicloabak; Eminocs; Itamit; Misofenact; Naclof; Normulent; Otriflu; Voltaren Emulge� Voltaren; Norw.: Arthrotec; Caraflam; Modifenac; Otriflut; Solaraze; Voltaren Ophtha; Voltaren; Voltarol; NZ: Apo-Diclo; Cataflam; Diclax; Diclohexalt; Plameril; Voltaren Ophtha; Voltaren; Voltfast; Philipp. : Acuflam; Canefol; Cata · flam; Cataflin; Clofenix; Clofil; Clonarent; Ci.uafen; Dafenac; Diclogen; Difenamin; Difenax; Diflapane; Doloflam; Dycon; Dynapar; Eslofent; Fenaspec; Fendil; Klaxon; Lobafen; Lofe­ nax; Maxi; Medclof; Neo-Pyrazon; Nepenthet; ·Parafortan; Rheuflam; Uniclonaxf; Vifenac; Vodefen; Volfenn; Voltaren; Voren; Votan; Zobid; PoL : Apo-Diclot; Arthrotec; Cataflam; Diclac; Dicloabak; Dicloberl; Diclobiont; DicloDuo; Dicloratio; Didoreum; Didoziaja; Difadol; Diklonat P; Dikloziajat; Dlky; Felogel;. Glimbax; Majamil; Nadof; Naklofen; Olfen; Ratiogelt; Rewodinat; Vera!; Voltaren; Voltenac; Port.: Arthrotec; Cata­ flam; Clofen; Dagesil; Didoabak; Didodent; Didofar; Dido!talt; Diclospray; Diclotect; Dofene; Dolacen; Dorcalor; Fenac; Fenil­ V; Flameril; Flector; Frenalgil; Olfen; Otriflu; Painex; Pennsaid; Solaraze; Voltadol; Voltaren; Rus.: Almira! (AJThrnpaJI)t; Apo­ Dido (Ano·)1HKJ1o)t; Arthrotec (Ap1porex); Bioran (BuopaH); Diclac (�ax); Diclo-F (�o-ljl); Didobene (,liHKJio6eHe); Didoberl (�o6epn)t; Diclogen (�oreH); Didonat (�oHaT); Dicloran (�opllH); Diclovit (�OBHT); Eryfenac (:}rnljleHaK); Flameril (mlMepiiJI); Nadof (HaKnoljl)t; Nakiofen (HIIKlloljleH); Naklofen Duo (HIIKlloljleH ,llyo ); Neodol (HeonOJI); Ortofen (OproljleH); Ortofer (Oproljlep); Ortoflex (OproljlneKc); Ortophen (OproljleH) ; Rapten Duo (PameR JIYO); Rapten Rapid ( ParrreH PaoHJI); Rheumavek (PesMaBeK); Unidophen (YHHKJioljleH); Voltaren (Bon&TapeH) ; S.Afr.: Adco-Clo!elam; Arcana!enact; Arthrotec; Arthru • Derm; Catafast; Cataflam; Dicloflam; Diclohexal; Difen; Difenject; Dynak; Penisun; Flexa­ gent; Fortfen; Infla-Bant; K-Fenak; Panamor; Veltex; Voltaren Ophtha; Voltaren; Singapore: Almira!; Analpan; Apo-Dido; Cataflam; Clofec; Clofenac; Diclo-Denk; Dido; Dicloran; Dife­ nac; Difnal; Fenac; Fenadium; Flector; Inac; Inflanac; Lesflam; Neodol; Olfen; Panaflex Extrat; Panamax; Pritaren; Remafen; Remethan; Rhewlin; SP-Nadofen; Ultrafen; Uniren; Voltaren Ophtha; Voltaren; Voltfast; Voren; Zolterol; Spain: Artrotec; Di Retard; Dicloabak; Dolo Nervobiont; Dolo-Voltaren; Dolotren; Luaset; Normulent; Ratioparcht; Solaraze; Voltadol; Voltaren; Xibol; Swed.: Arthrotec; Dicuno; Eeze; Eezeneo; Flectort; Solar­ aze; Voltaren Ophtha; Voltaren T; Voltaren; Switz.: Arthrotec; Didac; Dicloabak; Didosifart; Difen-Stulln; Ecofenac; Effigel; Fenisolet; Fenisun; Plam-X; Flector; Portenac; Grofenac; Infla­ mac; Olfen; Primofenac; Relova; Solaraze; Tonopan; Vifenac; Voltaren Dolo; Voltaren Emulgel; Voltaren Ophta; Voltarene; Voltfast; Thai. : Ammi-Votara; Amminac; Antenac; Arclonac; Cataflam; Catanac; Cencenac; Chinclona; Chinclonac; Clofec; Clofon; Covonac; D-Fiam; Demac; Dido; Diclogel; Diclogesic; Didolan; Didomolt; Didosian; Di!aren; Difelene; Difent; Dife­ nac; Difengesic; Difeno; Difensic; Dinac; Dinefec; Dolonil; Dosa­ nac; Perna; Fenac; Penacaine; Penacil; Penagel; Flexy; Infenac; Inflamma; Inflanac; Klyzen; Lesflam; Lofenac; Manfenac; Masaren; Myfenax; Myonac; N-Zen; Nadoft; Ostaren; P.ai­ Noren; Painelief; Posnact; Remethan; Rhumano� Sefnac; Sin­ danae; Subsyde; Takst; Taijen; Tarjena; Uniren; V ·Therien; Vasalent; Veenac; Ventarone; Vesconac; Volfent; Volfenac; Volnac; Volta; Voltanac; Voltaren; Voltex Kool; Volverac; Voren; Votamed; Turk.: Actinoma; Arthrotec; Cataflam; Deflci ­ mat; Dicloflam; Diclomec; Dicol; Difenak; Dildo-S; Diklopain; Dikloron; Dildoron; Dikloteva; Dolorex; Flector; Inflased; Kali­ dren; Miyadren; Romatim; Volfenaks; Voltaflam; Voltaren Ophta; Voltaren; UAE: Clofen; UK: Arthrotec; Defanac; Defe­ nac; Dexomon; Dicloflex; Didomax; Diclovol; Diclozip; Dylo­ je�; Econac; Penactol; Flamatak; Flamrase; Misofen; Mobigelt; Motifene; Pennsaid; Rheumatac; Rhumalgan; Slofenac; Solar­ aze; Volraman; Volsaid; Voltarol Ophtha; Voltarol; Ukr.: Cata· fast (Kln'llljJacT); Clodifen (Knonaljlea) ; Didac (,llmmaK ) ; Diclo-F (,llmom-); Diclobene (,!IHKJio6eae); Dicloberl (�o6epn); Diclobru (�o6pro); Didocain (�OK811H ); Diclopherol (,lii!KJioljlepon)t; Diftal (,!IHijJT8Jib); Megafen Plus (MeraljleH IImoc)t; Nadof (HaKnoljl); Naklofen (HIIKlloljleu); Olfen (OnljleH); Rapten (ParrreH); Voltaren (BOJibTapeH) ; USA: Arthrotec; Cam­ bia; Cataflam; Flector; Pennsaid; Solaraze; Voltaren; Voltaren;

The symbol t denotes a preparation no longer actively marketed

Zipsor; Zorvolex; Venez. : 3 A Ofteno; Arthrotec; Artren; Campal; Cataflam; Clofen; Clofenac; Diagesic; Diclofen P; Diclosal; Dife­ nac; Diklason; Diralon; Dival; Plogaren; Flotac; Klafenac; Via­ vox; Voltaren; Volten; Votaxil.

Multi-ingredient Preparations. Numerous preparations are listed in Volume B.

Phannacopoeial Preparations

BP 20 14: Didofenac Gel; Gastro-resistant Diclofenac Tablets;

Prolonged-release Diclofenac Capsules; Prolonged-release Diclo­ fenac Tablets; USP 36: Diclofenac Potassium Tablets; Diclofenac Sodium Delayed-release Tablets; Didofenac Sodium Extended-Release Tablets.

Pharmacopoeias. In Br. and Chin.

BP 20 14; (Diethylamine Salicylate). White or almost white, odourless or almost odourless crystals. Very soluble in water; freely soluble in alcohol and in chloroform. Protect from light. Avoid contact with iron or iron salts.

Profile Diethylamine salicylate is a salicylic add derivative used topically in rubefacient preparations similarly to methyl salicylate (p. 92. 1 ) lor rheumatic and muscular pain.

P..r�P.�.r�!��-� �---·········································································

Proprietary Preparations (details are given i n Volume B ) Single-ingredient Preparations. Belg. : Algesalt; Canad.: Chiroge­

sic; Physiogesic; China: Duo Rui ( $ JW ) ; Fin.: Algesalt; Fr.: Algesal; Gr. : Algesal; Hung.: Aciphen; India: Multigesic; Neth.: Algesalt; Norw. : Algesal; Pol.: Saldiam; Port.: Algicumt; Algi­ dermat; Massagim; Swed. : Algesal; Turk.: Algesal; Reparil; UK: Algesal; lloyd's Cream; Venez. : Alesal.

Multi-ingredient Preparations. Arg. : Algesal; Carti!lex; Crema Antiinflamatoria; Rati Salil Flex; Salicrem; Austral.: Rubesal; Austria: Algesal; Derivon; Dolo-Menthoneurin; Latesyl; Repar­ il; Rheugesalt; Rilfit·Rheumasalbe; Traumasal; Belg.: Reparil; Braz. : Reparil; Reparil; Chile: Repariven; China: Ou Lai ( liiX � ); Repatil-Gel N (i'U s �it£�); Cz.: Algesal; Reparil-Gel N; Fr.: Algesal Suractive; Repatil; Traumalgylt; Ger.: Algesalt; Reparil­ Gel N; Gr.: Algesal Suractive; Ponostop; Hong Kong: Reparil; Rubesalt; Hung. : Algesal; Reparil N; India: Neurophen; Indon. : Algesal Superactive; Ital.: Edeven; Liotontrauma; Reparil CM; Sedalpan; Viamal Trauma; Malaysia: Reparil- Gel N; Neth.: Algesal Fortet; Philipp. : Reparil N; Pol.: Reparil N; Port. : Algesal; Latesil; Medalginan; Venoparil; Rus.: Reparil·Gel N (Penapi!JI-ren& H); S.Afr. : Reparil; Singapore: Reparil-Gel N; Spain: Algesal; Contusin; Doltnitint; Feparil; Radio Salil; Switz.: Mavena Proctal-Gent; Reparil N; Thai.: Reparil; Veno· Gelt; Turk.: Algesal Suractive; Prepagel; UAE: Rubicaim; UK: Fiery Jack; Transvasin Heat Spray; Ukr.: Repatil-Gel N (PenapiiJI-reJ!b H); Venez. : Lemazol. Phannacopoeial Preparations

BP 20 14: Diethylamine Salicylate Cream.

Diflunisal (BAN. USAN, r/NN)

Pharmacopoeias. In Br., Chin., and US.

BP 2014; (Diflunisal) . A white or almost white, crystalline powder. Practically insoluble in water; soluble in alcohol. Dissolves in dilute solutions of alkali hydroxides. It exhibits polymorphism. Protect from light.

USP 36; (Diflunisal) . A white to off-white, practically odourless, powder. Insoluble in water and in hexane; freely soluble in alcohol and in methyl alcohol; soluble in acetone and in ethyl acetate; slightly soluble ln carbon tetrachloride, in chloroform, and in dichloromethane.

Uses and Administration Diflunisal is a salicylic acid derivative (see Aspirin, p. 2 2 . 3 ) but i t is not hydrolysed t o salicylate and its clinical effects resemble more closely those of propionic add derivative NSAIDs such as ibuprofen (p. 68. 3 ) . Diflunisal is given in the

52 acute or long�term management of mild to moderate pain, and pain and inflammation associated with osteoarthritis and rheumatoid arthritis. The usual initial oral dose for pain relief is 1 g followed by a maintenance dose of 500 mg every 12 hours although some patients may require 500 mg every 8 hours. In others, a lower initial dose of 500 mg followed by 2 5 0 mg every 8 to I 2 hours may be sufficient. The usual oral dose for arthritis is 500 mg to I g daily in 2 divided doses, adjusted according to response. Maintenance doses greater than 1. 5 g daily are not recommended regardless of indication. Doses may need to be reduced in patients with renal impairment, see below. Diflunisal arginine has been used similarly given orally or by intramuscular or intravenous injection.

Adverse Effects and Treatment As for NSAIDs in general. p. 1 04 . 3 . The commonest adverse effects occurring with diflunisal are gastrointestinal disturbances, headache, and rash. Peptic ulceration and gastrointestinal bleeding have been reported. Dizziness, drowsiness, insomnia, and tinnitus may also occur.

1.

diflunisal.

Arthritis Rheum 1 988; 3 1 : 148-9.

Effects on the kidneys. Acute interstitial nephritis, pre­ senting as acute oliguric renal failure, erythroderma, and eosinophilia has followed the use of diflunisal 1 et al.

Acute interstitial nephritis and erythroderma associated

BMJ 1 980; 280: 84-5.

Effects on the lungs.

For reference to pneumonitis asso­ ciated with diflunisal therapy, see Hypersensitivity, below.

Stevens-Johnson syndrome associated with diflunisaL u See also Hypersensitivity, below. l.

Hunter JA, Grom JA,

et al.

Eur J Clin Pharmacal 1995; 47: 5 1 9-2 3.

Diflunisal and Stevens-Johnson syndrome.

1.

Loewen GR

et a!. Effect of

dose on the glucuronidation and sulphation

kinetics of diflunisal in man: single dose studies.

1 988; 26: 3 1-9. 2 . Eriksson L-0, et al.

3.

Verbeeck RK,

Three cases of hypersensitivity to diflu· nisal in which the main clinical features were fever, ele­ vated liver enzyme values, erythroderma, and eosino­ philia, have been reported. ' Heinz-body haemolytic anaemia occurred in one of the patients. Other hyper­ sensitivity reactions associated with diflunisal therapy have included pneumonitis2 and fulminant necrotising fas­ ciitis.3

4.

Macdonald JI,

5.

1 990; 38: 1 7 5-9. et al. Pharmacokinetics Pharmacokinet 1 9 9 1 ; 20: 8 1-9.

et a/. Diflunisal-induced Formut i 986; 2 1 : 3 5 3-4.

erythema multifonne major.

et at. Three 1 988; 138: 1 029-30.

cases o f diflunisal hypersensitivity.

Rich MW, Thomas RA. A case of eosinophilic pneumonia and vasculitis

3.

Krige JEJ,

Br J Clin Pharmacol

Sex-difference and the effects of smoking and oral

Nuernberg B,

Eur J Clin Pharmacol

of diflunisal in patients.

Clin

P.r.�P.? r

·

•

·

·

NOTE. Compounded preparations of dihydrocodeine tartrate may be represented by the following names: • Co-dydramol (BAN)-dihydrocodeine tartrate 1 part and paracetamol 5 0 parts (w/w) .

Street names. The following terms have been used as 'street names' (see p. vii) or slang names for various forms of dihydrocodeine tartrate: DFs; Diffs; Duncan Flockharts.

Ph. Eur. 8: (Dihydrocodeine Hydrogen Tartrate; Dihydro­ codeine Tartrate BP 2 0 1 4 ) . A white or almost white crystalline powder. Freely soluble in water; sparingly soluble in alcohol; practically insoluble in cyclohexane. A 1 0 % solution in water has a pH of 3 . 2 to 4.2. Protect from light.

USP 36: (Dihydrocodeine Bitartrate) . pH of a 1 0 % solution in water is between 3.2 and 4.2. Store in airtight containers.

Uses and Administration Dihydrocodeine is an opioid analgesic (p. 1 08. 1 ) . It is related to codeine (p. 40. 3 ) and has similar analgesic activity. Dihydrocodeine is used for the relief of moderate to severe pain, often in combination preparations with paracetamol. It has also been used as a cough suppressant. For analgesia the usual oral dose of dihydrocodeine tartrate is 3 0 mg after food every 4 to 6 hours; up to 240 mg daily may be given for severe pain. Modified-release preparations are available for twice daily dosage in patients with chronic severe pain. Dihydrocodeine tartrate may also be given by deep subcutaneous or intramuscular injection in doses of up to 50 mg every 4 to 6 hours. For details of doses in children, see below. As a cough suppressant dihydrocodeine tartrate may be given in oral doses of 10 to 3 0 mg up to three times daily. Dihydrocodeine phosphate has also been used. Other salts of dihydrocodeine used, mainly for their antitussive effects, include the hydrochloride, the polistirex, and the thiocyanate. Dihydrocodeine polistirex has also been used in modified-release preparations.

Administration in children.

In the UK, dihydrocodeine tar­ trate may be given orally, or by deep subcutaneous or intramuscular injection, for analgesia in children aged from 4 to 12 years in usual doses of 0 . 5 to 1 mg/kg (to a maxlmum of 30 mg) every 4 to 6 hours; older children may be given the usual adult dose (see above ) . Although unlicensed in children aged under 4 years, the BNFC sug­ gests giving those aged 1 to 4 years 500 micrograms/kg every 4 to 6 hours.

Dyspnoea. Dihydrocodeine has been reported' to have produced benefit in normocapnic patients severely dis­ abled by breathlessness due to chronic airflow obstruction. A dose of I 5 mg was taken 3 0 minutes before exercise up to three times daily. l.

As for NSA!Ds in general. p. 1 0 7 . 1 . Diflunisal may need to be given in reduced dosage in patients with significant renal impairment and should not be given when renal impairment is severe . Aspirin and other acetylated salicylates are not recommended for use in children unless specifically indicated, because of the risk of Reye's syndrome. Although this precaution has not been specifically extended to diflunisal it is not generally licensed for use in children.

l.

D

Pharmacopoeias. In Bur. (see p. vii) and US.

References.

Effects on the skin. Reports of

2.

Effect of probenecid on the formation and

Diflunisal is well absorbed from the gastrointestinal tract and peak plasma concentrations occur about 2 to 3 hours after ingestion of a single dose. It is more than 9 9 % bound to plasma protein and has a plasma half-life of about 8 to 1 2 hours. Diflunisal exhibits non-linear pharmacokinetics s o that doubling t h e d o s e more than doubles drug accumulation. Due to the long half-life and non-linear kinetics, several days are required to reach steady-state plasma concentrations after multiple dosing. The time to steady-state concentrations can be reduced by giving an initial loading dose. Concentrations of diflunisal in synovial fluid reach about 70% of those in plasma. Diflunisal is excreted in the urine mainly as glucuronide conjugates. Some biliary recycling may also occur. Diflunisal is distributed into breast milk with concentrations reported to be about 2 to 7% of those in plasma.

Bobrove AM. Diflunisal-associated thrombocytopenia in a patient with

Chan LK,

et al.

Pharmacokinetics

Haematological adverse effects asso­ ciated with diflunisal appear to be infrequent. Thrombocy­ topenia associated with diflunisal-induced peripheral pla­ telet destruction has been reported in a patient with rheumatoid arthriti s . 1 Heinz-body haemolytic anaemia has also been reported, see Hypersensitivity, below.

with diflunisal.

Macdonald JI.

elimination kinetics of the sulphate and glucuronide conjugates of

Effects on the blood.

1.

DitJ.Idr�kodefn�. tarirato de; _DitridrokQ(I�1n·h1on I;Jarpvn1. · . . . • . . · .· . 1 ;phenyl·J pyrazolirc 4·yi),N· Sodium methyiamiftp[f1ethane$\llphonate monohydrate. . . CnH,6N3NaO,S,H20.,35 1 .4

• . N-(2.3-'dlme.ihyl-s-oxo·

{iipyto'le),' 591)7-313:-0 68-?9 3. (i:mhydroc,fs . monohyi:irate). A TC - N0288Q2. ATG" Vet � QN028802. UNH - 6429LOL52Y (dipyrone}; l/Si.f62Z740N dipyro.ne). ("AS . c-

NOTE. Confusingly the term dipyrone sodium also appears to he used synonymously for dipyrone itself. Dipyrone is referred to in some countries by the colloquial name 'Mexican aspirin'. The names noraminophenazonum and novaminsulfon have apparently been applied to dipyrone, but it is not clear whether these are the sodium salt.

Pharmacopoeias. In Chin., Eur. (see p . vii) , and Jpn.

Ph, Eur, 8: (Metamizole Sodium Monohydrate; Dipyrone BP 2 0 1 4 ) . A white or almost white crystalline powder. Very soluble in water; soluble in alcohol; practically insoluble in dichloromethane. Protect from light.

Uses and Administration Dipyrone is the sodium sulfonate of aminophenazone (p. 2 1 . 1 ) and has similar properties. Because of the risk of serious adverse effects, in many countries its use is considered justified only in severe pain or fever where no alternative is available or suitable. Dipyrone has been given orally in doses of 0 . 5 to 4g daily in divided doses. It has also been given by intramuscular or intravenous injection and rectally as a suppository. A magnesium congener of dipyrone, metamizole magnesium has been used similarly to dipyrone as has the calcium congener metamizole caldum.

Adverse Effects and Precautions Use of dipyrone is associated with an increased risk of agranulocytosis and with shock.

References. I.

Levy M. Hypersensitivity to pyrazolones.

Thorax 2000; 55

(suppl 2 ) : 572-

574.

Effects on the blood. Data collected from 8 population groups in Europe and Israel by the International Agranulocytosis and Aplastic Anemia Study1 revealed that there was a significant regional variability in the rate-ratio estimate for agranulocytosis and dipyrone ( 0 . 9 in Budapest to 3 3 . 3 in Barcelona ) . Although a large relative increase in risk between agranulocytosis and use of dipyrone was found, the incidence was less than some previous reports had suggested. Blood dyscrasias such as agranulocytosis and granulocy­ topenia have continued to be reported where dipyrone remains available.2·7 I.

The International Agranulocytosis and Aplastic Anemia Study. Risk:. of

2.

Hedenmalm K, Spigset 0 . Agranulocytosis and other blood dyscrasias

agranulocytosis and aplastic anemia: a first report of their relation to drug use with special reference to analgesics. associated with dipyrone (metamizol e ) .

lAMA 1986; 256:

1 749-57.

Eur J Clin Pharmacal 2002; 58:

265-74. 3.

Maj S, Lis Y. The incidence of metamizole sodium-induced agranulo­

4.

Maj

cytosis in Poland. S,

J lnt Med Res 2002; 30: 488-95.

Centkowski

P.

A prospective study of the

incidence

of

agranulocytosis and aplastic anemia associated with the oral use of metamizole sodium in Poland.

Med Sci Manit 2004; 10:

PI93-Pl95.

54 5.

Ibanez L, et al. Agranulocytosis associated Bur J Clin Pharmacal 2005; 60: 82 1-9.

6.

Hamerschlak N, dipyrone.

7.

Garda

S,

Cavalcanti AB.

with dipyrone (metamizol).

Neutropenia,

agranulocytosis and

Sao Paulo Med J 2005; 123: 247-9. et a!. Dipyrone-induced granulocytopenia: Pharmacotherapy 2006; 26: 440--2.

a

case

for

awareness.

Effects on the skin.

Dipyrone has been considered respon­ sible for a case of drug-induced toxic epidermal necroly­ sis . 1 I.

Roujeau

1 - C e t al.

epidermal necrolysis.

Sj6gren-Jike syndrome after drug-induced toxic

Lancet

1 98 5 ; i: 609-I l .

Hypersensitivity.

Cross-sensitivity between aspirin and dipyrone occurred in a patient . 1 Dipyrone produced an exacerbation of dyspnoea, cyanosis, and respiratory arrest. l.

Bartoli E.

et al.

Drug-induced asthma.

Lancet

1 976; i: 1 3 5 7 .

Porphyria.

The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies dipyrone (metami­ zole sodium) as possibly porphyrinogenic; it should be used only when no safer alternative is available and pre­ cautions should be considered in vulnerable patients. 1 l.

The Drug Database for Acute Porphyria. Available at: http://www. drugs-porphyria.org (accessed 1 0/ 1 1 / l l )

Pharmacokinetics After oral doses dipyrone is rapidly hydrolysed in the gastrointestinal tract to the active metabolite 4-methyl­ amino-antipyrine, which after absorption undergoes metabolism to 4-formyl - amino-antipyrine and other metabolites, Dipyrone is also rapidly undetectable in plasma after intravenous doses. None of the metabolites of dipyrone are extensively bound to plasma proteins. Most of a dose is excreted in the urine as metabolites. Dipyrone metabolites are also distributed into breast milk References. l.

Heinemeyer G,

et al.

The kinetics of metamizol and its metabolites in

critical-care patients with acute renal dysfunction.

Bur J Clin Phannacol

1 99 3 ; 45: 445-50. 2. 3.

Levy M,

et a!. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 1 99 5 ; 28: 2 1 6-34. Zylber-Katz E, et al. Dipyrone metabolism in liver disease. Clin Phannacol Ther 1 99 5 ; 58: 1 98-209.

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Arg.: Aoalgina; Dioxadol;

Dipi­ grand; Ditral; Fiebrol; Integrobe; Lisalgil; Novacler; Novalgina; Novemina; Taxenil; Unibios Simple; Austria: Novalgin; Belg. : Analgine; Novalgine; Braz.: Algirona; Anador; Analgesilt; Apir­ on; Baralgin; Conmel; Difebril; Dipigina; Dipimax; Dipiront; Dipix; Diprin; Domalt; Dorona; Dorpinont; Magnopyrol; Maxi­ liv; Mirador; Nofebrin; Novagreen; Novalgina; Pirogina; Prodo­ pironat; Santidor; Tennonal; Termopirona; Termoprinst; Chile: Baralgina M; Conmel; China: Di Shuang (iii! Wt ); Cz.: Novalgin; Ger.: Analgin; Berlosin; Nopaint; Novalgin; Novaminsulfon; Gr.: Natralgin; Telalgin; Hung.: Algopyrin; Algozone; Noval­ gint; Panalgorin; India: Analgin; Baralgan-M; Novalgin; Indon. : Antalgin; Antrain; Cornalgin; Foragin; Lexagin; Licogin; Norages; Novalgin; Panstop; Pragesol; Pyronal; Ronalgin; Sca­ nalgin; Unagen; Israel: Optalgin; Phanalgint; V-Dalgin; V-Tal­ gint; Ital. : Novalgina; Piralgin; Mex. : Alnex; Anaprolt; Anapyr­ olt; Avafontan; Conmel; Dalmasin; Dalsin; Defin; Dimetirol; Dipydol; Dofisan; Dolgan; Dolizol; Dolofurt; Domenalt; Exoda­ lina; Fandall; Fardolpin; Farlin; Gelcom; Indigon; Infatem; Lozi­ ma; Mach-2; Macodin; Magnidol; Magnil; Magno!; Magnolo­ nas; Magnopyrol; Magsons; Mayoprina; Medipirolt; Mennidt; Messelfenil; Metapirona; Midelin; Minora!; Mizoltec; Modi­ mett; Neo-Melubrina; Neomelint; Neosedal; Paleodinat; Pifrolt; Pirandall; Pirasod; Pirinovag; Piromebrina; Precidona; Prodolina; Prolubrin; Pyranol; Pyron; Suprin; Termonilt; Uti­ dol; Vegalt; Neth.: Novalgin; Pol.: Pyrahexal; Pyralgin; Pyralgi­ na; Pyralginumt; Port. : Dolocalma; Nolotil; Rus.: Analgin (AHaJihnm); Baralgin M (EapMn1H M); Spain: Algi; Dolemicin; Lasaint; Metalgial; Neo Melubrinat; Nolotil; Switz. : Minalgin; Novalgin; Thai.: Centagint; Deparont; Genergint; Invoigint; Kno-Painet; Mezaboxt; Nivagint; Novalgint; Olan-Gint; Pyr� onpac; V Day Pyrin; Turk.: Adepiron; Andolor; Baralgin M; Devaljin; Feninoxt; Geralgine-M; Kafalgin; Nogesic; Novakom­ S; Novalgin; Novo� Plan; Novopyrine; Sebon; Sedalmine; Seskal­ jin; Veraljin; Urug.: Dolane�; Venez. : Bral; Conmel; Delsal; Dipamona; Dipidol; Novalcina; Promel.

Butilamint; Cafilisador; Cefaldinat; Cefaliv; Dalgext; Dexalgen; Disbuspant; Doralgex; Doralgina; Dorciflext; Dorflex; Dorgil; Doricin; Doridina; Dorilen; Doriless; Dorsedin; Dorspan Com­ pasta; Dorzone; Drenogrip; Enxak; Espasmocront; Espasmodid Composto; Flexalgex; Flexdor; Gripsay; Hioariston; Hiospan Composto; Kindpasmt; Lisador; Lisanti!; Migraliv; Migranette; Mionevrix; Miorrelax; Neocopan; Neosaldina; Neuralgina; Nev­ ralgex; Nogripe; Novralflex; Par; Reflex; Relaflex; Rielex; Roy­ flex; Sedador; Sedalene; Sedalex; Sedalgina; Sedalint; Sedamed; Sedol; Spasmotropin; Tensaldin; Tetrapulmot; Trop­ inal; Veratropan Compostot; Chile: Bramedil Compuesto; Bus­ capina Compositum; Cefadol; Cefalmin; Cinabel; Crotalgina; Dolcopin; Dolnix; Dolonase; Esamigran; Fredol; Migragesic; Migranol; Migratam; Neo Butartrol; Nospasmin Compuesto; Piretanyl; Piretanyl; Precenid; Scopanil; Ultrimin; Viadil Com­ puesto; Viplan Compuesto; Viproxil Compuesto; Cz.: Algifen Neo; Algifen; Analgin; Fin.: Litalgin; Gr. : Dispalgine; Hung.: Algopyrin Complex; Quarelin; India: Ketonal-D; Indon.: Ana­ lsik; Arsinal; Biomegat; Cetalgin-T; Cetalgin; Corsanural; Dac­ tront; Danalgin; Deparont; Dolo Scanneuron; Dolo-Licobion; Dormi Camp; Foraneural; Goralgin; Hedix; Hexalgin; Ikaneur­ on Plus; Metaneuron; Neuralgin RX; Neurindo; Neuro Panstop; Neurobat A; Neurodial; Neurogent; Neurosanbe Plus; Neuro­ tropic Plus; Neuroval; Opineuron; Penagon; Potensik; Pritage­ sic; Procolic; Proneuron; Spaslic; Spasmal; Spasminalt; Stileran; Supranal; Tropineuron; Unthecolt; Viron; Mex. : Algosfar; Ali­ vin Plus; Anadil; Benfolt; Biomesina Compuesta; Bipasmin Compuesto; Buscapina Compositum; Busconet; Busepan; Busprina; Colepren; Dolo-Tiaminal; Espasmogress; Hiosultrina­ F; Korifent; Mebuxina; Neo-Brontylt; Neo-Pasmonal; Pasmo­ dilt; Pirobutil; Respicil; Retodol Compositum; Selpiran; Serral­ pina Compuesta; Singril; Viladol-Mett; Pol.: Gardan pt; Scopo­ lan Compositum; Spasmalgon; Tolargint; Rus.: Analgin-Chinin (AHMhnm-XHHHH); Andipal (AHJJ;Hnan); Antigrippin-ANVI (AHTHrpHnnHH-AHBli); Benalgin (EeHMhnm); Bioralgin Bral ( an); Bralangine Maxigan (MaKCJmlH); Nebalgan (He6a.rrr aH); Pentabufen Pentalgin-N Plenalgin (lineHa.arHH); Pyralgin (liHpa.arHH); Quintalgine (KBHHTaJITHH); Renalgan (PeHa.rrrBH); Revalgin (Pesannrn); Santoperalgin Santoti­ tralgin (CaHTOTIITpaJJr HH); Sedal-M (Ce)lan-M); Sedalgin-Neo ( ,n:aJihTIIH -H ); Spasgan Spasmalgon ( naJManr H); Spasmalin ( naJMaJi H); Tempalgin ( TeMII HH); Tempanginol (TeMnaHrHHOJI); Tetralgin ( TerparrrH H); S.Afr.: Buscopan Compo­ situm; Scopex Co; Spain: Buscapina Compositum; Thai.: Butar­ iont; Nalgin-P; Novapamt; Turk.: Buscopan Compositumt; Penikint; Peraljint; Skopolint; Ukr,: Baralginus ( a rummyc ) t; Bellalgin (EeManmH); Sedal-M (Ce)lan-M); Spasgan ( a3raH);

(Enopannm);

Ce

Ep (lieHTa.JITHH-H);

eo C

n

insoluble in water; soluble in dehydrated alcohol; sparingly soluble in dichloromethane, Protect from light.

Profile E noxolone is a complex triterpene prepared from glycyrrhizic acid (p, 2 5 2 0 , 2 ) , a constituent of liquorice (p. 1 8 5 6 . 2 ) . Enoxolone is used locally in preparations for the treatment of non-infective inflammatory disorders of the skin, mouth, throat, and rectum. Enoxolone potassium (potassium glycyrrhetinate) has been used similarly, Derivatives of enoxolone, including its aluminium salt (p, 1 84 3 . 3 ) and carbenoxolone (p. 1 82 8 . 3 ) have been used in the treatment of benign peptic ulcer disease and other gastrointestinal disorders. Enoxolone is a potent inhibitor of the enzyme 1 1 �­ hydroxysteroid dehydrogenase, which inactivates cortisol, and use with hydrocortisone has been shown in animal studies to potentiate the activity of hydrocortisone in skin . 1 Whether this also increased the systemic absorption and toxicity of hydrocortisone was unclear.2 However, for reference to adverse effects attributed to systemic inhibition of cortisol when enoxolone (glycyrrhetinic acid) is produced during metabolism of ingested liquorice, see Mineralocorti­ coid Effects, p . 1 85 6 . 3 , A cream containing enoxolone with hyaluronic add, telmesteine, and a grape extract, has been investigated with apparent benefit in the management of mild to moderate eczema3A and is available for such use in some countries. However, topical application of enoxolone has been associated with contact dermatitis. 5 I.

(Epanrumm); (lieHTa6yn. : Cybufent; Irl. :

Leder­ fertt; Port.: Basifen; Thai. : Cepal; Cinopal; Forbufen; Turk.: Cinopalt; UK: Lederfent.

Pharmacopoeial Preparations

BP 20 14: Fenbufen Capsules; Fenbufen Tablets.

Fenbufen, a propionic acid derivative, is an NSAID (p. 1 0 2 . 3 ) . It is given for the relief of pain and inflammation associated with musculoskeletal and j oint disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis in oral doses of 900 mg daily; the dose may be either 4 5 0 mg in the morning and evening or 300 mg in the mortling with 600 mg in the evening.

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Breast feed ing. that

UK licensed product information advises fenbufen should be avoided in breast-feeding

The symbol

Adverse Effects, Treatment, and Precautions As for NSAIDs in general. p. 1 0 4 . 3 . Dysuria, cystitis, haematuria, interstitial nephritis, and acute renal insufficiency have been reported with fenoprofen. Nephrotic syndrome, which may be preceded by fever, rash, arthralgia, oliguria, azotaemia, and anuria, has also occurred. Upper respiratory-tract infection and nasopharyngitis have been reported. There have been reports of severe hepatic reactions, including jaundice and fatal hepatitis.

Breast feeding. Fenoprofen is distributed into breast milk although the amount is considered by the BNF to be too small to be harmful to a breast-fed infant. In contrast, licensed product information does not recommend its use since safety has not been established. Effects an the blaad. Haematological adverse effects including agranulocytosis, 1 aplastic anaemia,2 and throm­ bocytopenia3.4 have been reported in patients taking feno­ profen; licensed product information also reports haemo­ lytic anaemia. l.

Simon SD, Kosmin M. Fenoprofen and agranulocytosis. N Engl J Med

2.

Ashraf M, et al. Aplastic anaemia associated with fenoprofen. BMJ 1 982;

3.

284: 1 3 0 1-2 . Simpson RB, et al. Acute thrombocytopenia associated with fenoprofen.

1 978; 299: 490.

N Engl J Med 1 978; 298: 629-30. Katz ME, Wang P. Fenoprofen-associated thrombocytopenia. Ann Intern Med 1 980; 92: 262.

Effects on the liver. Cholestatic jaundice and hepatitis developed in a 68-year-old woman after receiving feno­ profen 600 mg four times daily for 7 weeks. Subsequent use of naproxen and indometacin did not result in hepato­ toxicity . 1 However, there has been a report of cross­ hepatotoxicity between fenoprofen and naproxen.2 l.

Stennett DJ, et al. Fenoprofen-induced hepatotoxicity. Am J Hosp Pharm

2.

Andrejak M, e t al. Cross hepatotoxicity between anti-inflammatory drugs. BMJ 1 987; 295: 1 80-l .

1 978; ]5: 9 0 1 . non-steroidal

Effec1s on the skin. Toxic epidermal necrolysis was asso­ ciated with fenoprofen in 2 patients. 1 1.

Stotts JS, e t al. Fenoprofen-induced toxic epidermal necrolysis. J Am Acad Dermatol 1 988; 18: 7 5 5-7.

Overdosage. Coma, respiratory depression, hypotension, and metabolic acidosis occurred in a patient who had ingested between 24 and 3 6 g of fenoprofen 1 The patient responded to gastric lavage and activated charcoal and intensive supportive care. l. Kolodzik JM, et al. Nonsteroidal anti-inflammatory drugs and coma: a case report of fenoprofen overdose. Ann Emerg Med 1 990; 19: 378-8 1 .

Interactions For interactions associated with NSAIDs, see p. 1 0 7 . 3 . Aspirin is reported to reduce plasma concentrations o f fenoprofen.

Antiepileptics.

Phenobarbital might increase the rate of metabolism of fenoprofen. 1 US licensed product informa­ tion suggests that dosage adjustment of fenoprofen may be required when given with phenobarbital .

.

As for NSAIDs in general. p. 1 04.3, although tbe commonest adverse effects of fenbufen are rashes, usually occurring within the first 2 weeks of therapy, and particularly in women and in patients with seronegative rheumatoid arthritis or psoriatic arthritis. Disorders such as epidermal necrolysis, erytbema multiforme, and Stevens-Johnson syndrome have also been reported. A small number of patients who develop rash may go on to develop a severe illness characterised by pulmonary eosinophilia or allergic alveolitis. Treatment with fenbufen should be stopped immediately if a rash appears.

Uses and Administration Fenoprofen, a propionic acid derivative, is an NSAID (p. 1 0 2 . 3 ) used in the management of mild to moderate pain and for the relief of pain and inflammation associated with disorders such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. It is given as the calcium salt although doses are expressed in terms of the base; fenoprofen calcium (dihydrate) 1 .2 g is equivalent to about 1 g of fenoprofen. A usual oral dose is the equivalent of 3 0 0 t o 600 m g of fenoprofen three or four times daily, adj usted thereafter according to response. In the USA. lower doses of 200 mg every 4 to 6 hours are recommended for mild to moderate pain. It has been recommended that the total daily dose should not exceed 3 g (UK) or 3.2 g (USA) .

4.

Pharmacokinetics

BP 20 14: Felbinac Cutaneous Foam; Felbinac Gel.

Fenbufen

CSM. Fenbufen, rash and pulmonary eosinophilia. Current Problems

IdcService=GBT_FILE&dDocName=C ON202443 1 &RevisionSelection· Method=LatestReleased (accessed 0 1 1 1 1 10 7 )

2 7 1 989.

.

Andrews R, Russell N . Aplastic anaemia associated with a non-steroidal anti-inflammatory drug: relapse after exposure to another such drug.

http://www.mhra.gov.uk/home/idcplg? IdcService=GET_FILE&dDocName=CON2024444&RevisionSelection­ Method=LatestReleased (accessed 0 1 / 1 1 /0 7 )

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Martland T, Stone WD. Haemolytic anaemia associated with fenbufen.

BMJ 1 988; 297: 92 1 . 2.

59

I.

Helleberg L, et al. A pharmacokinetic interaction in man between phenobarbitone and fenoprofen, a new anti-inflammatory agent. Br J

Clin Pharmacol l 974; I: 37 1-4.

Pharmacokinetics Pharmacopoeias. In Br. , Chin., and

us.

BP 2 0 1 4: (Fenoprofen Calcium ) . A white or almost white odourless or almost odourless crystalline powder. Slightly soluble in water and in chloroform; soluble in alcohol.

USP 36: (Fenoprofen Calcium) . A white crystalline powder. Slightly soluble in water, in methyl alcohol, and in n­ hexanol; practically insoluble in chloroform. Store in airtight containers.

t denotes a preparation no longer actively marketed

Fenoprofen is readily absorbed from the gastrointestinal tract; bioavailability is about 8 5 % but food and milk may reduce the rate and extent of absorption. Peak plasma concentrations occur 1 to 2 hours after a dose. The plasma half-life is about 3 hours. Fenoprofen is 9 9 % bound to plasma proteins. About 90% of a dose is excreted in the urine in 24 hours, chiefly as the glucuronide and the glucuronide of hydroxylated fenoprofen. Fenoprofen is distributed into breast milk.

60

Analgesics Anti-inflammatory Drugs and Antipyretics

�:.�P.�.��-�i?,�� . . . . . . . . . . . . . . . . . . . . . .

..

........················............................

Proprielary Preparations (details are given in Volume B ) Single-ingredient Preparations- China: FeiLin ( 'O. *i' ) ; Fr. : sic; Gr.: Expron; Nazipons; UK: Fenopron; USA: Nalfon.

Nalge­

Pharmacopoeial Preparations

BP 20 14: Fenoprofen Tablets; USP 36: Fenoprofen Calcium Capsules; Fenoprofen Calcium

Tablets.

Street names. The following terms have been used as 'street names' (see p. vii) or slang names for various forms of fentanyl: Apache; China girl; China town; China white; Dance fever; Fentanest; Friend; Goodfellas; Great bear; He-man; Jackpot; King ivory; Murder 8; Poison; Tango & Cash; TNT; T.N.T.

Phannacopoeias. In Bur. (see p . vii) and US. Ph. Bur. 8: (Fentanyl) . A white or almost white polymorphic powder. Practically insoluble in water; freely soluble in alcohol and in methyl alcohol. Protect from light.

USP 36: (Fentanyl) . Store in airtight containers at a temperature of 25 degrees, excursions permitted between 15 degrees and 3 0 degrees. Protect from light.

0 . 9 % was stable for 30 days at 3 degrees or 23 degrees in PVC reservoirs for portable infusion pumps.2 In another study' fentanyl citrate diluted to 5 0 micrograms/mL with sodium chloride 0 . 9 % remained stable for at least 14 days when stored at room temperature in PVC reservoirs for portable patient-controlled systems. An admixture of fentanyl citrate and bupivacaine in sodium chloride 0 . 9 % appeared4 compatible and stable when stored for up to 30 days at 3 degrees or 23 degrees in a portable infusion pump. In another study' the stability of solutions containing fentanyl. bupivacaine, and adrenaline, alone and in combination was studied over a period of 5 6 days when stored a t various temperatures i n the light o r in the dark in PVC bags. B oth fentanyl and bupivacaine were adsorbed from solution onto the PVC for the first 3 days but thereafter concentrations of these drugs remained relatively stable; freezing appeared to slow the concentration change for bupivacaine but not for fentanyl. Solutions containing adrenaline became more acidic during the study as the adrenaline progressively deteriorated but this was greatly reduced by freezing. Autoclaving produced a further reduction in the concentration of all drugs. There was no sign of precipitation from any of the solutions studied. An admixture of fentanyl citrate, ketamine hydro­ chloride, and droperidol in sodium chloride 0 . 9 % was stable' for at least 3 0 days when stored in glass bottles at 2 5 degrees; the minor decrease i n the concentrations o f all 3 drugs was attributed to either hydrolytic degradation or adsorption. This admixture also appeared compatible when stored in PVC bags at 4 degrees and 2 5 degrees; the small increase in drug concentrations over 30 days may be a result of water permeation and evaporation through the bags. Fentanyl is potentially unstable in PVC containers when mixed with allcaline drugs (see Incompatibility, above) . 1.

Kowalski SR. Gourlay GK. Stability of fentanyl citrate in glass and plastic containers and in a patient-controlled delivery system. Am J Hosp Pharm

1 990; 47: 1 5 84-7. 2.

Allen LV, et al. Stability of fentanyl citrate in 0.9% sodium chloride solution in portable infusion pumps. Am J Hosp Pharm 1 990; 47: 1 5 72-4.

3.

Chapalain-Pargade S, et a!. Microbiological and physicochemical stability

4.

Tu Y-H, et a!. Stability of fentanyl citrate and bupivacaine hydrochloride

of fentanyl and sufentanil solutions for patient-controlled delivery systems. J Pain Symptom Manage 2006;

32.: 90-7.

in portable pump reservoirs. Am J Hosp Pharm 1 990; 47: 2037-40.

5 . Dawson PJ, et al. Stability of fentanyl, bupivacaine and adrenaline solutioru for extradural infusion. Br J Anaesth 1 992; 68: 4 1 4- 1 7 . 6. L e e DKT, e t a l . Compatibility of fentanyl citrate, ketamine hydro­ chloride, and droperidol in 0.9% sodium chloride injection stored in polyvinyl chloride bags. Am J Health-Syst Pharm 2005; 62.: 1 1 90-2.

Uses and Administration Phannacopoeias. In Chin., Bur. (see p . vii) , Jpn, and US. Ph. Bur. 8: (Fentanyl Citrate ) . White or almost white powder. Soluble in water; sparingly soluble in alcohol; freely soluble in methyl alcohol. Protect from light.

USP 36: (Fentanyl Citrate ) . A white crystalline powder or

white glistening crystals. Sparingly soluble in water; slightly soluble in chloroform; soluble in methyl alcohol. Store at a temperature of 25 degrees, excursions permitted between 15 degrees and 3 0 degrees. Protect from light.

Fentanyl Hydrochloride (BANM, rJNNMJ 0

Incompatibility. Fentanyl citrate is incompatible with thio­ pental sodium and methohexital sodium. A thick white precipitate formed in the intravenous tubing when fentanyl citrate with droperidol was given shortly after nafcillin sodium. There was no precipitate when fentanyl citrate alone was mixed with nafcillin sodium. I Fentanyl citrate underwent rapid and extensive loss when admixed with fluorouracil in PVC containers.2 The loss was due to sorption of fentanyl to the PVC as a result of the alkaline pH of the admixture, and presumably could occur from admixture of fentanyl citrate with any sufficiently alkaline drug. See also Stability, below. 1. Jeglum EL, et al. Nafcillin sodium incompatibility with addic solutions. Am J Hosp Pharm 1 9 8 1 ; 38: 462, 464. 2.

Xu QA, et a/. Rapid loss of fentanyl citrate admixed with fluorouracil in polyvinyl chloride containers. Ann Pharmacother 1 997; 3 1 : 297-302.

Stability.

In a 48-hour study fentanyl citrate in glucose 5% or sodium chloride 0 . 9 % was stable when stored at room temperature under usual light conditions in glass or PVC containers;1 the concentration of fentanyl delivered by a patient-controlled system was relatively constant throughout a 30-hour study period. Fentanyl citrate injec­ tion diluted to 20 micrograms/mL with sodium chloride All cross-references refer to entries in Volume A

Fentanyl. a phenylpiperidine derivative, is a potent opioid analgesic (p. 1 08 . 1 ) chemically related to pethidine (p. 1 2 1 . 3 ) and is mainly a J.I-Opioid agonist. Fentanyl is used as an analgesic, as an adjunct to general anaesthetics, and as an anaesthetic for induction and maintenance. It is also used as a respiratory depressant in the management of mechanically ventilated patients under intensive care. When used with an antipsychotic such as droperidol it can induce a state of neuroleptanalgesia in which the patient is calm and indifferent to his surroundings and is able to cooperate with the surgeon. Fentanyl is usually given parenterally, intranasally, or by the transmucosal route as the citrate, or in transdermal patches as the base. The hydrochloride was available as an iontophoretic transdermill delivery preparation but this was withdrawn from the market because of a defective delivery system. Fentanyl citrate ! 5 7 micrograms and fentanyl hydrochloride I l l micrograms are each equivalent to about 1 00 micrograms of fentanyl. Doses are expressed in terms of the base. It is more lipid soluble than morphine and after an intravenous injection of I 00 micrograms the effects of fentanyl begin almost immediately, although maximum analgesia and respiratory depression may not occur for several minutes; the duration of action of fentanyl depends on the dose and the intensity of the pain involved, and may vary from I 0 minutes to several hours. For premedication the equivalent of 50 to I 00 micr­ ograms of fentanyl may be given intramuscularly 30 to 60 minutes before the induction of anaesthesia. As an adjunct to general anaesthesia, fentanyl is usually given by intravenous injection. Dosage recommendations show a wide range depending on the technique. • Patients with spontaneous respiration may be given 50 to 200 micrograms as an initial dose with supplements of 50 micrograms. In the USA it is recommended that doses above 2 micrograms/kg be accompanied by assisted ventilation. Significant respiratory depression follows doses of more than 200 micrograms • Patients whose ventilation is assisted may be given 300 micrograms to 3 . 5 mg (up to 50 micrograms/kg) as an initial dose, with supplements of 100 to 200 micr­ ograms depending on the patient's response. High doses have been reported to moderate or attenuate the response to surgical stress (see Anaesthesia, p . 6 1 .2 )

Fentanyl may also b e given b y intravenous infusion. In ventilated patients a loading dose of about I microgram/kg per minute is given for the first 10 minutes followed by an infusion of about I OO nanograms/kg per minute; alterna­ tively, the loading dose may be given as a bolus. The infusion rate should be titrated according to response and rates of up to 3 micrograms/kg per minute have been used in cardiac surgery. Infusions should be stopped about 40 minutes before the end of surgery unless artificial ventilation is to be continued postoperatively. In patients with spontaneous respiration, lower infusion rates of 5 0 to 80 nanograms/kg per minute are used. Reduced doses are used in the elderly or debilitated patients. Similar doses to those used for premedication may also be given by intramuscular injection postoperatively, and by intramuscular or slow intravenous injection as an adjunct to regional anaesthesia. For the treatment of intractable chronic pain in adults when opioid analgesia is indicated transdermal patches delivering amounts of fentanyl ranging from 12 to 1 00 micrograms/hour are available. In the UK, fentanyl patches may be used in strong opioid-naive patients; however, in the USA, use is restricted to patients who are already tolerant to opioid therapy of comparable potency. • Doses should be individually titrated for each patient according to previous opioid usage. Initial dosages should not exceed 25 micrograms/hour in opioid-naive patients; in addition, it is recommended that these patients are initially titrated with low doses of short-acting opioids before transferring to fentanyl patches • For patients who have been receiving a strong opioid analgesic the initial dose of the fentanyl patch should be based on the previous 24-hour opioid requirement. Use of a patch providing 25 micrograms of fentanyl per hour is equivalent to about 60 to 90 mg daily of oral morphine sulfate. During transfer to treatment with fentanyl patches previous opioid analgesic therapy should be phased out gradually in order to allow for the gradual increase in plasma-fentanyl concentrations • More than one patch may be applied if doses greater than l OO micrograms/hour are required (applied at the same time to avoid confusion); additional or alternative analgesic therapy should be considered if doses greater than 300 micrograms/hour are required. Patches should be replaced every 72 hours; however, replacement after 48 hours is permitted in patients who have a marked decrease in analgesia before the 72 -hour period ends. The new patch should be applied to a different site; use of the same area of the skin should be avoided for several days • Elderly or debilitated patients should be observed carefully for signs of toxicity and the dose reduced if necessary Fentanyl patches are not appropriate for acute or postoperative pain. The bioavailability of different brands of fentanyl transdermal patches may not be equivalent and patients should not switch brands without further advice. A lozenge-on-a-stick dosage form of fentanyl citrate for transmucosal delivery is used as an analgesic in the management of breakthrough cancer pain in those already receiving and tolerant to opioid treatment. Lozenges containing the equivalent of 200 micrograms to up to 1 . 6 mg of fentanyl are available. An initial unit dose of 200 micr­ ograms may be taken over 15 minutes for an episode of brealcthrough pain and repeated once if necessary after a further 1 5 minutes. Doses are subsequently titrated according to response, up to a unit dose of 1 . 6 mg if necessary. Once the patient has been stabilised on an effective dose, no more than 4 unit doses should be taken daily. Buccal and sublingual tablets containing fentanyl citrate for transmucosal delivery are also available and licensed for the same indication as the lozenge. Tablets containing the equivalent of I 00 to 800 micrograms of fentanyl are available. An initial dose of 100 micrograms may be taken for an episode of breakthrough pain and repeated once if necessary after 3 0 minutes; thereafter, depending on the brand used, patients must wait at least 2 or 4 hours before treating another episode. A buccal film containing fentanyl citrate for transmucosal delivery is also available; the films contain the equivalent of 200 micrograms to 1 . 2 mg of fentanyl. An initial dose of 200 micrograms may be taken for an episode of breakthrough pain; thereafter, patients must wait at least 4 hours before treating another episode. Doses are subsequently titrated according to response . The dose of the maintenance opioid used for persistent pain should be re-evaluated if the patient has more than 4 episodes of breakthrough pain daily. Caution must be exercised when switching between the different transmucosal preparations as the extent of absorption may be substantially different. Intranasal preparations containing fentanyl citrate, equivalent to 5 0 to 400 micrograms of fentanyl per spray, are available for the same 'indication as the transmucosal

Fentanyl 6 1 preparations. Depending on the brand used, an initial dose of 5 0 or ! 00 micrograms is sprayed into one nostril for an episode of breakthrough pain and repeated once if necessary after 10 minutes; thereafter, depending on the brand used, patients must wait at least 2 or 4 hours before treating another episode. Doses are subsequently titrated according to response; up to a maximum of 4 episodes may be treated daily. The dose of the maintenance opioid used for persistent pain should be re-evaluated if the patient has more than 4 episodes of breakthrough paln daily. For details of doses in children, see below.

Administration. INHALAnON ROUTE. In a study1 inhaled fentanyl provided plasma concentrations similar to those after intravenous doses; use as patient-controlled analgesia was suggested. Inhaled formulations of fentanyl are under investigation for the treatment of breakthrough cancer paln and acute pain. 1.

Mather LE, et al. Pulmonary administration of aerosolised fentanyl:

9.

TRANSMUCOSAL ROUTE. Transmucosal fentanyl has been tried for sedation and analgesia before anaesthesia or pain­ ful procedures in adults1 and children'·' and is used for breakthrough cancer pain in opioid-tolerant patients.4-7 It has been noted8 that this dosage method can cause all the adverse effects of parenteral opioids; nausea and vomiting are common and potentially lethal respiratory depression can occur (see also under Precautions, p. 6 3 . 1 ) . Dosage guidelines have been suggested.9 l.

Macaluso AD, et al. Oral transmucosal fentanyl citrate for premedication

2.

in adults. Anesth Analg 1 996; 82: 1 5 8-6 1 . Nelson PS, et al. Comparison of oral transmucosal fentanyl citrate and an oral solution of meperidine, diazepam. and atropine for premedication

3.

in children. Anesthesiology 1 989; 70: 6 1 6-2 1 . Schechter NL, e t al. The u s e o f oral transmucosal fentanyl citrate for

4.

Blick SKA, Wagstaff AJ. Fentanyl buccal tablet: in breakthrough pain in

5.

opioid-tolerant patients with cancer. Drugs 2006; 66: 2 387-93. Zeppetella G, Ribeiro MDC. Opioids for the management

painful procedures in children. Pediatrics 1 995; 95: 3 3 5-9.

pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol 1 998;

46: 37-43.

INTRANASAL ROUTE. Studies1·3 have shown that intranasal fentanyl is as effective as the intravenous route for post­ operative paln management and that it can be used in a patient-controlled analgesia system. Intranasal fentanyl has also been studied4·6 for the management of acute pain in children. An intranasal spray formulation of fentanyl is available for the treatment of breakthrough cancer pain.7·9 1.

Striebel HW, et al. Intranasal fentanyl titration for postoperative pain Striebel HW, et al. Patient-controlled intranasal analgesia: a method for noninvasive postoperative pain management. Anesth Analg 1 996; 83: 548-5 1 .

3.

Toussaint S , e t a/. Patient-controlled intranasal analgesia: effective alternative to intravenous PCA for postoperative pain relief. Can J Anesth 2000; 47: 299-302.

4.

Manjushree R. et al. Intranasal fentanyl provides adequate postoperative

5.

analgesia in pediatric patients. Can J Anesth 2002; 49: 1 90-3. Borland ML, et al. Intranasal fentanyl is an equivalent analgesic to oral morphine in paediatric bums patients for dressing changes: randomised double blind crossover study. Burns 2005; 3 1 : 8 3 1-7.

6.

a

Borland M, et al. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007; 49: 3 3 5-40.

7.

Kress HG, et al. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase

m,

multinational, randomized, double-blind. placebo-controlled, crossover trial with a 1 0 - month, open-label extension treatment period. Clin Ther 2009; 3 1 : 1 1 77-9 1 . 8.

Portenoy RK, e t a/. A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (PPNS) in the treatment of breakthrough cancer pain. Pain 2 0 1 0; 1 5 1 : 6 1 7-24.

9.

Mystakidou K, et al. Fentanyl nasal spray for the treatment of cancer pain. Expert Opin Pharmacother 2 0 l l ; 12: 1 6 5 3-9.

INTRASPINAL ROUTE.

For a discussion on the intraspinal use of fentanyl, see Postoperative Pain, below. TRANSDERMAL

ROUTE.

Transdermal fentanyl is used for chronic intractable cancer pain in adults and children. 1 •7 It is also used in the treatment of chronic non-cancer pain;4•5•8 however, such use is contra-indicated in the management of acute or postoperative pain because the problems of dose titration in the short term increase the possibility of development of significant respiratory depres­ sion• (see also Effects on the Respiratory System, p. 62.2 and Transdermal Route, under Precautions, p. 6 3 . 1 ) . Although the usual interval for transdermal patches of fentanyl is 72 hours studies have suggested that up to about 2 5 % of cancer patients may require more frequent application with some patients requiring fresh patches every 48 hours.9•10 Equally, in an attempt to supply lower doses than are allowed for by existing transdermal dosage forms, patches have sometimes been cut, folded, or partially masked with non-porous dressings; the manufacturers do not recommend such practices as they consider the dose supplied will be unreliable, and there is potential for overdosage. An iontophoretic drug delivery preparation containing fentanyl hydrochloride was also available for the manage­ ment of acute moderate to severe postoperative pain in a hospital setting (see Postoperative Pain, below for some references) but was withdrawn from the market because of a defective delivery system. 1.

Jeal W, Benfield P. Transdermal fentanyl: a review of its pharmacol­ ogical properties and therapeutic efficacy in pain control. Drugs 1 997; 53: 1 09-38.

2.

Muijsers RBR, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs 200 1 ; 61: 2289-2 307.

3.

Gourlay GK. Treatment of cancer pain with transdermal fentanyl. Lancet

4.

Komick CA. e t a l . Benefit-risk assessment of transdennal fentanyl for the treatment of chronic pain. Drug Safety 2003; 26: 95 1-7 3 .

Onco/ 2 0 0 1 ; 2 : 1 6 5-72 .

5.

Zemikow B, e t al. Transdermal fentanyl i n childhood a n d adolescence: a

6.

7.

Hoy SM, Keating GM. Fentanyl transderma1 matrix patch (Durotep MT patch; Durogesic DTrans; Durogesic SMAT): in adults with cancer­ related pain. Drugs 2008; 68: 1 7 1 1-2 1 . Hair PI, e t al. Transdermal matrix fentanyl membrane patch (Matrifen) :

8.

i n severe cancer-related chronic pain. Drugs 2008; 68: 2 0 0 1 -9. A1lan L, et al. Randomised crossover trial of transdermal fentanyl and

comprehensive literature review. J Pain 2007; 8: 187-207.

sustained release oral morphine for treating chronic non-cancer pain. BMJ 2 0 0 1 ; 322: l l 54-8.

The symbol

of

breakthrough (episodic) pain in cancer patients. Available in the Cochrane Database of Systematic Reviews; Issue l. Chichester: John 6.

7. 8.

Wiley; 2006 (accessed 26/06/08 ) . Ranck R , e t al. Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized. double-blind, placebo­ controlled study. Ann Oncol 2 0 1 0; 2 1 : 1 3 08-14. Chwieduk CM, McKeage K. Fentanyl sublingual: in breakthrough pain in opioid-tolerant adults with cancer. Drugs 2 0 1 0 ; 70: 2281-8. Anonymous. Oral transmucosal fentanyl citrate. Med Lett Drugs Ther 1 994; 36: 2 4- 5 .

9.

Aronoff GM, et al. Evidence-based oral transmucosal fentanyl citrate (OTFC ) dosing guidelines. Pain Med 2005; 6: 305-14.

management in an unselected population. Anaesthesia 1 9 9 3 ; 48: 7 5 3-7. 2.

Donner B, et al. Long-term treatment of cancer pain with transdermal

fentanyl. J Pain Symptom Manage 1998; 1.5: 1 68-75 . 1 0 . Radbruch L , e t al. Transdermal fentanyl for the management o f cancer pain: a survey of 1 00 5 patients. Palliat Med 200 1 ; 15: 309-2 1 .

Administration in children.

Indications for fentanyl ther­ apy in children are similar to those in aduits (see Uses and Administration, p. 60.2 ) . Fentanyl i s usually given b y intravenous injection a s an adjunct to general anaesthesia. In the UK recommended initial doses range from 1 to 3 micrograms/kg in children aged 2 to 12 years with spontaneous respiration; supplements of l to 1 . 2 5 micrograms/kg may be given. (The BNFC suggests initial doses of 1 to 3 micrograms/kg for those aged from l month to 12 years, with supplements of 1 microgram/kg . ) When ventilation is assisted, the initial recommended dose is also 1 to 3 micrograms/kg, with supplements of l to 1 . 2 5 micrograms/kg. (The BNFC suggests an initial dose of l to 5 micrograms/kg for neonates and children up to 12 years of age, with supplements of I to 3 micrograms/kg.) In the USA, doses are similar to those licensed in the UK. The BNFC suggests that fentanyl may be given by intravenous infusion to provide analgesia and respir­ atory depression in ventilated children under intensive care. A loading dose of I to 5 micrograms/kg is given by intravenous inj e ction, followed by an infusion of 1 . 5 micrograms/kg per hour in neonates, or I to 6 micrograms/kg per hour in those aged I month to 1 8 years, adjusted according t o response. Transdermal . patches delivering amounts of fentanyl ranging from 12 to l O O micrograms/hour may be used for the treatment of intractable chronic pain in children aged 2 to 16 years who are already tolerant to opioid therapy of comparable potency. The initial dose should be based on the previous 24-hour opioid requirement. Use of a patch providing 12 micrograms of fentanyl per hour is equivalent to about 30 to 44 mg daily of oral morphine sulfate. See Uses and Administration, p. 60.2 for further details. Patches should be applied to the upper backs of young children to minimise the potential for removal. The transmucosal lozenge -on-a- stick formulation is licensed for use in adolescents aged 16 years and older for the management of breakthrough pain in those already receiving and tolerant to opioid treatment; the usual adult dose may be given (see p . 60.2 ) .

Anaesthesia.

Fentanyl and its congeners alfentanil, remi­ fentanil, and sufentanil are shorter-acting than morphine and appear to produce fewer circulatory changes; they are preferred for use as supplements during anaesthesia with inhalational or intravenous drugs. Fentanyl is widely used as the analgesic component of balanced anaesthesia. It has been used to attenuate cardiovascular stress responses to intubation (see Anaesthesia, p. 2028. 1 ) , and may be used in higher doses in an attempt to reduce the cardiovascular, endocrine, and metabolic changes that may accompany surgery. When attenuation of surgical stress is especially important, for example in cardiac surgery, intravenous fentanyl 50 to l OO micrograms/kg with oxygen and a neuromuscular blocker, and sometimes up to 1 5 0 micro­ grams/kg, may be used for general anaesthesia. Total intravenous anaesthesia with fentanyl and propofol has been successful. 1 Satisfactory anaesthesia has been reported' with high­ dose fentanyl citrate ( 3 0 to 50 micrograms/kg) in premature infants when used as sole anaesthetic, with pancuronium, for ligation of patent ductus arteriosus; cardiovascular stability was maintained throughout the procedure.

t denotes a preparation no longer actively marketed

The symbol

However, others' found significant hypotension i n preterm infants given either fentanyl 20 micrograms/kg, isoflurane, halothane, or ketamine; systolic arterial pressure was best maintained with the ketamine technique. The surgical stress response in preterm babies was abolished by the addition of fentanyl 10 micrograms/kg intravenously to an anaesthetic regimen of nitrous oxide and tubocurarine.4 Dose responses of fentanyl in neonatal anaesthesia have been discussed.' For details of doses in neonates and children, see. above. Neuroleptanalgesia. An injection of short-acting fentanyl 50 micrograms/mL with the longer-acting antipsychotic droperidol 2 . 5 mg/mL has been used for neuroleptanalgesia, premedication, and as an adjunct to anaesthesia. However, the use of such a fixed-ratio combination cannot be recommended. l. 2.

Jenstrup M, et al. Total iv anaesthesia with propofol-alfentanil or propofol-fentanyl. Br J Anaesth 1 990; 64: 7 1 7-22. Robinson S, Gregory GA. Fentanyl-air-oxygen anesthesia for ligation of patent ductus arteriosus in preterm infants. Anesth Analg 1 9 8 1 ; 60: 3 3 1 4.

3.

Friesen RH, Henry D B . Cardiovascular changes i n preterm neonates receiving isoflurane, halothane, fentanyl, and ketamine. Anesthesiology 1 986; 64: 238-42.

4.

Anand KJS, et al. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1 987; i: 243-8.

5.

Vaster M. The dose response of fentanyl in neonatal anesthesia. Anesthesiology 1 987; 66: 433-5.

PHAEOCHROMOCYTOMA. Unlike morphine and some other opioids, fentanyl and alfentanil do not release histamine and may be used safely in the anaesthetic management of patients with phaeochromocytoma. l l.

Hull CJ. Phaeochromocytoma: diagnosis, preoperative preparation and anaesthetic management. Br J Anaesth 1 986; 58: 1 4 5 3--6 8 .

POSTOPERATIVE SHIVERING.

As petltidine appears to be effec­ tive in the treatment of postoperative shivering, other opioids including fentanyl have also been tried. Not all opioids are necessarily effective but fentanyl has been reported to be so, 1 although information is scanty.' 1.

Alfonsi P, et al. Fentanyl, as pethidine, inhibits post anaesthesia

2.

shivering. Br J Anaesth 1 993; 70 (suppl 1 ) : 38. Kranke P, et al. Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg 2002; 94: 453-60.

Intensive care.

Despite the short duration of action of fentanyl after single doses, rapid redistribution in the body results in an elimination half-life longer than that of mor­ phine. C onsequently fentanyl is not a short-acting drug when used for analgesia in intensive care, and may offer little advantage over morphine. 1 l.

Aitkenhead AR. Analgesia and sedation i n intensive care. B r J Anaesth 1 989; 63: 1 96-206.

Pain. CANCER PAIN. Transdermal fentanyl is used in the management of chronic intractable cancer - pain; for refer­ ences see Administration, Transdermal Route, above. For references to the use of intranasal and transmucosal fentanyl in the management of breakthrough cancer pain, see Administration, Intranasal Route and Transmucosal Route, above. LABOUR PAIN. Fentanyl has been reported to be an effective intravenous analgesic during active labour. Epidural fentanyl is unreliable when used alone, 1.2 although it does enhance the epidural analgesia achieved with the local anaesthetic bupivacaine. The reduction in the minimum local analgesic concentration of epidural bupivacalne for labour pain increased with increasing dose of fentanyl added to bupivacaine. 3 However, the incidence of pruritus increased significantly with fentanyl in a dose of 4 micro­ grams/mL and therefore the optimum dose of fentanyl may be 3 micrograms/mL for bupivacaine-sparing epidural analgesia during labour. Respiratory depression has also been reported with the combination. 4 l. 2.

Reynolds F. Extradural opioids in labour. Br J Anaesth 1 989; 63: 2 5 1 - 3 . Lindow SW, et a l . A randomised double-blind comparison of epidural fentanyl versus fentanyl and bupivicaine [sic] for pain relief in the

3.

second stage of labour. Br J Obstet Gynaecol 2004; 1 1 1 : 1 075-80. Lyons G, et al. Extradural pain relief in labour: bupivacaine sparing by

4.

extradural fentanyl is dose dependent. Br J Anaesth 1 997; 78: 493-7. McClure JH, Jones G. Comparison of bupivacaine and bupivacaine with fentanyl in continuous extradural analgesia during labour. Br J Anaesth 1 989; 63: 637-40.

POSTOPERATIVE PAIN.

Small intravenous bolus doses of an opioid analgesic may be injected immediately after surgery for postoperative analgesia and faster acting opioids such as fentanyl may be preferable to morphine.1 Fentanyl has also been given by epidural injection in doses of !00 or 200 micrograms or by continuous epidural infusion in doses of 20 to 80 micrograms/hour; patient-controlled sys­ tems have been used. 2 Epidural fentanyl or sufentanil provided effective postoperative analgesia after caesarean section with comparable adverse effect profiles.' The suggested optimal dose of fentanyl was l 00 micrograms. For references comparing epidural fentanyl with alfentanil, see Postoper­ ative Analgesia under Uses and Administration of Alfent­ anil, p. 1 9 . 1 . In a review' of perioperative paln management epidural opioids were · considered to provide effective

Q9 denotes a substance whose use may be restricted in certain sports (see p. viii)

62 analgesia at lower doses than systemic opioids. Fentanyl may be given through a lumbar epidural catheter that is often inserted immediately postoperatively. After an initial loading dose of I to 1 . 5 micrograms/kg of fentanyl, infusion at the rate of 0. 7 to 2 micrograins/kg per hour is begun and continued for about 48 hours on average. Some prefer to use intermittent injection. A small study5 comparing 2 patient-controlled routes of administration found that cervical epidural fentanyl provided better postoperative pain relief at rest than intravenous fentanyl; however, there was no decrease in the total dose required and the authors considered that the benefits of epidural fentanyl did not outweigh its potential complications. C ombine d opioid and local anaesthetic epidural infusions have also proved effective, for example fentanyl I microgram/mL with bupivacaine 0 . 1 %; both could be infused at lower rates than either drug alone. Although a study6 comparing bupivacaine-fentanyl combinations with each drug alone for epidural analgesia after caesarean section confirmed an additive analgesic effect for the combination, there was no demonstrable clinical benefit compared with fentanyl alone in this patient group who expect early mobilisation. However, the combination may be of greater benefit in patients for whom early ambulation is not routine. Fentanyl has also been given by epidural injection to children for postoperative analgesia. 7 Fentanyl has been tried by intrathecal injection for postoperative pain.8 As mentioned in Administration, Transdermal Route, p . 6 1 . 1 , an iontophoretic transdermal system for postoper­ ative pain was also available.9 - 1 1 1.

Mitchell RWD, Smith G. The control of acute postoperative pain. Br J Anaesth 1 989; 63: 147-58.

2.

Morgan M. The rational use of intrathecal and extradural opioids. Br J Anaesth 1 989; 63: 1 6 5-88.

3.

Grass JA, et al. A randomized, double-blind, dose-response comparison of epidural fentanyl versus sufentanil analgesia after cesarean section. Anesth Analg 1 997; 85: 3 6 5-7 1 .

4.

Swarm RA, e t al. Pain treatment i n the perioperative period. Curr Prahl

Surg 2 0 0 1 ; 38: 8 3 5-920. 5.

Roussier M, et a!. Patient-controlled cervical epidural fentanyl compared with patient-controlled i.v. fentanyl for pain after pharyngolaryngeal surgery. Br J Anaesth 2006; 96: 492-6.

6.

Cooper DW, et a!. Patient-controlled extradural analgesia with bupivacaine, fentanyl, or a mixture of both, after caesarean section. Br

J Anaesth 1 996; 76: 6 1 1-1 5 . 7.

B.

Lejus C, e t al. Postoperative extradural analgesia i n children: comparison of morphine with fentanyl. Br J Anaesth 1 994; 77.: 1 5 6-9.

Sudarshan G, et al. Intrathecal fentanyl for post-thoracotomy pain. Br J

Anaesth 1 9 9 5 ; 75: 1 9-22. 9.

Chelly JE. An iontophoretic, fentanyl HCl patient-controlled transdennal system for acute postoperative pain management. Expert Opin Pharmacother 2005; 6: 1205-14.

IO. Koo PJ. Postoperative pain management with a patient-controlled transdermal delivery system for fentanyL Am J Health-Syst Pharm 2005;

62: 1 1 71-6. 1 1 . Mayes S, Ferrone M . Fentanyl HCl patient-controlled iontophoretic

transdermal system for the management of acute postoperative pain. Ann Pharmacother 2006; 40: 2 1 78-86.

l?.�P��.c!����.c:J�� .\IY.i_t�.c!r.a.�?'.

. As for Opioid Analgesics, p. 1 0 9 . 1 . Fentanyl and illicitly manufactured analogues are subject to abuse (see under Precautions, below) . Plasma concentrations required to produce satisfactory sedation have been reported to increase steadily in neonates receiving continuous infusions, suggesting the development of tolerance to the sedating effects of fentanyJl Movement disorders, extreme irritability, and symptoms characteristic of opioid abstinence syndrome have been reported in children after withdrawal of prolonged fentanyl infusions.2•3 Similarly, withdrawal symptoms and, in one case, myoclonus have occurred in adults when fentanyl transdermal patches have been stopped.'· 5 Acute opioid withdrawal syndrome has also been seen in cancer patients switched from modifiedwrelease oral morphine to transderw mal fentanyl despite adequate analgesia being maintained.6 l.

Arnold JH, et al. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1 9 9 1 ; 1 1 9 : 639-43.

2.

Lane JC, et a!. Movement disorder after withdrawal of fentanyl infusion. J Pediatr l 9 9 1 ; 119: 649-5 1 .

3.

Dominguez KD, e t al. Opioid withdrawal i n critically ill neonates. Ann Pharmacother 2003 37: 473-7.

4.

Han PKJ, et a!. Myoclonus secondary to withdrawal from transdermal fentanyl: case report and literature review. J Pain Symptom Manage 2002;

5.

Ishihara C, et al. Withdrawal symptom after discontinuation of transdermal fentanyl at a daily dose of 0.6 mg. Pharm World Sci 2005; 27:

6.

Anonymous. Opiate withdrawal vvith transdennal fentanyl. Phann J

23: 66-72.

1 3- 1 5 . 1 99 5 ; 255: 680.

Adverse Effects and Treatment As for Opioid Analgesics in general, p. I I 0. 1 . Respiratory depression, which occurs espedally with high doses of fentanyl, responds to naloxone (see also Effects on the Respiratory System, below ) . Atropine may be used to block the vagal effects of fentanyl such as bradycardia. Unlike morphine, fentanyl is reported not to cause significant histamine release . Transient hypotension All crosswreferences refer to entries in Volume A

may follow intravenous dosage. Muscle rigidity can occur and may require neuromuscular blockers. Local reactions such as rash, erythema, and itching have been reported with transdermal use. Gum bleeding and irritation, and taste perversion have been reported with transmucosal use. Intranasal use may cause throat irritation, epistaxis, nasal ulcers, and rhinorrhoea.

Effects on the cardiovascular system.

For a reference to the effects of fentanyl on histamine release compared with some other opioids, see under Pethidine, p. 1 2 2 . 3 .

Effects on mental function, Fentanyl h a d some dose­ related effects on mental function and motor activity in healthy subjects, 1 but immediate and delayed recall were not affected. See also under Alfentanil (p. 1 9 . 2 ) . Acute toxic delirium has been reported after treatment with transdermal fentanyl.' l.

Scamman FL, et al. Ventilatory and mental effects of alfentanil and

2.

fentanyl. Acta Anaesthesiol Scand 1 984; 28: 63-7. Kuzma PJ, et al. Acute toxic delirium: a uncommon reaction to transdermal fentanyl. Anesthesiology 1 995; 83: 869-7 1 .

Effects on the nervous system. There have been reports o f seizures with low a n d high doses of fentanyl or sufenta­ niJ . l There was, however, no EEG evidence of cortical sei­ zure activity in a patient who had seizure-like muscle movements during a fentanyl infusion;2 the muscle movew ments might have been due to myoclonus produced by depression of higher CNS inhibitory centres or to a pro­ nounced form of opioidwinduced muscle rigidity. For a report of encephalopathy associated with prolonged use of fentanyl and rnidazolam in infants in intensive care, see Encephalopathy under Adverse Effects of Diazepam, p . 1 06 6 . 2 . l.

Zaccara G , e t al. Clinical features, pathogenesis and management o f drug-induced seizures. Drug Safety 1 990; 5: 1 09�5 1 .

2.

Scott JC, Sarnquist FH. Seizure-like movements during a fentanyl infusion with absence of seizure activity in a simultaneous EEG recording. Anesthesiology 1 9 8 5 ; 62: 8 1 2-14.

Effects on the respiratory system,

Fentanyl, like other opioid agonists, causes dose-related respiratory depression; it is significant with intravenous fentanyl doses of more than 200 micrograms and may be more prolonged than analgesia. Anaesthesia with fentanyl may result in either prolonged or delayed respiratory depression postopera­ tively. 1 Consequently, patients should continue to be monitored postoperatively until spontaneous breathing has been re-established. Severe respiratory depression in a 1 4-month-old child after intravenous sedation with fentanyl and midazolam has also highlighted the necessity for careful monitoring when giving with other respiratory depressants -' If present at the end of operation respiratory depression may be reversed by an opioid antagonist such as naloxone; alternatively, a respiratory stimulant such as doxapram that does not reverse analgesia has been given. Rigidity of the respiratory muscles (chest wail rigidity) may occur during fentanyl anaesthesia. The effects can be minimised by using a slow intravenous injection but a neuromuscular blocker may be required to allow artificial ventilation; rigidity has been reversed postoperatively by naloxone. Similar muscle rigidity induced by a!fentanil could be attenuated by pretreatment with a benzodiazepine whereas small doses of neuromuscular blockers appeared to be ineffective . ' C oughing h a s been associated4 with intravenous fentanyl; incidence was decreased with a longer injection time, 5 in light cigarette smokers, 5•6 and in older patients. 6 For the use of beclometasone and lidocaine to prevent cough associated with intravenous fentanyl in anaesthesia, see p. 1 622 . 1 and p. 1 980.3, respectively. The risk of respiratory depression associated with epidural doses of fentanyl, a highly lipid-soluble opioid, has been considered relatively small and only slight ventilatory depression was noted7 after a dose of 50 micrograms. However, profound delayed respiratory depression has been reported in 2 women 100 minutes8 and 80 minutes, 9 respectively after fentanyl 1 0 0 micrograms had been given epidurally for caesarean section. No adverse effects on neonatal respiration or neurobehaviour were detected in a study10 of neonates of mothers given epidural infusions of bupivacaine and fentanyl during labour. However, a later report 1 1 described 2 neonates who developed respiratory depression after their mothers were given epidural fentanyl during labour; the effect was reversed by intramuscular naloxone 400 micrograms. The authors noted that the doses of fentanyl used were higher than those in the previous study. Respiratory depression is also a risk with topically applied fentanyl preparations. Severe hypoventilation with some fatalities has occurred in patients given fentanyl as a transdermal patch for minor painful conditions. 12 More recently, Health Canada had received 2 reports of fatal respiratory depression associated with the use of transdermal fentanyl patches in adolescents for relatively

minor conditions (chronic headache and throat pain ) ; 1 3 in both cases the respiratory depression developed within 24 hours of applying the first and only patch. See also Administration, Transdermal Route, under Precautions p. 6 3 . 1 . I . Bennett MRD, Adams AP. Postoperative respiratory complications of opiates. Clin Anaesthesiol 1 9 8 3 ; 1 : 41-56.

3.

Yaster M, et al. Midazolam-fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics 1 990; 86: 463-7. Sanford TJ, et al. Pretreatment with sedative-hypnotics, but not with

4.

Tweed WA, Dakin D . Explosive coughing after bolus fentanyl injection.

2.

nondepolarizing muscle relaxants, attenuates alfentanil-induced muscle rigidity. 1 Clin Anesth 1994; 6: 473-80. 200 1 ; 92: 1442�3. 5. 6. 7.

·

Lin J-A,

Prolonged injection time and light smoking decrease the

incidence of fentanyl-induced cough. Anesth Analg 2005; 1 0 1 : 670-4. Oshima T, et al. Identification of independent risk factors for fentanyl­ induced cough. Can J Anesth 2006; 53: 7 5 3-8. Morisot P, eta!. Ventilatory response to carbon dioxide during extradural

8.

anaesthesia with lignocaine and fentanyl. Br J Anaesth 1 989; 63: 97-102. Brockway MS, et al. Profound respiratory depression after extradural

9.

fentanyl. Br J Anaesth 1 990; 64: 243-5. Wang CY. Respiratory depression after extradural fentanyl. Br J Anaesth 1 992; 69: 544.

1 0 . Porter J, et al. Eff'ect of epidural fentanyl on neonatal respiration. Anesthesiology 1 998; 89: 79-8 5 . 1 1 . Kumar M, Paes B . Epidural upioid analgesia a n d neonatal respiratory

depression. J Perinatol 2003; 23: 425-7. 12. FDC Reports Pink Sheet 1994; January 24: ' 1 2 . 1 3 . Health Canada. Transdermal fentanyl (Duragesic): respiratory arrest i n

adolescents. Can Adverse Read News 2004; 14 ( 4 ) : l - 2 . Also available at: http: //www .hc-sc.gc.ca/ dhp-mps/ alt_formats/hpfb-dgpsa/pdf/medeffl carn-bcei_vl4n4-eng.pdf (accessed 26/06/08)

Effects on the skin,

A patient developed a macular rash covering the whole body, except for the face and scalp, while using transdermal fentanyl patches. 1 I.

Stoukides CA, Stegman M . Diffuse rash associated with transdermal fentanyl. Clin Phann 1 992; 1 1 : 222.

Effects on the urinary tract. Urinary retention developed in 2 premature infants after sedation with fentanyl infu­ sian at a dose of 3 micrograms/kg per hour. 1 In both cases catheterisation relieved symptoms. l.

Das UG, Sasidharan P. Bladder retention of urine as a result of continuous intravenous infusion of fentanyl: 2 case reports. Pediatrics 2 0 0 1 ; 108: 1 0 12-1 0 1 5 .

Precautions As for Opioid Analgesics in general, p. 1 1 0. 3 . Caution i s advised i n patients with myasthenia gravis; the effects of muscular rigidity on respiration may be particularly pronounced in these patients. US licensed product information contra-indicates the use of standard transdermal fentanyl patches in opioid-naive patients because of the risk of fatal respiratory depression (see Effects on the Respiratory System, above and Administration, Transdermal Route, p. 6 3 . 1 ) . Similar contrawindications apply to transmucosal formulations of fentanyl (see also Administration, Transmucosal Route, p. 6 3 . 1 ) . The use of fentanyl intranasal spray is contra-indicated in opioidwnaive patients, and in those with previous facial radiotherapy or recurrent episodes of epistaxis. Absorption of fentanyl irom standard transdermal patches may be increased as the temperature rises and patients should therefore avoid exposing the patch to external heat; similarly, patients with fever may require monitoring because of increased absorption. It may take 1 7 hours o r longer for plasma concentrations o f fentanyl to decrease by 50% after removal of a transdermal patch; patients who have had adverse effects should be monitored for up to 24 hours and those requiring replacement opioid therapy should initially receive low doses increased gradually thereafter. Similar advice has also been given for patients receiving fentanyl via an iontophoretic drug delivery system; the mean half-life of fentanyl in this system is l l hours. The bioavailability of different transmucosal fentanyl preparations is not equivalent and consequently they should not be substituted on a dose -per-dose basis.

Abuse.

Several synthetic analogues of fentanyl, so-called 'designer drugs', have been manufactured illicitly for recreational use, particularly in the USA. They are highly potent, and respiratory depression and death may occur very rapidly 1 The 'fentanyls' have been smoked or snorted as. well as injected intravenously. Fentanyl analogues identified by WH02·3 as being subject to street abuse or likely to be abused include: u­ methylfentanyl ( also known as 'China white' or 'synthetic heroin'), 3 -methylfentanyl, acetyl-a-methylfentanyl, u­ methylthiofentanyl, p-f!uorofentanyl, �-hydroxyfentanyl, � - hydroxy - 3 - m ethylfe ntanyl, thiofentany!, and 3 methylthiofentanyl. Fentanyl itself is also subject to illicit use. It is chemically unrelated to morphine and does not react in screening tests for morphine-related opioids. It has therefore been recommended4 that fentanyl should be tested for specifically in cases with suspected opioid misuse .

Used fentanyl transdermal systems may contain significant amounts of fentanyl and have been subject to abuse. In some cases the contents of the patches have been injected intravenously; such abuse has resulted in death.5,6 Licensed product information advises that used patches should be folded firmly in half, adhesive side inwards to conceal the release membrane, and disposed of safely. l.

Buchanan JF, Brown CR. Designer drugs': a problem in clinical toxicology. Med Toxicol l 988; 3: 1�1 7 .

2.

W H O . W H O expert committee o n drug dependence: twenty-fourth report. WHO Tech Rep Ser 761 1 988.

3.

WHO . WHO expert committee on drug dependence: twenty-sixth report. WHO Tech Rep Ser 787 1 989.

4. 5.

Berens AIL, et at. Illicit fentanyl in Europe. Lancet 1 996; 347: 1 3 34-5. Reeves MD, Ginifer CJ. Fatal intravenous misuse of transdermal

6.

Tharp AM, et al. Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from trans dermal patches. Am J Forensic Med Pathol 2004; 25: 1 78--8 1 .

fentanyl. Med 1 Aust 2002; 177: 5 52-3.

Administration.

INTRAVENOUS ROUTE. Fentanyl i s much more lipid-soluble than morphine and after standard sin­ gle intravenous doses has a rapid onset and short duration of action. However, fentanyl is rapidly redistributed in the body and its half-life (see under Pharmacokinetics, below) is longer than that of morphine. Hence, with high or repeated doses, fentanyl becomes a relatively long-acting drug; to avoid accumulation patients should be monitored and doses adjusted accordingly. Repeated intra-operative doses of fentanyl should be given with care, since not only may the respiratory depression persist into the postoperative period but it may become apparent for the first time postoperatively when the patient is away from immediate nursing attention. TRANSDERMAL ROUTE. Fatalities have been associated with the use of standard fentanyl transdermal patches (see Effects on the Respiratory System, p . 62 . 2 ) . Incorrect or inappropriate use resulting in serious adverse effects and fatalities had prompted regulatory authorities to issue warnings and recommendations for changes to product labelling; in particular transdermal fentanyl patches are not appropriate for the treatment of acute or postoperative pain. Nonetheless, reports of fatalities and life-threatening adverse reactions have continued to be received1-4 and, in December 2007, the FDN reiterated that: • fentanyl patches are indicated for the management of persistent, moderate to severe chronic pain in opioid­ tolerant patients • licensed product information must be consulted when determining the initial dose as overestimating when converting patients from another opioid analgesic can result in fatal overdose with the first dose • use with any inhibitors of the cytochrome P45 0 isoenzyme CYP3A4 may result i n a n increase in plasma-fentanyl concentrations, which may cause potentially fatal respiratory depression; patients who are taking CYP3A4 inhibitors and using fentanyl patches for an extended period of time should be monitored and the dose of fentanyl adjusted if necessary

I. FDA. Information for healthcare professionals: fentanyl transdermal system (marketed as Duragesic and generics) (issued 2 1 st December,

at: Available http://www.fda.gov/Drugs/DrugSafety/ 2007 ) . PostmarketDrugSafetylnformationforPatientsandProviders/ucm084307 (accessed 02/0 8 1 1 0 ) 2.

Health Canada. Fentanyl transdermal patch and fatal adverse reactions. Can Adverse Read News 2008; 18 ( 3 ) : 1-2. Also available at: http://www. hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn-bceL v 1 8n 3 - eng.pdf (accessed 2 3/07/08)

3.

MHRA/CHM. Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use. Drng Safety Update 2008; 2 ( 2 ) : 2-3. Available at: http://www.mhra.gov.uk/Publications/

4.

Health Canada. Fentanyl tramdermal patches and acddental child exposure. Can Adverse React News 2009; 19 ( 3 ) : 3. Also available at: http: II www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/carn­

Safetyguidance/DrugSafetyUpdate/CON02 5 6 3 1 (accessed 03/ 1 1 /09)

bcei_v l 9n3 -eng.pdf (accessed 03 / 1 1 /0 9 )

TRANSMUCOSAL ROUTE. The FDA1 has received reports of ser­ ious adverse effects, including fatalities, in patients who have taken the fentanyl buccal tablets, Fentora ( Cephalon, USA ), resulting from inappropriate use in patients who were not opioid tolerant, misunderstanding of dosing instructions, or inappropriate substitution for other fentanyl-containing formulations. The FDA reiterated that Fentora: • should only be used for breakthrough pain in opioid­ tolerant cancer patients • should not be used in those who only need an opioid on an intermittent, or as required, basis and who are not on around-the-dock opioids • should not be used for the management of acute or postoperative pain including headaches, migraines, and pain due to injury • should not be directly substituted for other fentanylcontaining formulations Similar restrictions are also mentioned in the licensed product information for other transmucosal preparations of fentanyl. l.

FDA. Information for healthcare professionals: fentanyl buccal tablets (marketed as Fentora) (issued 26th September, 2007 ) . Available at:

http:/ /www .fda.gov /Drugs/DrugSafety /PostmarketDrugSafetylnforma­

liver by N-dealkylation and hydroxylation via the cytochrome P450 isoenzyme CYP3A4. Metabolites and some unchanged drug are excreted mainly in the urine. The Breast feeding. The American Academy of Pediatrics1 short duration of action is probably due to rapid states that there have been no reports of any clinical effect redistribution into the tissues rather than metabolism and in infants of breast-feeding mothers given fentanyl, and excretion. The relatively longer elimination half-life reflects that therefore it may be considered to be usually compati­ slower release from tissue depots. About 80% has been ble with breast feeding. However, licensed product infor­ reported to be bound to plasma proteins. Fentanyl appears mation states that, since fentanyl is distributed into breast in the CSF. It crosses the placenta and has been detected in milk, it should be avoided in nursing mothers because of breast milk. the possibility of sedation or respiratory depression in Marked differences in results of pharmacokinetic studies breast-fed infants. The BNF recommends that breast-fed of fentanyl have been attributed1 to differences in assay infants should be monitored for opioid-induced adverse methods. The need for sensitive assay methods has been effects. emphasised because the potency of fentanyl means that A study2 using fentanyl 1 00 micrograms intravenously small doses are used. However, there are differences in for induction of anaesthesia in 5 mothers concluded that the pharmacokinetics between bolus doses and prolonged amount of fentanyl excreted into breast milk within 24 infusion with highly lipophilic drugs such as fentanyl. ' hours of induction was less than 0. 1 % of the maternal dose, Terminal half-lives ranging from 2 to 7 hours have been and hence unlikely to affect a healthy full-term breast­ reported in healthy subjects and surgical patients. However, feeding infant. ! the duration of action of fentanyl after a single intravenous l. American Academy of Pediatrics. The transfer of drugs and other dose of up to 1 00 micrograms may be only 3 0 to 60 minutes chemicals into human milk. Pediatrics 200 1 ; 108: 776-89. [Retired May as a result of rapid redistribution into the tissues. US licensed 2 0 1 0 ] Correction. ibid.; 1 02 9 . Also available at: http : / /aappolicy. a a ppublications. org/ cgi/ content/full/pediatrics% 3b l 08/3/77 6 (accessed product information has given values for a three ­ 26/06/08) compartment pharrnacokinetic model with a distribution 2 . Nitsun M, et al. Pharmacokinetics of midazolam, propofol, and fentanyl time of 1 . 7 minutes, a redistribution time of 1 3 minutes, and transfer to human breast milk. Clin Pharmacol Ther 2006; 79: 549-57. a terminal elimination half-life of 2 1 9 minutes. Giving Children. The half-life of fentanyl is prolonged in neonates repeated or large doses, or continuous infusions, may result in accumulation and a more prolonged action. and accumulation is likely with prolonged use; muscle The clinical significance of secondary peak plasma­ rigidity may occur and the use of muscle relaxants may be fentanyl concentrations and the possible role of entero­ required. See also under Pharmacokinetics, p. 64. 1 . systemic recirculation3 has been controversial, but some4 Exercise. Opioid toxicity requiring naloxone treatment considered that irregular decay curves were not unlikely for lipophilic compounds such as fentanyl, especially in patients occurred in a patient who wore a fentanyl patch while undergoing operations and subject to large changes in blood engaging in vigorous outdoor exercise. 1 Physicians should flow. Unexpectedly high plasma-fentanyl concentrations in be aware that along with fever and external heat sources, a patient following epidural use were thought to be a result physical activity may cause increased absorption of trans­ of aortic clamping and might reflect the effect of changes in dermal fentanyl. blood flow. ' 1. Carter KA . Heat -associated increase in transdermal fentanyl absorption. The main metabolites of fentanyl, which are excreted in Am J Health-Syst Pharm 2003; 60: 1 9 1-2. the urine, have been identified as 4-N- (N-propionylanilino) Handling. Avoid contact with skin and the inhalation of piperidine and 4-N- (N-hydroxypropionylanilino) piperi­ dine; 1 - (2 -phenethyl ) -4-N- ( N-hydroxypropionylanilino) fentanyl citrate particles. piperidine is a minor metabolite.6 Fentanyl has no active Porphyria. The Drug Database for Acute Porphyria, com­ or toxic metabolites.4 piled by the Norwegian Porphyria Centre (NAP O S ) and I . Mather LE. Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin Pharmacokinet 1 983; 8: 422-46. the Porphyria Centre Sweden, classifies fentanyl as prob­ 2 . Scholz J, et a!. Clinical pharmacokinetics of alfentanil, fentanyl and ably not porphyrinogenic; it may be used as a drug of first sufentanil: an update. Clin Phannacokinet 1 996; 3 1 : 2 7 5-92. choice and no precautions are needed.1 3 . Bennett MRD, Adams AP. Postoperative respiratory complications of tionforPatientsandProviders/ucm l 26082 (accessed 02/08 / 1 0 )

I.

T h e Drug Database for Acute Porphyria. Available a t : http://www. drugs-porphyria.org (accessed 2 2 / 1 0/ 1 1 )

Interactions For interactions associated with opioid analgesics, see p. 1 1 1 .2 . Use of fentanyl with non-vagolytic neuromuscular blockers may produce bradycardia and possibly asystole. Fentanyl is metabolised via the cytochrome P450 isoenzyme CYP3A4; use with potent inhibitors of this isoenzyme, such as ritonavir and other HIV-protease inhibitors, may increase fentanyl plasma concentrations.

Antidepressants.

For reference to a possible case of sero­ tonin syndrome associated with use of fentanyl and SSRls, see Opioid Analgesics under Interactions of Fluoxetine, p. 427. 1 .

opiates. Clin Anaesthesiol 1 983; 1: 41-56. 4.

l.

Benzodiazepines. For the effects of opioids such as fentanyl with benzodiazepines, see Analgesics under Inter­ actions of Diazepam, p . 1 068. 1 and Effects on the Respir­ atory System, p . 6 2 . 2 .

et a l . Opiate metabolism and excretion. Baillieres Clin

Bullingham RES, et al. Unexpectedly high plasma fentanyl levels after

6.

Goromaru T, et al. Identification and quantitative determination of fentanyl metabolites in patients by gas chromatography-mass spectro­

epidural use. Lancet 1 980; i: 1 3 6 1-2.

metry. Anesthesiology 1 984; 61: 73-7.

Administration.

Some references to the pharmacokinetics of fentanyl after constant rate intravenous infusion, 1 transdermal application,'·' use of the oral sublingual' and transmucosaF-II routes, intranasal dosage, 1 2• 1 3 subcuta­ neous infusion, 14 and epidural use . 1 5- 1 7 1.

Duthie DJR, e t al. Pharmacokinetics o f fentanyl during constant rate iv

2.

Grond S, et al. Clinical pharmacokinetics of transdermal opioids: forus on transdermal fentanyl. Clin Pharmacoki71et 2000; 38: 59-89.

3.

Solassol I, et al. Inter- and intraindividuat variabilities in pharmacoki­ netics of fentanyl after repeated 72-hour transdermal applications in cancer pain patients. Ther Drug Monit 2005; 27: 491-8. Marier J-F, et al. Pharmacokinetics, tolerability, and performance of a

infusion for the relief of pain after surgery. Br 1 Anaesth 1 986; 58: 9 5 0-6.

4.

novel matrix transdermal delivery system of fentanyl relative to the commercially available reservoir formulation in healthy subjects. 1 Clin Pharmacol 2006; 46: 642-5 3 .

5.

Marier J - F , et a l . Comparative bioequivalence study between a novel

6.

matrix transdermal delivery system of fentanyl and a commercially available reservoir formulation. Br 1 Clin Pharmacol 2007; 63: 1 2 1-4. Lennerni:is B, eta!. Pharmacokinetics and tolerability of different doses of

Olkkola KT, e t a!. Ritonavir'� role i n reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1 999; 91: 6 8 1 - 5 .

RA,

5.

Antivirals.

Ritonavir, an inhibitor o f the cytochrome P45 0 isoenzyme CYP3A4, might prolong fentanyl-induced resp­ iratory depression. The plasma clearance of fentanyl was decreased, and the elimination half-life and area under the plasma concentration-time curve increased, when given with ritonavir in a study in healthy subj ects . 1

Moore

Anaesthesiol 1 987; 1: 829-58.

fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain. Br 1 Clin Phannacol 2005; 59: 249-5 3 .

7.

Streisand J B , e t al. Absorption and bioavailability o f oral transmucosal

8.

Darwish M, et a!. Pharmacokinetics and dose proportionality of fentanyl

F o r reference to t h e effect that fentanyl h a s on blood concentrations of propofol, see p . 1 9 1 5 . 2 .

9.

Darwish M, et al. Comparison of equivalent doses of fentanyl buccal tablets and arteriovenous differences in fentanyl pharmacokinetics. Clin

Pharmacokinetics

10. Darwish M, et al. Single-dose and steady-state pharmacokinetics of

fentanyl citrate. Anesthesiology 1 9 9 1 ; 75: 22 3-9. effervescent buccal tablets in healthy volunteers. Clin Pharmacokinet

Propofol.

After parenteral doses fentanyl citrate has a rapid onset and short duration of action. After transmucosal delivery, up to 5 0 % of the dose is rapidly absorbed from the buccal mucosa; the remainder is swallowed and slowly absorbed from the gastrointestinal tract. Some first-pass metabolism occurs via this route. The absolute bioavailability of transmucosal delivery is about half that for intravenous fentanyl but varies between formulations. The absolute bioavailability of intranasal delivery is about 89% and fentanyl is absorbed very rapidly through the nasal mucosa. Absorption is slow after transdermal application. Fentanyl is metabolised in the

2005; 44: 1 279-86.

Pharmacokinet 2006; 45: 843-50.

fentanyl buccal tablet in healthy volunteers. J Clin Pharmacol 2007; 47: 56-63 . 1 1 . Darwish M , e t al. Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacal 2007; 47: 343-5 0 . 1 2 . Walter S H , et a l . Pharmacokinetics of intranasal fentanyl. Br 1 Anaesth 1993; 70 (suppl l ) : 1 08 . 1 3 . Foster D, et a l . Pharmacokinetics a n d pharmacodynamics of intranasal versus intravenous fentanyl in patients with pain after oral surgery. Ann Phannacother 2008; 42:_ 1 380-7. 14. Miller RS, et al. Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients. Br J Clin Pharmacol 1 995; 40: 5 5 3-6. 15. Gourlay GK, et al. Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration. Pain 1 989; 38: 2 5 3-9.

64

Analgesics Anti-inflammatory Drugs and Antipyretics

16. Bader

AM.

et al. Maternal and neonatal fentanyl and bupivacaine

concentrations after epidural infusion during labor. Anesth Analg 1 9 9 5 ;

81: 829-32 . 1 7 . Moises EC, et a ! . Pharmacokinetics a n d transplacental distribution of

fentanyl in epidural anesthesia for normal pregnant women. Bur J Clin Pharmacol 2005; 6 1 : 5 1 7-22.

Cardiopulmonary bypass. In general, studies I.2 indicate that serum concentrations of fentanyl during cardio­ pulmonary bypass decrease initially and then remain stable. The fall in concentrations has been attributed to haemodilution although adsorption to the bypass appara­ tus has also been found. 1.

Buylaert WA, et al. Cardiopuhnonary bypass and the pharmacokinetics of drugs: an update. Clin Pharmacokinet 1 989; 17: 1 0-26.

2.

Gedney JA. Ghosh S . Pharmacokinetics of analgesics, sedatives and anaesthetic agents during cardiopulmonary bypass. Br J Anaesth 1 9 9 5 ;

75: 344-5 1 .

Children. The disposition of intravenous fentanyl 1 0 to 5 0 micrograms/kg in 14 neonates undergoing various major surgical procedures was highly variable.' The mean elimination half-life of 3 1 7 minutes and other pharmaco­ kinetic parameters including volume of distribution and total body clearance were greater than reported in adults, but both pharmacodynamic and pharmacokinetic mechan­ isms appeared responsible for the very prolonged respir­ atory depression that can occur in neonates after fentanyl anaesthesia. In 9 premature neonates given fentanyl 3 0 micrograms/kg intravenously for induction of anaes­ thesia' the elimination half-life ranged from 6 to 32 hours, but cautious interpretation was advised because of the method of calculation. I.

Koehntop DE, et al. Pharmacokinetics of fentanyl in neonates. Anesth Analg I 986; 65: 227-32.

2.

Collins C, et al. Fentanyl pharmacokinetics and hemodynamic effects in

Hong Kong: Durogesic; Hung.: Dolforin; Durogesic; Matrifen; Sedaton; India: Durogesic; Fendrop; Fenilate; Fenstud; Pent; Trofentyl; Indon. : Durogesic; Irl.: Abstral; Actiq; Breakyl; Duro­ gesic; Effentora; Fentadur; Fental; Fetanex; Instanyl; Matrifen; Mytanyl; PecFent; Sublimaze; Israel: Abstral; Actiq; Durogesict; Penta; Tanyl; Ital. : Actiq; Durogesic; Fentanest; Fenvel; Matri· fen; Quatrofen; Jpn: Durotep; E-fen; OneDuro; Malaysia: Dur­ ogesic; Talgesil; Mex. : Durogesic; Fenodid; Fentanest; Filtaten; Neth.: Abstral; Actiq; Breakyl; Durogesic; Effentora; Fenylat; Instanyl; PecFent; Norw.: Abstral; Actiqt; Buquel; Durogesic; Instany� Leptanal; Matrifent; NZ: Durogesic; Sublimaze; Phi­ lipp. : Durogesic; Sublimax; Sublimaze; Trofentyl; Pol.: Dolforin; Durogesic; Effentora; Penta MX; Fentagesic; Fentahexalt; Insta· nyl; Lunaldin; Matrifen; PecFent; Port. : Actiq; Ardicat; Duroge­ sic; Effentora; Fentanest; Instanyl; Nilfene; PecFent; Rus.: Duro­ gesic (,1\Iopore:mK); Fendivia (eBJ1HBIDI); S.Afr.: Durogesic; Sublimaze; Tanylt; Singapore: Durogesic; Fantamax; Spain: Abstral; Actiq; Durogesic; Effentora; Fendivia; Fentanest; Insta­ nyl; Matrifen; PecFent; Quidorfent; Swed.: Abstral; Actiq; Dur­ ogesic; Instanyl; Leptana� Matrifen; Switz.: Abstral; Actiq; Dur­ ogesic; Effentora; Matrifen; Sintenyl; Thai. : Durogesic; Turk.: Actiq; Durogesic; UK: Abstral; Actiq; Breakyl; Durogesic; Elfen­ tora; Fentalis; Instanyl; Matrifen; Mezolar; Opiodur; Osmach; Osmanil; PecFent; Sublimaze; Tilofyl; Ukr. : Matrifen (Ma:rpHijlea)t; USA: Abstral; Actiq; Duragesic; Fentora; Ionsyst; Lazanda; Onsolist; Sublimaze; Subsys; Venez. : Durogesic.

Muhi-ingredient Preparations.

Arg.: Disifelit; Austral.: Marcain with Fentanyl; Naropin with Fentanyl; Braz. : Nilperidol; Gr. : Thalamonal; NZ: Bupafen; Marcain with Fentanyl; Naropin with Fentanyl; UK: Bufyl.

Pharmacopoeial Preparations

BP 2 0 14: Bupivacaine and Fentanyl Injection;

Fentanyl

Inje ction; USP 36: Fentanyl Citrate Injection.

preterm infants during ligation of patent ductus arteriosus. Anesth Analg I 985; 64: I078-80.

The elderly.

In one study the elimination half-life of intra­ venous fentanyl increased from 2 6 5 minutes in patients with a mean age of 36 years to 945 minutes in those with a mean age of 67 years . ' The authors of another study were critical of the relatively short sampling time used and in contrast found that major fentanyl pharmacokinetic parameters did not correlate with age.2 However, elderly patients had increased brain sensitivity to intravenous fentanyl, as shown by EEG changes2 and lower doses might be indicated in older patients for pharmacodynamic rather than pharmacokinetic reasons. I.

Bentley JB, et al. Age and fentanyl pharmacokinetics. Anesth Analg I 982;

61: 968-7 1 . 2.

Scott J C , Stanski D R . Decreased fentanyl and alfentanil dose requirements with age: a simultaneous pharmacokinetic and phannacodynamic evaluation. J Pharmacal Exp Ther I 987; 240: 1 59-66.

Hepatic impairment.

The pharmacokinetics of fentanyl were not affected significantly in surgical patients with drrhosis of the liver.' A 1 987 review2 considered that fentanyl had not been assodated with clinical problems when given to patients with liver dysfunction. I. 2.

RA,

et al.

P..��P.�.��!�?.��············································································

Proprietary Preparations (details are given i n Volume B ) Single-ingredient Preparations. Mex. : Sinalgia; Spain: Dalgen.

Profile Feprazone, a phenylbutazone (p. 1 2 5 . 1 ) derivative, is an NSAID (p. 1 0 2 . 3 ) . It has been given orally in the treatment of mild to moderate pain, fever, and inflammation associated with musculoskeletal and joint disorders . Feprazone has also been given rectally and used topically as a 5% cream. Pinazone, the piperazine salt of feprazone, has been used similarly.

P..r�f.lJJaMaKc) ; Flexen (Cl.�.!��.n.� ........................................................................... .

Prapriela ry Preparations

(details are given in Volume B )

Single-ingredient Preparations. Ital.: Dolodenn.

Profile Methyl gentisate has been used topically for the relief of musculoskeletal and joint pain. It is also used as a skin lightening agent. References.

of methadone in the early post-bum period. J Clin Pharmacol l 990; 30: 70--5.

I.

Gallo R, Baldari M. Allergic contact dermatitis from methyl gentisate in a

3.

Shir Y, et al. Plasma concentrations of methadone during postoperative

2.

bleaching cream. Contact Dermatitis 2006; S4: 220-- l . Serra-Baldrich E, e t a l . Allergic contact dermatitis t o methyl gentisate.

4.

patient-controlled extradural analgesia. Br J Anaesth 1 990; 65: 204-9. Dale 0, et al. Bioavailabilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol 2004; 58: I 5 6-62.

Hepatic impairment.

Overall hepatic dysfunction does not seem unduly to disrupt methadone metabolism1 and it has been suggested2 that maintenance dosage of methadone need not be changed in stable chronic liver disease, although abrupt changes in hepatic status might result in substantial alterations in methadone disposition requiring dosage adjustments. In a study of patients on methadone maintenance therapy2 apparent terminal half-life of methadone was prolonged from a mean of 1 8 . 8 hours in those with healthy livers to 3 5 . 5 hours in patients with severe chronic liver disease. However, plasma concentrations were not increased in such patients. I. 2.

Moore RA, et al. Opiate metabolism and excretion. Baillieres Clin Anaesthesiol 1 987; I: 829-58. Novick DM, et al. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther I 9 8 I ; 30: 3 5 3-62.

Pregnancy. Plasma concentrations of methadone were reduced in methadone-maintained pregnant women, probably due to enhanced metabolism. 1•2 It was suggested that the dose of methadone might need to be increased in such patients. 1.

Pond SM, et al. Altered methadone pharmacokinetics in methadone­

2.

maintained pregnant women. J Pharmacol Exp Ther I985; 233: l-6. Wolff K, et al. Changes to methadone clearance during pregnancy. Bur J

Clin Pharmacol 2005; 61: 763-8.

Renal impairment. The urinary excretion of methadone was reduced in renal failure, 1 but plasma concentrations were within the usual range and faecal excretion accounted for the majority of the dose. Very little metha­ done was removed by peritoneal dialysis or haemodialysis. 1. Kreek MJ, et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 1 980; 5 : I 9 7-20 5 .

�-�f:>Cl.rwH.

Street names. The following terms have been used as 'street

names' {see p. vii) or slang names for various forms of morphine: Adolf; Block; China White; Cube; Dreamer; Drug store dope; Drugstore dope; Emsel; First line; German boy; God's drug; Goma; Hard stuff; Hospital Heroin; Haws; Hydrogen Bomb; M; Miss Emma; Mister blue; Mojo; Monf; Monkey; Morf; Marfa; Marls; Morphia; Morphina; Morpho; Morphy; Mr. Blue; M . S . ; MS; Mud; Murphy; Nasty; Nazi; Sweet Jesus; Sweet Morpheus; Tar; Unkie; White Stuff.

Morphine Hydrochloride (BANMJ ® Mprfi i ni.hydrdkloridi; · Martin · Hic!roklorur . Martina, . hidmclor­ · . de; Morfin-hidwk!Nid; Morfln,h;•dr0chlorid trihydrat; . IV\orfinhydroklorid: Motfino · hidrochloridas; Morll n y •. chlor� owodorek; . Morphine, chkJrhydrate de:. . Morphinhydrochlor� id; 1vlorphini . hydrothlorldum; Morphini . Hydrochlorid\.I'J' Trihydricum; Morphinii. Chlolidum; Morphinum . Chloratum;

�ro

MopQMHa f 11AQOXDopMJl. C r 1-H,,NiJ3,HCL3H,iJ:"375.8 0\S. .- 52 26-6 icrnhyd�ous rnorphine !lydroch!ori(fe); 6055,[)67 (morphine hydmchioridt! 1rihydrate). UN/i �. J28GEGROV.!(

Pharmacopoeias. In Chin., Bur. (see p. vii) , Int., Jpn, and Viet.

Ph. Eur. 8: (Morphine Hydrochloride ) . Colourless, silky needles, cubical masses or a white or almost white, crystalline powder. It is efflorescent in a dry atmosphere. Soluble in water; slightly soluble in alcohol; practically insoluble in toluene. Protect from light.

Incompatibility.

Stress L72t; Fr.: L 7 2 .

!BAN! ®

Morfiioi; Morfin; Martina; Morphinum; 7,8cDidehydro-4,5-epoxy- 1 7-methylmorphinan�3.&dioL

See under Morphine Sulfate, below.

Morphine Sulfate (BANMJ ® Morfiinisulfaatti; Momn Sulfat; Morfina, . sulfato de; Motfino sulfatas; .. Morfinsulfat, Morfin-suifat pe!ltahyd(at; . .orfin­ szulfat; rv1orfi ny . siarczan; Morphine. sulfate de; Morphine Sulphate; Morphi n i . sulfas; · Morppini Sulfa s . Pentabyoricus; Morp11lnsulfat; MofJa, tartrato de; Mop¢>�Ha TapTpar. debilitated patients. ranitidine hydrochloride in various ratios stored at (C, ,H,,NOJJ,,C,H,Oe,3H;0=774.8 • Intraspinal doses are in the region of 5 mg for an initial different temperatures13 CA5 � 302-3 ! -8 (anl>ydrous morphine wtrQte J: 6032-59-3 epidural injection; if pain relief is unsatisfactory- after one • Tetracyclines--colour change from pale yellow to light tartrate trihydrare), hour, further doses of I to 2 mg may be given up to a total green occurred when solutions of minocycline hydro­ U3NSU23LHD. dose of I 0 mg per 24 hours. The recommended initial chloride or tetracycline hydrochloride were mixed with dose for continuous epidural infusion in opioid-naive morphine sulfate in 5 % glucose injection14 l. Patel JA, Phillips GL. A to physical compatibility of intravenous patients ranges from 3.5 to 7 . 5 mg daily; those who have Incompatibility. See under Morphine Sulfate, p. 9 2 . 3 . 1966; 23: 409-l l . drug admixtures. some degree of opioid tolerance may be given 4. 5 to and compatibility of morphine. Int J 2 . Vermeire A , Remon JP. 1 0 mg daily. However, dosage requirements may Pharm 1999; 187: 1 7-5 1 . increase significantly during treatment and up to 2 0 to 3 . Pugh C B , e t al. Visual compatibility o f morphine sulphate and meperidine hydrochloride with other injectable drugs during simulated 30 mg daily may be required in some patients. A Morphine, a phenanthrene derivative, is the main alkaloid Y-site injection. Am J Hasp Pharm 1 9 9 1 ; 48: 1 2 3-5. modified-release formulation of liposomal morphine of opium (p. 1 1 1 . 3 ) . It is now commonly obtained from 4. Crapper JB. Mixing chlorpromazine and morphine. BMJ 1975; i: 3 3 . sulfate for lumbar epidural use is also available for the whole opium poppies (Papaver somniferum) which are 5. Trissel L A , et a l . Compatibility of doxorubicin hydrochloride liposome treatment of pain after major surgery; doses range from injection with selected other drugs during simulated Y-site administraharvested as poppy straw; a concentrate of poppy straw is 1997; 54: 2 708- 1 3 . tion. 10 to 20 mg, depending on the type of surgery, and known as CPS. 6. Xu Q A , e t a l . a n d compatibility of fluorouracil with morphine should be given before the operation, or after clamping of Morrhine is an opioid analgesic (p. 1 0 8 . 1 ) with agonist sulfate and hydromorphone hydrochloride. Ann Pharmacather 1 996; 30: the umbilical cord if used during caesarean section. It is activity mainly at !.I. opioid receptors and perhaps at K and 0 7 5 6-6 1 . intended for single-use only and no other drugs should 7. LeBelle MJ, et al. Compatibility of morphine and midazolam or receptors. It acts mainly on the CNS and smooth muscle. haloperidol in parenteral admixtures. Can J Hasp Pharm 1 995; 48: 1 5 5be administered into the epidural space for at least the Although morphine is mainly a CNS depressant it has some 60. next 48 hours. central stimulant actions which result in nausea and 8. Baker DE, et a!. Compatibility of heparin sodium and morphine sulfate. Intrathecal use of morphine and its salts has tended to be vomiting and miosis. Morphine generally increases smooth Am J Hasp Pharm 1 985; 42: 1 1 '52-'5. less common than epidural. A single dose of 0.2 to I mg 9. Parker WA. Physical compatibilities of preanesthetic medications. Can J muscle tone, especially the sphincters of the gastrointestinal Hasp Pharm 1 976; 29: 9 1 -2 . given by intrathecal injection may provide satisfactory and biliary tracts. 1 0 . Stevenson J G , Patriarca C. Incompatibility of morphine sulfate and pain relief for up to 24 hours . The recommended initial Morphine may produce both physical and psychological prochlorperazine ectisylate in syringes. Am J Hasp Pharm 1 985; 42: 265 1 . dose for continuous intrathecal infusion in opioid-naive 1 1 . Zuber DEL. Compatibility o f morphine sulfate injc(·tion and prochlor­ , dependence (see p . I 09 . I ) and should therefore be used patients ranges from 0.2 to I mg daily; those who have perazine edisylate injection. Am J Hasp Pharm 1 987; 44: 67. ' with discrimination. Tolerance may also develop. 1 2 . Fleischer NM. Promethazine hydrochloride-morphine sulfate incomsome degree of opioid tolerance may be given I to I 0 mg Morphine is used for the relief of moderate to severe patibility. Am 1 973; 30: 665. daily. However, dosage requirements may increase pain, especially that associated with cancer, myocardial 1 3 . Vermeire A, et new method to obtain and present complete during treatment and up to 2 0 mg daily may be required infarction, and surgery. In addition to relieving pain, information on the compatibility: study of its validity for eight binary in some patients. mixtures of morphine with drugs frequently used in palliative care. morphine also alleviates the anxiety associated with severe Palliat Med 2002; 16: 41 7-24. For details of doses in children, see p. 94. 1 . pain and it is useful as a hypnotic where sleeplessness is due 14. Nieves-Cordero AL, et a!. Compatibility of narcotic analgesic solutions In acute pulmonary oedema 5 t o I 0 mg may b e given to pain. It is also used in the management of neonatal with various antibiotics during simulated Y-site injection. Am J Hasp by intravenous injection at a rate of 2 mg/minute; half this abstinence syndrome (see Administration in Children, Pharm 1 985; 42: 1 1 08-9. dose should be used in elderly or debilitated patients. p. 94. 1 ) . For the control of intractable cough associated with Morphine reduces intestinal motility but its role, i f any, Stability. INTRAVENOUS PREPARATIONS. Solutions of morphine terminal lung cancer, morphine oral solution is given in an in the symptomatic treatment of diarrhoea is very limited. It sulfate for intravenous infusion appear to be relatively initial dose of 5 mg every 4 hours. also relieves dyspnoea associated with various conditions, stable. In a study1 solutions containing 40 micrograms/mL As a deterrent to abuse a combined oral preparation of including that due to pulmonary oedema resulting from left or 400 micrograms/mL retained more than 90% of their morphine sulfate and naltrexone hydrochloride is available ventricular failure. It is an effective cough suppressant, but initial concentration of morphine sulfate when stored at 4 in some countries. codeine is usually preferred as there is less risk of degrees or 23 degrees for 7 days, whether or not they dependence; morphine may however be necessary to 1 were protected from light. Solutions prepared from com­ Administration. CONTINUOUS INFUSION. B oth acute and control intractable cough associated with terminal lung mercially available injection or from powder, in 0.9% sod­ chronic pain have been controlled satisfactorily by contin­ cancer. Morphine has been used pre-operatively as an ium chloride or 5% glucose, and stored in PVC bags or uous intravenous or subcutaneous infusions of morphine adjunct to anaesthesia for pain relief and to allay anxiety. It glass bottles did not differ in stability from one another. In sulfate 1•3 but diamorphine hydrochloride or hydromor­ has also been used in high doses as a general anaesthetic in a further study' 10 mg/mL or 5 mg/mL solutions of mor­ phone hydrochloride may be preferred for subcutaneous specialised procedures such as open-heart surgery. phine sulfate in glucose or sodium chloride and stored in infusion because their greater solubility in water allows a Morphine is usually administered as the sulfate, portable infusion pump cassettes retained more than 9 5 % smaller dose volume. Continuous subcutaneous infusions although the hydrochloride and the tartrate are used in o f their initial concentration when kept a t 2 3 degrees for may be preferred to continuous intravenous infusions.4 the salts. Dosage routes similar doses. Doses are expressed as 30 days. A 0. 9% solution of sodium chloride containing Continuous subcutaneous infusion may be less effective include the oral, subcutaneous, intramuscular, intravenous, morphine sulfate 2 mg/mL was stable for 6 weeks when than epidural morphine for relief of postoperative pain; 5 stored in polypropylene syringes at ambient temperatures 1 intraspinal, and rectal routes. Subcutaneous injections are however, it was still considered to provide simple and rela­ considered unsuitable for oedematous patients. Parenteral in the light or dark but a similar solution that also con­ tively effective analgesia with a low rate of adverse effects. doses may be intermittent injections or continuous or tained 0. 1 % sodium metabisulfite lost 1 5 % of its potency See also Patient-controlled Analgesia, p . 94. 1 . intermittent infusions adjusted according to individual during the same period.3 Stability of such a solution with analgesic requirements. 1 . Waldmann CS, et al. Serum morphine levels: a comparison between or without sodium metabisulfite was considered to be continuous subcutaneous infusion and continuous intravenous infusion Doses should generally be reduced in the elderly or unacceptable when stored in glass syringes in the dark 4 in postoperative patients. Anaesthesia 1 984; 39: 768-7 1 . debilitated, or in patients with hepatic or renal impairment A later review' (which included some of the above 2 . Goudie TA, et al. Continuous mbcutaneous infusion of morphine for (see also under Precautions, p. 9 5 . 1 and p. 9 5 . 2 ) . studies) has concluded that the degradation of morphine postoperative pain relief. Anaesthesia 1 985; 40: 1 086-92. 3. Stuart GJ, et at. Continuous intravenous morphine infusions for For pain: solutions is not affected by oxygen, light, diluent type, salt terminal pain control: a retrospective review. DruH Intel! Clin Pharm • Oral doses are usually equivalent to 5 to 20 mg every 4 form, or morphine concentration when stored under 1 986; 20: 968-72. hours and may be given as an aqueous solution of the normal conditions; it was considered that morphine 4. Drexel H. Long-term continuous subcutaneous and intravenous opioid hydrochloride or sulfate, as modified-release granules or solutions could be stored for at least 3 months without infusions. Lancet 1 9 9 1 ; 337: 979. 5. Hindsholm KB, et al. Continuous subcutaneous infusion of morphine­ tablets, or as immediate-release tablets. With modified- 1 stability problems. an alternative to extradural morphine for postoperative pain relief. Br J release preparations the 24-hour dose is usually given as ' l. Vecchio M, et al. The stability of morphine intravenous infusion Anaesth 1 993; 71: 580-2. a single dose or in 2 divided doses; in the USA, a solutions. Can J Hasp Pharm 1 988; 41: 5-9, 43. 2 . Walker SE, et al. Hydromorphone and INTRA-ARTICULAR ROUTE. Intra-articular injection of morphine modified-release preparation (MS Cantin, Purdue) that infusion pump cassettes and minibags. into the knee at the end of arthroscopy has been reported allows dosing every 8 or 12 hours is also available. With 82. to provide some degree of postoperative pain relief; U such all modified-release preparations, additional doses of a 3 . Grassby PF. The of morphine sulphate in 0.9 per cent sodium pain relief may be more pronounced than that produced chloride stored in Pharm J 1 9 9 1 ; 248: HS24-HS25. conventional formulation may be needed if breakFluorouracil-immediate precipitate formed after admixture of fluorouracil 1 or 16 mg/mL with morphine sulfate I mg/mL in dextrose 5% or sodium chloride 0 . 9 %

4.

Grassby PF, Hutchings L. Factors affecting the physical and chemical stability of morphine sulphate solutions stored in syringes. Jnt J Pharm

Pract 1 993; 2: 39-43.

Uses and Administration

The symbol t denotes a preparation no longer actively marketed

The symbol

Q9 denotes a substance whose use may be restricted in certain sports (see p. viii)

94 by the same dose given intravenously1 or intramuscu­ larly -' The effect appears to be due to the action of mor­ phine on peripheral opioid receptors2 although a systemic effect has not been completely excluded 1 There have been conflicting results on whether addition of morphine to intra-articular bupivacaine improves analgesia3A and a systematic review5 concluded that from the few well-controlled studies there was no evidence of an added analgesic effect of morphine compared with saline alone. Doses of morphine reported to have been injected intra­ articularly have ranged from 1 to 10 mg. I. Gupta A, et a!. A systematic review of the peripheral analgesic effects of intraarticular morphine. Anesth Analg 2 0 0 1 ; 93: 76 1-70. 2 . Raj R et al. Comparison of the analgesic efficacy and plasma concentrations of high-dose intra-articular and intramuscular morphine for knee arthroscopy. Eur J Anaesthesiol 2004; 2 1 : 932-7. 3 . Laurent SC, et al. Addition of morphine to intra-articular bupivacaine does not improve analgesia after day-case arthroscopy. Br J Anaesth 1 9 94; 72: 1 70-3. 4. Heine MF, et a!. Intra-articular morphine after arthroscopic knee operation. Br J Anaesth 1 994; 73: 4 1 3 - 1 5 . 5 . Rosseland L A . No evidence f o r analgesic effect of intra-articular morphine after knee arthroscopy: a qualitative systematic review. Reg Anesth Pain Med 2005; 30: 83-98.

INTRANASAL ROUTE. An intranasal formulation of morphine has been investigated for the relief of acute pain. INTRASPINAL ROUTE. Morphine is given epidurally and intrathecally to relieve both acute and chronic pain. How­ ever, reviews on the role of spinal opioids have generally concluded that they should be reserved for pain not con­ trolled by more conventional routes. 1 ·3 When converting from conventional routes it has been suggested that 1 % of the total daily dose could be tried as the daily intrathecal dose and 1 0 % as the epidural dose.3 Conversion from intrathecal to oral dosage has also been investigated.4 Intrathecal morphine may be delivered continuously via an implanted programmable infusion pump for the long­ term management of chronic non-malignant and cancer pain. See also Patient-controlled Analgesia, below. Anonymous. Spinal opiates revisited. Lancet 1 986; i: 6 5 5-6. 2 . Gustafsson LL, Wiesenfeld-Hallin Z . Spinal opioid analgesia: a critical update. Drugs 1 988; 35: 597-603. 3 . McQuay HJ. Opioids in chronic pain. Br J Anaesth 1 989; 63: 2 1 3-2 6. 4. Sylvester RK, et al. The conversion challenge: from intrathecal to oral morphine. Am J Hasp Pallial Care 2004; 2 1 : 143-7. I.

PATIENT-CONTROLLED ANALGESIA. Morphine is one of the most frequently used opioid analgesics for patient-controlled analgesia (see p. 5 . 3 ) . Most experience has been with the intravenous route, but the intramuscular, subcutaneous, oral, pulmonary, and epidural' routes have also been used. Reasonable initial settings recommended for intra­ venous use have been a demand dose of I to 2 mg of mor­ phine sulfate (or its equivalent) and a lockout interval of 5 to IO minutes.2 1. SjOstrOm S, et al. Patient-controlled analgesia with extradural morphine or pethidine. Br J Anaesth 1 988; 60: 3 5 8-66. 2 . Grass JA. Patient-controlled analgesia. Anesth Analg 2005; 101 (suppl): $44-5 6 1 .

PULMONARY ROUTE. F o r reference to the u s e of nebulised morphine see Dyspnoea, below. TOPICAL ROUTE. Morphine has been applied topically for local analgesia in oral mucositis1,2 and cutaneous ulcer­ ation3-6 including epidermolysis bullosa.7 1.

2. 3. 4. 5. 6. 7.

Cerchietti LC. et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2000; 95: 22 30-6. Correction. ibid. 2003; 97: 1 1 37. Cerchietti L. Morphine mouthwashes for painful mucositis. Support Care Cancer 2007; 1 5 : 1 1 5- 1 6 . Twillman R K , e t a l . Treatment of painful skin ulcers with topical opioids. J Pain Symptom Manage 1 999; 17: 288-92. Krajnik M, et al. Potential uses of topical opioids in palliative care-report of 6 cases. Pain 1 999; 80: 1 2 1-5. Zeppetella G, et al. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage 2003; 2 5 : 5 5 5-8. Zeppetella G, Ribeiro MDC. Morphine in Intrasite gel applied topically to painful ulcers. J Pain Symptom Manage 2005; 29: 1 1 8- 1 9 . Watterson G , et a!. Peripheral opioids i n inflammatory pain. Arch Dis Child 2004; 89: 679-8 1 .

Administration in children.

Opioid analgesics are used in children in the management of moderate to severe pain (see p. 5 . 2 ) ; morphine is the most widely used opioid for severe pain in children and is the standard against which other opioids are compared. Morphine may be given to children requiring acute analgesia as a result of surgery or invasive procedures. It may also be given for chronic non-malignant pain and is the opioid of choice for the oral treatment of severe pain in palliative care. Its analgesic and sedative properties are useful in the management of children in intensive care (see p. 1 03 3 . 1 ) ; morphine is considered to be a more rational choice than fentanyl in settings where long�term infusions are required. Respir� atory depression with morphine treatment is a risk in all children; however, neonates ( and particularly those who are breathing spontaneously) may have an enhanced sus� ceptibility because of the pharmacokinetic differences of morphine in this age group (see p. 96.2 ) . All cross-references refer t o entries i n Volume A

The following initial doses are recommended by the

BNFC according to age; doses should thereafter be adjusted according to response:

By subcutaneous injection: • •

neonates: 1 00 micrograms/kg every 6 hours 1 to 6 months: 1 00 to 200 micrograms/kg every 6 hours • 6 months to 2 years: 1 0 0 to 200 micrograms/kg every 4 hours • 2 to 12 years: 200 micrograms/kg every 4 hours • 12 to 18 years: 2 . 5 to 1 0 mg every 4 hours By intravenous injection over at least 5 minutes: • neonates: 50 micrograms/kg every 6 hours • 1 to 6 months: 1 00 micrograms/kg every 6 hours • 6 months to 12 years: 1 00 micrograms/kg every 4 hours • 12 to 18 years: 5 mg every 4 hours The following doses given by slow intravenous injection are suggested as loading doses for continuous intravenous infusion: • neonates: 5 0 micrograms/kg • 1 month to 12 years: 1 00 micrograms/kg • 12 to 18 years: 5 mg The loading dose may be followed by an infusion given as follows: • neonates: 5 to 20 micrograms/kg per hour • 1 to 6 months: 10 to 3 0 micrograms/kg per hour • 6 months to 18 years: 2 0 to 30 micrograms/kg per hour

By mouth or rectum: • •

1 to 3 months: 50 to 1 00 micrograms/kg every 4 hours 3 to 6 months: 1 00 to 1 5 0 micrograms/kg every 4 hours • 6 to 12 months: 200 micrograms/kg every 4 hours • 1 to 12 years: 200 to 300 micrograms/kg every 4 hours • 12 to 18 years: 5 to 10 mg every 4 hours In palliative care, modified-release oral preparations may be used; they are given as a single daily dose or in 2 divided doses.

By continuous subcutaneous infusion: • •

1 to 3 months: 10 micrograms/kg per hour 3 months to 18 years: 2 0 micrograms/kg per hour Intraspinal doses of morphine that have been tried1 in children are as follows: • caudal epidural block, 1 00 micrograms/kg • thoracic or lumbar epidural block, 5 0 micrograms/kg • intrathecal doses of 20 or 3 0 micrograms/kg have provided satisfactory postoperative pain relief, but respiratory depression occurred in 10 and 2 5 % , respectively Guidelines2 for analgesia in children in Accident and Emergency departments in the UK recommend the use of intravenous morphine as an alternative to, or after initial treatment with, intranasal diamorphine for severe pain such as that associated with large burns, long bone fracture or dislocation, appendicitis, or sickle�cell crisis, but it should be used with caution if there is risk of depression of airway, breathing, or circulation. In the UK, morphine is also used in the management of neonatal abstinence syndrome (p. 1 1 0 . 1 ) under specialist supervision. The BNFC recommends an initial oral dose of 40 micrograms/kg (increase dose if necessary) every 4 hours until symptoms are controlled; the dosage frequency should be reduced gradually over 6 to 10 days until a dose of 40 micrograms/kg once daily is achieved after which the drug should be stopped. 1. Lloyd-Thomas AR. Pain management in paediatric patients. Br J Anaesth 1 990; 64: 85-104. 2 . The College of Emergency Medicine. Best practice guideline: manage­ ment of pain in children (issued July 2 0 1 3 ) . Available at: http://secure. collemergencym e d . a c . u k/asp/document.asp?ID""4682 (accessed l l ! l2 / 1 3 )

Cancer pain.

Morphine is the opioid of choice f o r moder­ ate to severe cancer pain (p. 7 . 1 ) ; guidelines for its use issued by the European Association for Palliative Care1 include: • the optimal route for use is orally. For best effect, both immediate -release (for dose titration) and modified­ release (for maintenance) dosage forms are required • the simplest method of dose titration is with immediate­ release morphine dosage every 4 hours, and the same dose for breakthrough pain. This 'rescue dose' may be given as often as required, up to hourly. The total daily dose of morphine should be reviewed each day and the regular dose adjusted to take into account the amount needed for breakthrough pain • if pain returns consistently before the next dose is due the regular dose should be increased. Immediate-release formulations do not generally need to be given more often than every 4 hours, and modified-release products should be given according to the intended duration of the preparation (usually every 12 or 24 hours ) . Patients stabilised on regular oral morphine require continued access to a rescue dose for breakthrough pain • if an immediate-release formulation of morphine is not available and treatment is started with modified-release

morphine, changes to the regular dose should not be made more often than every 48 hours, which means that dose titration will be prolonged • for patients taking immediate-release morphine pre­ parations every 4 hours, a double dose at bedtime is effective to prevent pain disturbing sleep • if patients are unable to take morphine orally the preferred alternative route is subcutaneous. There is no indication for intramuscular morphine for cancer pain since subcutaneous dosage is simpler and less painful • when converting dosage, the relative potency of oral to subcutaneous morphine is between about 1 :2 and 1 : 3, so 20 to 30 mg of oral morphine is equianalgesic to 1 0 mg by subcutaneous injection • in patients who need continuous parenteral morphine the preferred route is by subcutaneous infusion. However, intravenous infusion may be preferred: in patients who already have an indwelling intravenous line in those with generalised oedema if erythema, soreness, or sterile abscess develop during subcutaneous dosage in patients with coagulation disorders where peripheral circulation is poor • when converting dosage, the relative potency of oral to intravenous morphine is also between about 1 :2 and 1 : 3 • the buccal, sublingual, and nebulised routes o f administration are not recommended i n the absence of evidence for clinical advantage over more usual routes • a small proportion of patients develop intolerable adverse effects with oral morphine (with adjuvant non-opioid analgesics as appropriate) before achieving adequate pain relief. In such patients a change to an alternative opioid, or a change in the route should be considered. Although switching between opioids complicates pain management, adequate pain relief for some may depend on the use of alternative drugs, the use of intraspinal routes, or non-drug methods of pain control Similar recommendations are given in guidelines issued by the US National Comprehensive Cancer Network 2 l.

2.

Hanks GW, et al. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 200 I; 84: 587-9 3 . National Comprehensive Cancer Network. Clinical practice guidelines in oncology: adult cancer pain (version 1 . 2 0 1 0 ) . Available at: http:/lwww. nccn.org/profcssionals/physician_gls/PDF/pain .pdf (accessed 02/08/l 0)

Dyspnoea. in the treatment of dyspnoea (p. 1 08 . 3 ) , doses of morphine tend to be smaller than those used for pain relief. Morphine hydrochloride or sulfate may be given as an oral solution in carefully titrated doses, starting at a dose of 5 mg every 4 hours; as little as 2 . 5 mg every 4 hours may be sufficient for opioid-naive patients. 1 In acute pulmonary oedema, 5 to 10 mg may be given by slow intravenous injection. In patients aJready receiving morphine for pain relief the following doses have been suggested:2 • mild dyspnoea: 2 5 to 50% of usual analgesic dose • moderate dyspnoea: 5 0 to 100% of usual analgesic dose • severe dyspnoea: I 00% or more of usual analgesic dose Patients have also obtained relief from subcutaneous inj ection. 3 Although it has been reported that a low dose of nebulised morphine (mean dose 1. 7 mg) improved exercise endurance in patients with dyspnoea due to advanced chronic lung disease,4 several subsequent studies5·7 have failed to obtain significant improvements with doses up to 40 mg. It is considered that current evidence does not support the use of nebulised morphine for breathless­ ness. l,S-IO Furthermore, bronchospasm can be a problem, particularly at high doses, and there is no consensus on the optimal dose, schedule, or method of dose titration. 1.

2. 3. 4.

5.

6. 7.

8.

9. I 0.

Davis C, Percy G. Breathlessness, cough, and other respiratory problems. In: Fallon M, Hanks G, eds. ABC ofpalliative care. 2nd ed. London: BMJ Publishing Group, 2006: 1 3-16. Twycross R, Wilcock A. Palliah've Care Fonnulary. 3 rd ed. Nottingham, Palliativedrugs.com Ltd, 2007: 280. Bruera E, et al. Subcutaneous morphine for dyspnea in cancer patients. Ann Intern Med 1 993; 119: 906-7. Young m, et al. Effect of low dose nebulised morphine on exercise endurance in patients with chronic lung disease. Thorax 1 989; 44: 38790. Beauford W, et al. Effects of nebulized morphine sulfate on the exercise tolerance of the ventilatory limited COPD patients. Chest 1 9 9 3 ; 104: 1758. Noseda A, et a l . Disabling dyspnoea in patients with advanced disease: lack of effect of nebulized morphine. Eur Respir J 1 997; 10: 1 079-83. Jankelson D, et al. Lack of effect of high doses of inhaled morphine on exercise endurance in chronic obstructive pulmonary disease. Bur Respir J 1 997; 10: 2270-4. Polosa R, et al. Nebulised morphine for severe interstitial lung disease. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2002 (accessed 26/06/08). Fora! PA, et al. Nebulized opioids use in COPD. Chest 2004; 1 2 5 : 691-4. Brown SJ, et al. Nebulized morphine for relief of dyspnea due to chronic lung disease. Ann Phannacother 2005; 39: 1 088-92.

�P.��.c!e.'!�� - c:J'!c! "'Yi.'�.c!r.c:J':Y?.'..

.. As for Opioid Analgesics, p . 109 . 1 .

avoided or the dose reduced because of the risk of precipi­ tating a coma. However, it has also been noted that many patients with hepatic impairment tolerate morphine well. Others have considered that severe hepatic impairment may affect morphine metabolism but less severe impair­ ment does not. 1 The mean elimination half-life of morphine in 1 2 patients with cirrhosis was almost twice that i n 1 0 healthy subjects after administration of a modified-release oral morphine preparation (MST-Continus; Napp, UK) and peak serum concentrations were almost three times as high. 2 Patients with cirrhosis had a greater degree of sedation but As for Opioid Analgesics in general, p. 1 1 0 . 1 . none developed encephalopathy. It was recommended that the dose for modified-release preparations should be References. 1. Cherny N, et at. Strategies to manage the adverse effects of oral reduced and that it be given less often when patients have morphine: an evidence-based report. J Clin Oncol 200 1 ; 19: 2542-54. cirrhosis. In a later study3 1 5 patients with liver cancer were given Effects on the cardiovascular system. For a reference to the same oral morphine preparation and compared with I 0 the effects of morphine on histamine release compared healthy subjects from the previous study; the area under the with some other opioids, see under Pethidine, p. 1 2 2 . 3 . ; serum concentration-time curve of morphine was increased three- to fourfold in those with cancer. The elimination Effects on the muscles. Severe rectovaginal spasms that half-life of morphine was also prolonged in patients with occurred in a patient given intrathecal morphine1 were primary cancer when compared with healthy subjects and successfully controlled with midazolam. those with secondary metastatic disease. Adverse effects I. Littrell RA, et a!. Muscle spasms associated with intrathecal morphine were more frequent in the primary cancer group and therapy: treatment with midazolam. Clin Pharm 1 992; 11: 57-9. included 2 cases of respiratory depression; the authors Effects on the nervous system. Myoclonus, often asso­ commented that altered blood-brain transportation may have been partly responsible for such effects. ciated with hyperalgesia, has been reported in patients I. Twycross R, Wilcock A. Palliative Care Formulary. 3rd ed. Nottingham, with advanced malignant disease treated with mor­ Palliativedrugs.com Ltd, 2007: 274. phine. 1 ·5 It appears to be uncommon with typical oral 2 . Kotb HIM, et al. Pharmacokinetics of controlled release morphine {MST) doses of morphine and is more often associated with high in patients with liver cirrhosis. Br J Anaesth 1 997; 79: 804-6. 3. Kotb HIM, et at. Pharmacokinetics of controlled release morphine (MST) intravenous and spinal doses. Neuroexcitatory metabolites in patients with liver carcinoma. Br J Anaesth 2005; 94: 95-9. of morphine are often implicated in the development of myoclonus;2A5 however, other possible mechanisms such as drug interactions cannot be ruled out.4·6 Phaeochromocytoma. Morphine and some other opioids It has been reported that myoclonus induced by can induce the release of endogenous histamine and morphine can be successfully controlled using a benzodia­ thereby stimulate catecholamine release making them zepine such as midazo]am.7 Indeed, some researchers8 unsuitable for use in patients with phaeochromocytoma. consider benzodiazepines to be the drugs of choice: For further details, see p. 1 1 1 . 2 . clonazepam, diazepam, and lorazepam were most fre­ quently used. Dantrolene5•8 and gabapentin9 have also been Porphyria. The Drug Database for Acute Porphyria, com­ tried. piled by the Norwegian Porphyria Centre (NAP O S ) and 1. Potter JM. et al. Myoclonus associated with treatment with high doses of the Porphyria Centre Sweden, classifies morphine as not morphine: the role of supplemental drugs. BMJ 1 989; 299: 1 50-3. 2. Glare PA, et al. Nonnorphine, a neurotoxic metabolite? Lancet 1 990; 335: porphyrinogenic; it may be used as a drug of first choice 72 5-6. and no precautions are needed . 1 D ependence associated with morphine and closely related 11-agonists appears to result in more severe withdrawal symptoms than that associated with K-receptor agonists. With morphine, withdrawal symptoms usually begin within a few hours, reach a peak within 36 to 72 hours, and then gradually subside. Morphine is used for substitution therapy in the management of neonatal abstinence syndrome (see Administration in Children, p. 94. 1 ) .

Adverse Effects and Treatment

3.

4. 5. 6. 7.

8. 9.

De Conno F, et a!. Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine. Pain 1 992; 47: 3 3 7-9. Sjogren P, et a!. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993; 55: 93-7. Mercadante S. Pathophysiology and treatment of opioid-related myoclonus in cancer patient�. Pain 1 998; 74: 5-9. Quinn N. Myoclonus associated with high doses of morphine. BMJ 1 989; 299: 683--4. Holdsworth MT. et al. Continuous midazolam infusion for the management of morphine-induced myoclonu�. Ann Pharmacother 1 9 9 5 ; 29: 25-9. Ferris OJ. Controlling myoclonus after high-dosage morphine infusions. Am J Health-Syst Pharm 1999; 56: 1 00 9-1 0 . Mercadante S, et a l . Gilbapentin f o r opioid-related myoclonus i n cancer patients. Support Care Cancer 200 1 ; 9: 205-6.

Precautions As for Opioid Analgesics in general, p. 1 1 0 . 3 .

Biliary-tract disorders.

See under Precautions of Opioid

Analgesics, p. 1 1 1 . 1 .

Breast feeding. Measurable blood concentrations o f mor­ phine have been detected in 2 breast-fed infants whose mothers received oral or intrathecal morphine during and after their pregnancies; however, no adverse effects were reported in either of these infants. 1.2 In a group of 7 women given patient-controlled analgesia with intra­ venous morphine after caesarean delivery, the concentra­ tions of morphine and its metabolite morphine-6 glucuro­ nide in the colostrum were found to be very small.3 Although no infants were breast fed during the study, it was considered that the effects of maternal morphine on breast-fed infants would be negligible 3 The American Academy of Pediatrics4 also states that the use of mor­ phine is usually compatible with breast feeding. I.

Robieux I, et al. Morphine excretion in breast milk and resultant exposure of a infant. J Toxicol Clin Toxicol 1 990; 28: 365-70. Prenatal and breast milk morphine exposure Oberlander TF, et following maternal intrathecal morphine treatment. J Hum Lact 2000; 16: 1 37--42. 3 . Baka N-E, et a!. Colostrum morphine concentrations during postcesarean intravenous patient-controlled anillgesia. Anesth Analg 2002; 94: 184-7. 4. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2 0 0 1 ; lOS: 776-89. [Retired May 2 0 1 0 ] Correction. ibid.; 1 029. Also available at: http://aappolicy. aappublication s.org/ cgi I content/full/pediatrics % 3b 1 0 8/3/77 6 (accessed 26/06/08) 2.

Hepatic impairment. In view of its hepatic metabolism, caution is generally advised when giving morphine to patients with hepatic impairment (but see under Pharma­ cokinetics, p. 96 . 3 ) . The BNF advises that use should be

1.

The Drug Database for Acute Porphyria. Available a t : http:ffwwvv. drugs-porphyria.org {accessed 2 2 / 1 0/ l l )

Renal impairment.

Severe and prolonged respiratory depression has occurred in patients with renal impairment given morphine. Toxicity in 3 such patients was attributed to the accumulation of the active metabolite morphine-6glucuronide . 1 Plasma concentrations of this metabolite were found2 to be ten times higher than normal in a 7year-old girl with haemolytic uraemic syndrome given morphine intravenously although the half-life of mor­ phine was also prolonged. Plasma concentrations of mor­ phine-6-glucuronide were also reported3 to be persistently increased 19 days after stopping morphine by intravenous infusion in a 17 -year-old girl with normal renal function. The authors of the report suggested that alterations in bowel flora after antibacterial therapy or inhibition of morphine- 3 - glucuronide glucuronidation by lorazepam might be responsible. It has also been reported4 that accu­ mulation of morphine can occur in renal failure, although to a lesser extent than accumulation of metabolites (see also under Pharmacokinetics, p. 96. 3 ) . Osborne RJ , e t al. Morphine intoxication i n renal failure: the role of morphine-6-glucuronide. BMJ 1 986; 292: I 548-9. HasselstrOm J, et al. Long lasting respiratory depression induced by morphine-6-glucuronide? Br J Clin Pharmacol 1 989; 27: 5 1 5- 1 8 . 3 . Calleja MA, et a l . Persistently increased morphine-6-glucuronide concentrations. Br J Anaesth 1 990; 64: 649. 4. Osborne R, et al. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1 993; 54: 1 5 8-67. 1.

2.

Interactions For interactions associated with opioid analgesics, see p. 1 1 1 . 2 . US licensed product information for some once-daily modified-release preparations of morphine sulfate states that patients must not ingest alcohol. including alcohol­ containing medicines, at the same time due to the risk of rapid release and absorption of a potentially fatal dose of morphine; in-vitro studies showed that alcohol accelerated the release of morphine. For references to myoclonus associated with morphine and the concurrent use of other drugs, see Effects on the Nervous System under Adverse Effects, above.

Antibacterials.

Potent enzyme inducer rifampicin can reduce the serum concentration of morphine and decrease its analgesic effect;1 induction of the enzymes responsible

for conversion of morphine to the active glucuronide metabolite did not seem to occur. 1.

Fromm M.F, et at. Los� of analgesic effect of morphine due to coadministration of rifampin. Pain 1997; 72: 26 1-7.

Benzodiazepines. An additive sedative effect is to be expected between opioid analgesics and benzodiazepines and has been reported with morphine and midazolam. 1 For reference to a suggestion that lorazepam may inhibit morphin e - 3 - glucuronide glucuronidation, see Renal Impairment under Precautions, above. I.

et a!. Midazolam-morphine sedative interaction in patients.

1 989; 68: 282-5.

Cisapride. Plasma concentrations of morphine have been increased by oral cisapride. 1

L Rowbotham OJ, et at. Effect of cisapride on morphine absorption after owl administration of sustained-release morphine. Br J Anaesth 1 9 9 1 ; 6 7 : 42 I-5.

Histamine H2·antagonists.

See under Opioid Analgesics,

p. 1 1 1 . 3 .

Local anaesthetics. Prior u s e o f epidural chloroprocaine, when compared with lidocaine, has been reported to reduce the duration1 and efficacy2 of epidural morphine analgesia. However, a later study3 found no such effects; the authors suggested that findings from the previous 2 studies were due to breakthrough pain caused by the early resolution of chloroprocaine anaesthesia occurring before the maximum onset of morphine analgesia.

L Eisenach JC, et al. Effect of prior anesthetic solution on epidurn!

morphine analgesia. Anesth Analg 1 9 9 1 ; 73: 1 1 9-2 3 . antagonism of Karambelkar OJ, Ramanathan S. epidural morphine analgesiil. 1 997; 41: 774-8. 3 . Hess PE, et al. Chloroprocaine may not affect epidurill morphine for postcesarean delivery analgesia. J Clin Anesth 2006; 18: 29-33 .

2.

Metoclopramide. The effects of metoclopramide on mor­ phine have included an increased rate of onset and degree of sedation when oral metoclopramide was given with modified-release morphine1 and antagonism of the effects of morphine on gastric emptying by intravenous metoda� pramide.2 I. Manara AR, etal. The effect of metoclopramide on the absorption of oral controlled release morphine. Br J Clin Pharmacol 1 988; 25: 5 1 8-2 1 . 2 . McNeill l'vU, et al. Effect o f i v metoclopramide o n gastric emptying after opioid premedication. Br J Anaesth 1 990; 64: 450-2.

Tricyclic antidepressants.

Both clomipramine and amitripty­ line significantly increased the plasma availability of mor­

phine when given to cancer patients taking oral nwrphine solution. 1 It was noted however that the potentiation of the analgesic ef!ects of morphine by these drugs might not be confined to increased bioavailability of morphine; the dose of tricyclic to use vvith morphine in the treatment of cancer pain should be decided by clinical evaluation rather than by pharmacokinetic data. I.

Ventafridda V, eta!. Antidepressic elficacy and safety of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution tor ocular pain and photophobia after excimer laser surgery: a phase II, randomized, double-ma�ked trial. Clin 28: 527-3 6. 2 . Lane SS. Nepafenac: a unique nonsteroidal prodrug. 2006; 46: 1 3-20. 3 . Lane SS, et al. Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract smgery. J Cataract Refract Surg 2007; 33: 53-8. Correction. ibid.;

ATC� M91AX02/ M02AA II.

ATeVet.'-'- QM[f.II'fX();z; 0/f{(OZAAI;t, UN!I c:• 4U�MP$IU/J8.

Pharmacopoeias. In Bur. (see p . vii ) . Eur. 8: (Niflumic Acid) . A pale yellow, crystalline powder. Practically insoluble in water; soluble in alcohol and in methyl alcohol; freely soluble in acetone.

Ph.

564.

.. . . . . .

Uses and Administration

Proprietary Preparations (details are given in Volume B)

Niflumic add, a nicotinic acid derivative, is an NSAID Arg.: Nevanac; Braz.: Nevanac; (p. 1 02 . 3 ) . It has been used in infla mmatory and Canad.: Nevanac; Chile: Nevanac; Cz. : Nevanac; Denm.: Neva­ musculoskeletal and joint disorders in usual oral doses of nac; Gr.: Nevanac; India: Nevanac; Irl. : Nevanac; Israel: Neva­ about 2 5 0 mg three or four times daily; up to 1 5 00 mg daily , nac; Jpn: Nevanac; Malaysia: Nevanac; Mex. : Nevanac; Neth.: Nevanac; Norw.: Nevanac; NZ: Nevanac; Philipp.: Nevanac; ' has been used in severe disorders. It has also been used Pol. : Nevanac; Port.: Nevanac; Singapore: Nevanac; Spain: topically as a 3% ointment or 2 . 5 % gel. The morpholi­ Nevanac; Swed. : Nevanac; Switz.: Nevanac; Thai.: Nevanac; noethyl ester, momiflumate (p. 92 . 2 ) , has similar uses. Turk.: Nevanac; UK: Nevanac; USA: Ilevro; Nevanac. Niflumic acid glycinamide has been used topically in

Single-ingredient Preparations.

inflammatory mouth disorders.

Adverse Effects,. . .Treatment, and Precautions .. . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . .

Nicoboxil (r!NN)

Nicoboxlium; HMK66oKButoxyethyl N icotinate; Nicoboxilo: ·. ·

As for NSAIDs in general, p. 1 04 . 3 . Fluoride-associated osteosis h a s been reported with prolonged use. Niflumic acid should be stopped if hypersensitivity skin reactions appear.

·

2-Buto�yethyl nicotinate.

r;;�naT. 4.5o-Epoxy-1 4·hydroxy-3-methoxy-1.7-mett\)itmorpi'if�a,·6· one 1,4-benzenedicarboxylate (2: 1 J salt. K1oHnNQ;h,C,H,O.i"'796.9 .

0\,$ 6433!)-55-6. UN!! - M04XWV43UF.

Pharmacopoeias. In US.

Pharmacokinetics

USP 36: ( Oxycodone Terephthalate ) . containers.

References. l.

Karim A. Inverse nonlinear pharmacokinetics of total and protein unbound drug ( oxaprozin) : clinical and phannacokinetic implications. J

Clin Pharmacol l 996; 36: 985-97. 2.

Karim A, et al. Oxaprozin and piroxicam, nonsteroidal antiinflammatory dmgs with long half-lives:

effect of protein-binding differences on

steady-state pharmacokinetics. J Clin PhamJacol l 997; 37: 267-78.

1.

Davies NM. Clinical pharmacokinetics of oxaprozin. Clin PhamJacokinet

1 998; 35: 425-36.

P repa rations

Proprietary Preparations (details are given in Volume B) Chile: Duraproxt; Walix; China: Ao Ke Qing (�.£7-ti); Ao Pu Xin (�i!l'/iX); Lu Ming Ao Xin (f!-fi)J�/iX); Nuo Bi Song (ur"' t..:): Nuo De Lun (i.l'i�tfl;); Nuosong (ll'iM); Cz. : Dayrunt; Gr.: Duraprox; Misaf; Nisaid; Oxapron; Trimelot; Ital. : Walix; Jpn: Alvo; S.Afr. : Deflamt; Turk. : Duraprox; USA: Daypro.

Single-ingredient Preparafions. Be/g. : Duraprox; Canad.: Daypro;

Pharmacopoeial Preparafions USP 36: Oxaprozin Tablets.

Oxycodone

(BAN, USAN, r/NN) 0

DH1ydrohe; 14-Hydrpxydihydro�n6y1'a30H. 3.5·didne. 4-tlutyl· l .:Hliphenyipyrazoildine· . C:qH](JN202od30l!.4

l.

i

Multi-ingredient Preparations.

Phenylbutazone {BAN, r/NN)

P.r.�P.�.r) ; USA: Feldene; Venez. : chloride. Feldene; Feldenedi; Flamalit; Maxipiro; Pixorid.

Profile

Berl V, et al. Mechanism of allergic contact dermatitis from propacetamol: sensitization to activated N,N-diethylglycine. Contad Dermatitis I 998; 38: 1 8 5-8. 5. Hersch M, et al. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy 2008; 28: I205-IO.

4.

Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies propacetamol as probably not porphyrinogenic; it may be used as a drug of first choice and no precautions are needed. 1 I.

The Drug Database for Acute Porphyria. Available at: http:l/www. drugs-porphyria.org (accessed II ! 1 0 / 1 1 )

P.r.epa rations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . .

Proprietary Preparations (details are given in Volume B) Single�ingredient Preparations. Gr. : Pro-Dafalgant; Mex. : Tern�

pra.

Prepa ra ti ons

Multi-ingredient Preparations. Arg.: Buta Rut B l 2; Flexicamin A;

Flexicamin B l 2; Flexicamin B l 2; Flexicamin; Flogiatrin B l 2; Flogiatrin B l 2; Flogiatrin; Peganix; Rumisedan Fuerte; Rumise� dan; Solocalm Plus; Solocalm Plus; Solocalm�B; Solocalm�Flex; Braz. : Rheumafim; India: Capsidal; Indon.: Counterpain�PXM; Thai. : Counterpain Plus.

Pharmacopoeial Preparafions

¢eH.

Pranoprofenum; flpaHonpo­

C,5H,,N03S255.3 C4S - 5254!/-17-4. ATC - SOIBC09. ATC Vet - QS01BC09. UN!! �.2Eil07ET613.

a-Methyt-5H-[1 l-benzopyrano[2,3-b]pyridii1,.7-acetic acid.

Pharmacopoeias. In Jpn.

Profile Pranoprofen, a propionic acid derivative, is an NSAID (p. 1 0 2 . 3 ) . It is used as eye drops in a concentration of 0. 1 % for ocular inflammation. Pranoprofen has also been given orally for the treatment of pain, inflammation, and fever. References. I.

Notivol R. et a!. Treatment of chronic nonbacterial conjunctivitis with a cyclo-oxygenase inhibitor or a corticosteroid. Am J Ophthalmol I 994; l l 7 : 6 5 1-6.

Prepa ra ti ons

Proprietary Preparations (details are given in Volume B) Belg.: Pranox; Braz. : Difen; China: Pranopulin (tf1¥J1�.R.); Gr.: Pranofen; Ital. : Oftalar; Pra� noflog; Jpn: Niflan; Mex. : Niflan; Port.: Oftalart; Spain: Ofta­ lart; Turk.: Oftalar.

Single-ingredient Preparations.

Proglumetacin Maleate (BANM, rtNNMI

Maleato de proglumetacina; Proglumetacina, maleate. de; ProQiumetacine, Maleate de; Proglumetacinum Maleas; Protacine Maleate; npomyMeT31.lvtHa Manear,

CR-604;

The symbol

t

8 : (Propacetamol Hydrochloride ) . A white or almost white crystalline powder. Freely soluble in water; slightly soluble in dehydrated alcohol; practically insoluble in acetone. Protect from moisture.

Profile

Pranoprofen (r!NN)

Pranoprofeno;

Pharmacopoeias. In Bur. (see p. vii ) .

Ph. Eur.

BP 20 14: Piroxicam Capsules; Piroxicam Gel; USP 36: Piroxicam Capsules; Piroxicam Cream.

Pranoprofef1:l. · · ·

�

;

C45 :- 70288-$6-7 (ivem'!ectin): 1182NJ3-7 {component 8;,J; 70209-8L3 (component 81;,!. A TC .....: PG2CFO/. ATC Vet - OP54AA0 1; Q502QA03. i;JNI! - 8883YP2R6D {i\i'ermect(n): 91 Y22020UW Pvermectin mmpo11ent OW28L"'Yt.nu (ivermec.tin component H.Bril

Pharmacopoeias. In Bur. (see p. vii) and US.

Ph. Eur. 8: (Ivermectin ) . A mixture of ivermectin component H 2B 1 , ( 5 - 0-demethyl-22,23-dihydroavermectin A 1 a; C 48H 74 0 t 4 = 87 5 . 1 ) and ivermectin component H2B 1 b ( 5 - 0 - demethyl - 2 5 - d e ( 1 -methylpropyl ) - 2 5 - ( 1 -methy­ lethyl) -22,23-dihydroaverrnectin AI,; c.,Hn0 1 4 = 86 1 . 1 ) . A white or yellowish-white, slightly hygroscopic, crystalline powder. Practically insoluble in water; soluble in alcohol; freely soluble in dichloromethane. Store in airtight containers.

USP 36: (Ivermectin) . A mixture of component H2B 1 , ( 5 -0-

d e m e t h y l - 2 2 , 2 3 - d i h y d r o - a v e r 1n e c t i n A 1 a ; C 48 H 74 0 1 4 = 87 5 . 1 ) and component H 2B 1 b ( 5 -0-demethyl2 5 - d e ( 1 - m ethylpropyl ) - 2 2 , 2 3 - dihydro - 2 5 - ( 1 -methy­ lethyl) -avermectin A 1 ,; C 47H7 2 0 1 4 = 86 1 . 1 ) . It may contain small amounts of suitable antoxidant and chelating agents. A white to yellowish-white, slightly hygroscopic, crystalline powder. Practically insoluble in water and in petroleum spirit; soluble in acetone and in acetonitrile; freely soluble in dichloromethane and in methyl alcohol. Store in airtight containers at a temperature of 2 degrees to 8 degrees. Where the use of an antoxidant is allowed, store at 25 degrees, excursions permitted between 1 5 degrees and 30 degrees.

Uses and Administration Ivermectin is a semisynthetic derivative of one of the avermectins, a group of macrocyclic lactones produced by Streptomyces avermitilis. It has a microfilaricidal action in onchocerciasis and reduces the microfilarial load without the toxicity seen with diethylcarbamazine. Ivermectin also has a microfilaricidal action in lymphatic filariasis and is used in endemic areas as part of a mass treatment regimen. Ivermectin is active in some other worm infections. It is used in the treatment of strongyloidiasis and has been tried in some Mansonella infections. For details of these infections and their treatment, see under Choice of Anthelmintic, p. 1 43 . 1 , The symbol

of serious adverse events in patients with high numbers of microfilaria. Low-dose regimens (about 2 5 micrograms/kg) have been investigated9 but did not seem to offer much advantage in redudng neurotoxicity. 1.

Martin-Prevel Y, et al. Reduction of microfilaraemia with single high­ dose of iverrnectin in loiasis. Lancet 1 993; 342: 442.

2.

Ranque S, et a!. Decreased prevalence and intensity of Loa loa infection

3.

Duong TH, et a!. Reduced Loa loa microfilaria count ten to twelve months after a single dose of ivermectin. Trans R Soc Trop Med Hyg 1 997; 91: 592-3.

4.

Gardon J, et a!. Marked decrease in Loa loa microfilaraemia six and twelve months after a single dose of ivermectin. Trans R Soc Trop Med Hyg

in a community treated with ivermectin every three months for two years. Trans R Soc Trap Med Hyg 1 996; 90: 429-30.

5.

1 997; 91: 5 9 3--4. Chippaux J-P, et al. Impact of repeated large scale iverrnectin treatments

6.

on the transmission of Loa loa. Trans R Soc Trop Med Hyg 1 998; 92: 454--8 . Anonymous. Encephalitis following treatment o f loiasis. WH O Drng In{

7.

1 9 9 1 ; 5: l l 3-14. Gardon J, et al. Serious reactions after mass treatment of onchocerciasis with iverrnectin in an area endemic for Loa loa infection. Lancet 1 997;

350: 1 8-22 . 8.

Bourguinat C, et a!. Analysis o f the mdr- 1 gene in patients co-infected with Onchocerca volvulus and Loa loa who experienced a post-ivermectin serious adverse event. Am J Trap Med Hyg 2 0 1 0;

1 Antimicrob

9.

83: 28--32.

Kamgno J, et at. Randomi7ed, controlled, double-blind trial with iverrnectin on Loa loa microfilaraemia: efficacy of a low dose ( - 2 5

1 Antimicrob

�

g/kg) versus current standard dose ( 1 50

Hyg 2007; 101: 777-85.

1.1

g/kg ) . Trans R Soc Trap Med

Iverrnectin may be given oral­ i. Lymphatic filariasis. Ivermectin is used in the manage­ ment of lymphatic filariasis (p. 146. 3 ) . In endemic areas ly to children weighing more than 1 5 kg and over 5 years mass treatment of the entire population (excluding neo­ of age, for the management of onchocerciasis and lympha­ nates, pregnant women, and debilitated individuals) can tic filariasis and also for the treatment of strongyloidiasis. reduce the intensity of transmission and the incidence of Doses used are the same by weight as those used for adults disease. In countries where there is co-endemic loiasis or (see above ) . onchocerciasis, the Global Programme to Eliminate Lym­ Cutaneous larva migrans, There are some reports 1 •5 of phatic Filariasis launched by WHO, with other interna­ tional agencies, advocates a single oral dose of ivermectin ivermectin being effective in the treatment of cutaneous ! 5 0 to 200 micrograms/kg with a single oral dose of larva migrans (p. 1 44. 3 ) . An oral dose of 200 rnicro­ albendazole 400 mg given once each year for at least 5 grams/kg daily for I to 2 days has been recommended 6 years. l . Caumes E, et al. Efficacy of ivermectin in the therapy of cutaneous larva migrans. Arch Dermatol 1 992; 128: 994-- 5 . Higher doses of albendazole and ivermectin ( 800 mg and 2 . Caumes E, et al. A randomized trial of ivennectin versus albendazole for 400 micrograms/kg respectively) given twice a year for 2 the treatment of cutaneous larva migrans. Am .J Trop Med Hyg 1 993; 49: years, to 25 residents of an area of high Wuchereria bancrofti 641--4. endemicity in Mali, were found to be more effective in 3 . Bouchaud 0, et a!. Cutaneous larva migrans in travelers: a prospective study, with assessment of therapy with ivermectin. Clin lnfed Dis 2000; reducing microfilarial levels than the standard annual dose 31: 493-8. Correction. ibid. 2 0 0 1 ; 32: 5 2 3 . regimen reconunended by WHO . Higher-dose and/or more 4. delMar Semycin oxime),· OS3YPP119C (m'lbemycin A5 5-oxime); 6ZWB94628 (.milbemycin A, 5oxime), oxlme.

Profile

Profile

Uses and Administration

Moxidectin is an anthelmintic used in veterinary medicine. It is also used as a systemic veterinary ectoparasiticide and for the treatment of intestinal roundworms and lungworms. It is under investigation for the treatment of human onchocerciasis.

Niclosamide is an anthelmintic that is active against most tapeworms, including the beef tapeworm ( Taenia saginata) , the pork tapeworm ( T. solium), t h e fish tapeworm (Diphyllobothrium latum) and the dog tapeworm (Dipylidium caninum); it has also been given for infections with the dwarf tapeworm, Hymenolepis nana. For discussions of the treatment of tapeworm infections, see Diphyllobothriasis, p. 1 45 . 1 , Hymenolepiasis, p. 146. 1 , and Taeniasis, p. 148.2. The activity of niclosamide against these worms appears to be due to inhibition of mitochondrial oxidative phosphoryl­ ation; anaerobic ATP production is also affected. Niclosarnide is given as tablets, which must be chewed thoroughly before swallowing and washed down with water. For infections with pork tapeworm a single 2-g dose is given after a light breakfast. Niclosamide is not active against the larval form (cysticerci) and, although the risk of inducing cysticercosis appears to be theoretical, a laxative is given about 2 hours after the dose to expel the killed worms and minimise the possibility of the migration of ova of T. solium into the stomach; an antiemetic may also be given before treatment. For infections with heel or fish tapeworms the 2-g dose of niclosamide may be divided, with l g taken after breakfast and 1 g an hour later. In dwarf-tapeworm infections an initial dose of 2 g has been given on the first day followed by 1 g daily for 6 days. Unless expulsion of the worm is aided by a laxative, portions are voided in a partially digested form after treatment with niclosamide; the scolex is rarely identifiable. For details of doses in children, see p. 1 6 3 . 1 . In schistosomiasis (p. 148. 1 ) , niclosamide i s used a s a molluscicide in water-treatment control programmes.

References. l.

2.

Cotreau MM,

et a!. The antiparasitic moxidectin: safety, tolerability, and

pharmacokinetics in humans. J Clin Pharmacal 2003; 43: 1 1 08-1 5 . Korth-Bradley JM, e t al. Excretion o f moxidectin into breast milk and pharmacokinetics in healthy Chemother 2 0 1 1 ; 55: 5200--4.

Milbemycin oxime is an anthelmintic used in veterinary medicine.

lactating

women.

Naftalofos {BAN, USAN, r!NN)

Morantel (BAN, ptNN) Morame !i; MorraJ10oc. · Qiethyl naphtl;alirnido:Oxyphospho•iate. C,6H16NO;f'=34)t.3 . . .. .

CAS - J491·4f-4. ATC Vee -- QPS2AB06.

. UN/I. -'- HSIT2P$HSI.

Morante! Citrate (BANM, p!NNM!

Profile

teh citrate Citratd de m o rantel; Morante!, Citrate de; Moran · · de; Morariteli Citras; Mopa>nena L\�rTpar.

Naftalofos is an organophosphorus compound (see Organo­ phosphorus Insecticides, p. 2 1 58 . 3 ) used as an anthelmintic in veterinary medicine.

ATC Vet - QP52AF01.

Netobimin (BAN, USAN, r/NN)

The name Exhelm has been used as a trade mark for morantel citrate. NOTE.

Morante! Tartrate (BANM, USAN, p!NNM)

CP-t]OO'i- l!l; Morantee!i�?tyia rtra att� Morante!, hydrogen(K tartrate de; M o ra nte \, Tartrate d and resistance to azithromydn and ceftriaxone in the Indian subcontinent.• A systematic review• of 1 6 studies ( 1 748 subjects) to evaluate the safety and efficacy of antibacterials in the treatment of Shigella dysentery found limited evidence that most of the commonly used antibacterials (ampicillin, co-trimoxazole, nalidixic add, fluoroquinolones, pivmecillinam, ceftriaxone, and azithro­ mydn) reduced diarrhoea and the duration of fever compared with no antibacterial treatment, but insufficient evidence to recommend any specific antibacterial. To accommodate temporal and geographical shifts and antibacterial resistance in Shigella strains around the world, it recommended that empirical therapy should be guided by local or regional antibacterial sensitivity patterns.• Effective antibacterial treatment should lead to symptomatic improvement within the first 48 hours; where this does not occur, the possibility of antibacterial resistance should be considered. 1 Vitamin A may be a useful adjunct to treatment, especially in children in developing countries who are at risk for malnutrition (see Diarrhoea, under Vitamin A, p. 2 1 00. 1 ) .6 Supplemental zinc, which may reduce the incidence and severity of diarrhoea both in the acute period and in the next 2 to 3 months, is also recommended for children up to 5 years of age (see Diarrhoea, under Zinc Sulfate, p. 2 1 2 7 . 2 ) . 1 Oral shigella vaccines are being studied for prophylaxis.

Shigellosis.

1. WHO. Guidelines for the control of shigellosis, including epidemics due shigella dysenteriae type 1. Geneva: WH0,2005. Available at http:/! whqlibdoc.who.int/publications/2005/9241 592330.pdf (accessed 02/09/09) 2. Niyogi SK. Shigellosis. J Microbiol 2005; 43: 133-43. 3. Mensa L, et al. Quinolone resistance among Shigella spp. isolated from travellers returning from India. Clin Microbiol lnfect 2008; 14: 279-81. 4. Sarkar K, e t al. Shigella dysenteriae type I with reduced susceptibility to fluoroquinolones. Lancet 2003; 361: 785. 5. Sur D, et al. Multidrug-resistant Shigella dysenteriae type 1: forerunners of a new epidemic strain in eastern India? Emerg Infect Dis 2003; 9: 404-5. 6. American Academy of Pediatrics. 2012 Red Book: Report ofthe Committee on Infectious Diseases, 29th ed. Elk Grove Village, fllinois, USA: American Academy of Pediatrics, 2012.

to

All cross-references refer to entries in Volume A

7. Boumghar-Bourtchai L. et al. Macrolide-resistant Shigella sonnei. Emerg Infect Dis 2008; 14: 1297-9. 8. Rahman M, et al. Increasing spectrum in antimicrobial resistance of Shigella isolates in Bangladesh: resistance to azithromydn and ceftriaxone and decreased susceptibility to dprofloxacin. J Health Popul Nutr 2007; 25: 158-67. 9. David KV, et al. Antibiotic therapy for Shigella dysentery. Available in The Cochrane Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2010 (accessed 27/04110).

Yersinia enterocolitica is a Gram-negative bacterium of the Enterobacteriaceae family and the species most co=only responsible for yersiniosis. Y. enterocolitica has been isolated in patients worldwide, but the infection appears to occur mainly in cooler climates and in some of these countries it rivals Salmonella and Campylobacter and exceeds Shigella as a cause of acute bacterial gastro-enter­ itis. Pigs are a major reservoir for Y. enterocolitica strains that infect humans and infection is usually transmitted by eating contaminated food, especially raw or undercooked pork products, or drinking contaminated unpasteurised milk or untreated water; transmission through blood transfusion is rare. Infection with Y. enterocolitica occurs most often in young children. Symptoms usually develop 3 to 7 days after exposure and vary depending on the age of the person infected. Common symptoms in children include diarrhoea (which is often bloody), fever and abdominal pain, which last for up to three weeks or longer. Older children and adults can present with right -sided abdominal pain and fever that may be confused with appendicitis. In some patients, complications such as reactive polyarthropathy, erythema nodosum, and life-threatening bacteraemia may develop. Increased susceptibility to Yersinia infection has occurred in patients with iron overload treated with desferrioxamine (see p. ! 54 7 .2 ) . A s with any form o f diarrhoea (p. 1 80 8 . 2 ) , rehydration is the key to treatment and most forms of mild uncomplicated enteritis do not require antibacterials. However, systemic infection and bacteraemia require antibacterial treatment. I Reports of antibacterial suscept­ ibility from different parts of the world indicate that Y. enterocolitica is susceptible to many antimicrobial agents. 1 Drugs with good intracellular activity such as trimethoprim, co-trimoxazole, tetracycline, chloramphenicol, or fluoro­ quinolones may be preferred.2 Doxycycline or co-trim­ oxazole have been recommended' for complicated gastrointestinal and focal extra-intestinal infections or doxycycline and an aminoglycoside empirically in bacteraemia. C o-trimoxazole as first choice or alternatively a fluoroquinolone, an aminoglycoside, or cefotaxime have also been recommended.4 A study1 undertaken in a paediatric hospital in the USA to determine the antibacterial susceptibility pattern of Y. enterocolitica reported that susceptibility patterns of the organism had not changed over the 1 2 -year study period. The most active agents in vitro were cefotaxime, ceftriaxone, cefepime, co-trimoxazole, gentamicin, tobramydn, imipenem, and dprofloxadn; all were also considered to be clinically appropriate. Systemic cefotaxime and ceftriaxone were effective for treating bacteraemia. The majority of isolates were resistant to ampicillin and first-generation cephalosporins. Similar susceptibility patterns were reported in a study conducted in China. ' A patient with chronic Yersinia infection who responded well to tetracycline or co-trimoxazole, but relapsed on withdrawal, was treated successfully with ciprofloxacin. 6

Yersinia enteritis.

1. Abdel-Haq NM, et al. Antibiotic susceptibilities of Yersinia enterocolitica recovered from children over a 12-year period. lnt J Antimicrob Agents 2006; 27: 449-52. 2. Hoogkamp-Korstanje JAA. Antibiotics in Yersinia enterocolitica infections. J Antimicrob Chemother 1987; 20: 123-31. 3. CoverTL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989; Jll: 16-24. 4. Abramowicz M, ed. The choice of antibacterial drugs. In: Handbook of antimicrobial therapy. 19th ed. New Rochelle NY: The Medical Letter, 201 1: 67. 5. Zheng H, et al. Yersinia enterocolitica infection in diarrheal patients. Bur J Clin Microbial Infect Dis 2008; 27: 741-52. 6, Read RC, Barry RE. Relapsing yersinia infection. BMJ 1990; 300: 1694.

Gonorrhoea See under Sexually Transmitted Diseases, p. 2 0 6 . 2 .

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Haemophilus inf/uenzae is a Gram-negative bacterium that colonises the upper respiratory tract in the majority of healthy people. Most are carriers of non-encapsulated (or nontypeable) strains, but a small proportion carry H. injluenzae type b (Hib ) , the most virulent of the 6 encapsulated strains. Transmission is by close contact with an infected person or by inhalation of respiratory tract droplets. In most developed countries there has been a decrease in the rate of nasopharyngeal colonisation by Hib and in the incidence of Hib infection since the introduction

and widespread use of Hib conjugate vaccine. However, Hib infection still occurs in uninununised children or those who have not completed the childhood Immunisation schedule; Hib infections are uncommon in children more than 6 years old. Hib strains cause systemic disease, the most serious being meningitis which mainly affects children less than 2 years old. Other invasive conditions include bacteraemia, cellulitis, epiglottitis, septic arthritis, and pneumonia and empyema. In developing countries pneumonia is respon­ sible for more deaths than meningitis. Non-encapsulated strains invade the mucosal surface causing infections such as otitis media, sinusitis, and conjunctivitis and infect patients with chronic bronchitis. These strains are a common cause of community-acquired pneumonia in adults, especially those with chronic obstructive airways disease or AIDS . Choice o f treatment. For further details o f these infections and their management, see under the specific disease side- headings. Ampicillin and chloramphenicol have been the antibacterials of choice against H. inf/uenzae, but increasing resistance, especially to ampicillin, should be borne in mind; there have been several reports of multiresistant strains. 1•4 Parenteral cephalosporins such as ceftriaxone or cefotaxime have been found to be effective' and are currently preferred for serious H. injluenzae type b infections.6 There have been treatment failures in H. injluenzae meningitis with cefuroxime and there is argument over its efficacy.' Meropenem is a further alternative . ' For upper respiratory infections and bronchitis caused by nontypable strains oral antibacterials may be used. About 20 to 3 5 % of these strains are resistant to ampicillin and some experts suggest co-trimoxazole (or trimethoprim in the UK) as the preferred antibacterial; ampicillin, amoxidllin (with or without clavulanic acid), oral second- or third-generation cephalosporins, a tetracycline, a fluoroquinolone, or the macrolides azithromydn or clarithromydn are suggested alternatives.' Prophylaxis. Immunisation is the most effective way of preventing Hib in infants and children and vaccination is included in the infant Immunisation schedules in some developing and most developed countries including the UK and USA. However, there are no vaccines available for the prevention of disease caused by nontypable H. injluenzae. For further information on haemophilus influenzae vaccines see p. 2 3 8 7 . 2 . Young children who develop invasive Hib disease have a low but significant risk of a second episode of Hib infection and are also more likely to become asymptomatic carriers and transmit the organism to others. Household contacts of index cases, especially young children and those with underlying medical problems such as Immunosuppression and asplenia, are also at increased risk of developing invasive Hib disease. Recommendations for the prevention of secondary Hib disease have been made7•8 and usually include chemoprophylaxis with rifampicin (or alternatively ceftriaxone) for the index case and for close contacts of the index case. For further information on chemoprophylaxis see Meningitis Prophylaxis, under Uses and Administration of Rifampicin, p. 3 5 3 . 2 .

1. Sturm AW, e t al. Outbreak of multiresistant non�encapsulated Haemophilus influenzae infections in a pulmonary rehabilitation centre. Lancet 1990; 335: 214-16. 2. Brightman CAJ, e t al. Family outbreak of ctJ_loramphenicol-ampicillin resistant Haemophilus in:fluenzae type b disease. Lancet 1990; 335: 3512. 3. Barclay K, e t a l . Multiresistant Haemophilus influenzae. Lancet 1990; 335: 549. 4. Scott GM, et al. Outbreaks of multiresistant Haemophilus influenzae infection. Lancet 1990; 335: 925. 5. Powell M. Chemotherapy for infections caused by Haemophilus influenzae: current problems and future prospects. J Antimicrob Chemother 1991; 27: 3-7. 6. Abramowicz M. ed. The choice of antibacterial drugs. In: Handbook of antimicrobial therapy. 19th ed. New Rochelle NY: The Medical Letter, 2011: 69. 7. DolL Public Health England. Revised recommendations for the prevention of secondary Haemophilus influenzae type b (Hib) disease (updated 1 July, 2013). Available at: https:flwww.gov.uk/govemment/ uploads/system/uploads/attachment_data/file/231009/Revised_recom­ mendations_for_the_preventions_of_secondary_Haemophilus_influ­ enzae_type_b_disease.pdf (accessed 1 1/09/13) 8. American Academy of Pediatrics. 2012 Red Book: Report of the Committee on Infectious Diseases, 29th ed. Elk Grove Village, Dlinois, USA: American Academy of Pediatrics, 2012.

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. Antibacterial therapy is used to eradicate He/icobacter pylori infection in peptic ulcer disease (p. 1 8 1 6 . 2 ) and MALT lymphoma of the stomach (p. 698. 1 ) . The role of H. pylori and the value of its eradication in dyspepsia (p. 1 80 9 . 3 ) and gastro-oesophageal reflux disease (p. 1 8 1 0 . 2 ) is less clear.

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. Patients with a defective immune system are at increased risk of infection. Primary immune deficiency is rare, whereas secondary deficiency is more common: immuno­ suppressive therapy, cancer and its treatment, HIV infection, or splenectomy may cause neutropenia and

Antibacterials 1 87 impaired humoral and cellular immunity in varying Patients in whom fever persists throughout the first 3 to 5 days but for whom no aetiology is determined may have a degrees. The risk and severity of infections depends upon non-bacterial infection, a bacterial infection that is the duration of compromised immunity, the degree to refractory to treatment the emergence of a second which immune function is compromised, whether cellular infection, or drug fever. 5 Such patients should be reassessed or humoral functions are affected, and upon breaches in and then one of three options followed. If the patient's physical barriers, for example due to severe mucositis or condition is clinically stable, the same antibacterial prolonged vascular access. Thus patients with profound treatment may be continued; if there is still no change in neutropenia or a history of splenectomy are prone to rapidly the patient's condition, consideration should be given to progressive and potentially life-threatening infections; stopping vancomycin if it has been given. Alternatively, if those with neutropenia induced by cytotoxic chemotherapy there is evidence of progressive disease or drug toxicity, the or by preparation for transplantation are particularly antibacterials given may be changed; if vancomycin has not vulnerable to acute infections whereas those in whom been given, it may be added to the regimen. The third immunosuppression results from viral infections or option is to add an antifungal drug (amphotericin B) with or congenital defects are at lower risk of acute infections 1 without a change t o the antibacterial regimen i f the patient Patients in whom neutropenia persists for more than 1 0 is febrile through days 5 to 7 and resolution of neutropenia days are not only at risk of opportunistic bacterial infections is not imminent. 5 but also susceptible to viral, fungal, and parasitic infections. The optimum duration of therapy is governed by the Infectious diseases are a major cause of morbidity and clinical situation. The most important determinant of mortality in patients with AID S (see HIV-associated successfully stopping antibacterials is the neutrophil count:' Infections and Complications, p . 960.3 ). some are due to • if no infection is identified after day 3, the neutrophil common pathogens, but others are opportunistic and are count exceeds 500 cells/mm3 for 2 consecutive days, and caused by normally avirulent commensals. Children with the patient has been afebrile for at least 48 hours, then HIV infection appear to be at special risk of serious bacterial ! antibacterial treatment may be stopped infections with common encapsulated bacteria. For further • if neutropenia persists in the absence of fever, it is reference to some bacterial infections associated with AID S, reasonable to stop antibacterial treatment after 5 to 7 see Gastro-enteritis (p. 1 82 . 2 ) , Nontuberculous Mycobacdays i n patients who were initially considered a t low risk terial Infections (p. 1 9 6 . 1 ). and Tuberculosis (p. 2 1 2 . 2 ) . and who are clinically well, though such patients should Detailed guidelines for the prevention and treatment of be closely monitored and intravenous antibacterials opportunistic infections (including some bacterial infecreinstigated immediately on recurrence of fever or lions) among HIV-infected adults, adolescents, and children evidence of infection.' In afebrile patients with profound have been developed in the USA. 2 . 3 Fungal. protozoal. and neutropenia (less than 1 00 cells/mm3 ) , or in those with viral infections which can affect immunocompromised mucositis or other risk factors, continuous antibacterial patients are discussed in the relevant chapters under treatment should be considered throughout the entire Infections in Immunocompromised Patients, p. 566.2, neutropenic period p. 923.3, and p. 962.2, respectively. • in patients with persistent fever and prolonged Reports from Europe and the USA show that over the neutropenia in whom haematological recovery cannot past few decades there has been a shift in the occurrence of be anticipated, consideration may be given to stopping bacteraemia in febrile neutropenic patients from Gramantibacterials after 2 weeks if no infection has been negative organisms to GramRpositive organisms.4 Factor identified and careful observation is possible. 5 influencing this change include changes in clinical practice • clinically well patients with persistent fever may have such as the use of central venous catheters, changes in their antibacterials stopped after 4 to 5 days if the antibacterial use, and antibacterial resistance; when neutrophil count remains at least 5 0 0 cells/mm3 antibacterial prophylaxis is given, local resistance patterns throughout this period and there is no sign of infection have been shown to affect the aetiology of infections.4 and no response to therapy; such patients should be TREATMENT. Onset of fever in neutropenic patients is closely monitored for subsequent infections which are indicative of potentially serious infection that may progress usually easily treatable, and empirical amphotericin B to septicaemia and death. The severity of infections depends should be considered despite cessation of antibacterials if on many factors (see above) and it is therefore difficult to fever persists for 5 to 7 days after the start of initial produce a standard drug regimen; in addition, the choice of therapy5 empirical therapy must be adapted according to prevailing • patients who remain febrile after recovery from local antibacterial susceptibility patterns. Guidelines have neutropenia and despite broad-spectrum antibacterials been produced in many countries, of which those issued by should be reassessed for undiagnosed infection which the Infectious Diseases Society of America 5 for both the may be fungal. mycobacterial, or viral initial and subsequent management of febrile neutropenic The routine use of colonyRstimulating factors as an adjunct patients are fairly typical: to antibacterial treatment is not generally recommended5 • empirical antibacterial therapy should be given promptly but may be indicated in febrile neutropenic patients at high to all neutropenic patients at the onset of fever; afebrile risk of serious infections or infection-related complications; neutropenic patients who show signs and symptoms examples include some patients with malignant neocompatible with infections should also receive empirical plasms7, s and those with persistent severe neutropenia and antibacterial treatment infections that are not responsive to antibacterials alone. 5 A • consideration should be given to whether the patient systematic review9 of the use of colony-stimulating factors requires vancomycin therapy. If so, treatment should in patients with febrile neutropenia due to cancer begin with vancomycin plus cefepime, ceftazidime, or a chemotherapy concluded that their use did not affect carbapenem, with or without an aminoglycoside. overall mortality but did reduce time spent in hospital and • if vancomycin is not indicated, intravenous monothe neutrophil recovery time. therapy should be given with PROPHYLAXIS. Most infections in immunocompromised • either a cephalosporin (cefepime, although concerns patients are caused by organisms from their own alimentary have been raised about its safety,6 or ceftazidime) or a tract and in cancer patients, for example, may follow carbapenem (imipenemRcilastatin or meropenem) for chemotherapy-induced mucosal damage to the tract. uncomplicated cases Several prophylactic strategies have been used to try to • in more complicated cases, or where resistance is a reduce the risk of infection during severe neutropenia, such problem, combined treatment should be given with as isolation of the patient, granulocyte transfusion, active or an aminoglycoside and one of cefepime, ceftazidime, a passive immunisation, acceleration of granulocyte recovery, carbapenem, or an antipseudomonal penicillin such and antibacterial prophylaxis. Possible antibacterial proas ticarcillin with clavulanic acid or piperacillin with phylactic regimens have included selective decontaminatazobactam. tion of the alimentary tract using oral nonabsorbable • low-risk patients may be treated empirically either orally antibacterials (see also under Intensive Care, p. 1 8 9 . 3 ) or with ciprofloxacin and amoxicillin with clavulanic acid, treatment with absorbable antibacterials (most commonly a or intravenously as for uncomplicated cases above. Initial fluoroquinolone or co-trimoxazole ) . A systematic review of treatment with oral antibacterials alone is, however, not 1 0 1 randomised, controlled, studies in 12 599 afebrile recommended for children' neutropenic patients (mostly with leukaemia) found that The initial regimen usually needs to be given for 3 to 5 days antibacterial prophylaxis significantly decreased the risk of in order to determine its efficacy. In patients in whom fever death from all causes by 34% when compared with no resolves and in whom a causative organism is identified, intervention; the most significant reduction in mortality antibacterial treatment should be modified for the specific 1 was associated with the use of fluoroquinolones . 10 organisms and broad-spectrum antibacterials continued for ; Although antibacterial prophylaxis is also effective in at least 7 days or until culture results are negative and the afebrile patients likely to be neutropenic, the efficacy of patient has clinically recovered. 5 In afebrile patients in empirical treatment means that prophylaxis is less widely whom no causative organism is found but who were used 1 1 and the Infectious Diseases Society of Arnerica5 considered at high risk at the onset of treatment, the same discourages routine use; reasons include toxicity of the antibacterials should be continued intravenously; those antibacterial. potential fungal overgrowth, and problems of considered at low risk initially may be switched to oral bacterial resistance. therapy with ciprofloxacin plus either amoxicillin-clavuImmunocompromised patients may benefit from approlank acid (adults) or cefixime (children) . 5 priate immunisation against common infections, although

precautions relating to the use of live vaccines in such patients should be observed (p. 2 3 7 5 . 2 ) . The duration and severity o f neutropenia can b e reduced by the use granulocyte or granulocyte-macrophage colony­ stimulating factors, and this may be a useful adjunct in infection control in selected patients? B one marrow protective agents such as amifostine are also being studied.

l. Pizzo PA. Fever in immunocompromised patients. N Engl J Med 1999; 341: 893-900. 2. CDC. Guidelines for the prevention and treatment of Opportunistic infections among HIV-exposed and HIV-infected children: recommen­ dations from CDC, the National Institutes of Health, the HlV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR 2009; 58 (RR-1 1 ): l-166, Also available at: http://www,cdc.gov/ mmwr/PDF/rr/rr58ll.pdf (accessed 10/05110) 3, CDC. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the mv Medicine Association of the Infectious Diseases Society of America. MMWR 2009; 58: (RR-4): 1-207. Also available at http://www .cdc.gov /mmwr/pdf/rr I rr5804.pdf (accessed I0/05110) 4. Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis 2004; 39 (suppl l): S25-S3l. 5. Hughes WT, e t al. Infectious Diseases Society of America. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730-51. Also available at: http:// www.journals. uchicago.edu/doi/pdf/1 0.1086/3 392 1 5 (accessed 18/08/08) 6. Paul M, et al. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2006; 57: 176-89. 7. Smith TJ, et aL American Society of Clinical Oncology. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 31873205. Also available at: http://www.jco.org/cgi/reprint/JC0.2006.06. 445lv2.pdf (accessed 18/08/08) 8. Aapro MS, et al. European Organisation for Research and Treatment of Cancer (EORTC) Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party. EORTC guidelines for the use of granulocyte­ colony stimulating factor to reduce the incidence of chemotherapy­ induced febrile neutropenia in adult patients with lymphomas and solid tumours. Bur J Cancer 2006; 42: 2433-53, 9. Clark OAC, et a!. Colony stimulating factors for chemotherapy induced febrile neutropenia. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2000 (accessed 16/05/05). 10. Gafter-Gvili A, et a!. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester; John Wiley; 2005 (accessed 10/05/10). 11. Kerr KG, The prophylaxis of bacterial infections in neutropenic patients. J Antimicrob Chemother 1999; 44: 587-91.

Intensive care Like immunocompromised patients (p. 1 8 6 . 3 ) , those in intensive care units (ICUs) are often very susceptible to endogenous infections, especially respiratory and urinary­ tract infections, arising from gastrointestinal colonisation by aerobic Gram-negative bacilli acquired in hospital. The incidence of pneumonia in ICU patients ranges from 7 to more than 40%,1 and mortality from ventilator-associated pneumonia may exceed 3 0 to 5 0 % . 2, 3 For further information on ventilator-associated pneumonia see under Pneumonia, p . 202 . 1 . Selective decontamination regimens aim t o reduce this risk by eliminating potentially pathogenic organisms from the throat and intestines while preserving the indigenous, mostly anaerobic, flora.4 • selective decontamination of the digestive tract ( S D D ) , u s e s n o n-absorbable antibacterials given orally and through a nasogastric tube; in some studies systemic antibacterials (usually cephalosporins) were added in the first 4 days of the ICU stay to prevent early infections • selective oropharyngeal decontamination, (SOD) uses topical oral application of antibacterials or antiseptics, such as chlorhexidine gluconate or povidone-iodine In an initial report' in 1 984 SDD reduced the incidence of nosocomial infection from 81 to 1 6 % in a group of multiple trauma patients. Since then further studies have been done to evaluate the efficacy of SDD in ICU patients. While results showed that SDD reduced infection-related morbidity, its effect on mortality was not clear. Furthermore other outcomes, such as beneficial effects on duration of ventilation, ICU or hospital stay, and cost-efficacy were also uncertain. 6 Selection of antibacterial resistance is considered a serious adverse effect6 and the preventive effects of SDD have been considerably lower in ICUs with high endemic levels of antibacterial drug resistance 7 SOD may therefore be an attractive option because the antiseptics and antibacterials used have a low potential for induction and selection of antibacterial resistance. 8 A systematic review and meta -analysis3 of 1 1 randomised controlled studies (up until May 2006) suggested that in mechanically ventilated patients, antiseptic SOD prophy­ laxis reduced the incidence of ventilator-associated pneu­ monia; but no firm conclusions could be made on the effect of antibacterial SOD. Neither of the two oral decontamina­ tion regimens appeared to affect mortality, duration of mechanical ventilation, or stay in the !CU. A later meta­ analysis1 of 3 6 randomised controlled studies (published up until March 2009 and involving 6 9 1 4 patients) assessed the effect of prophylactic antibacterial regimens for the

1 88

Antibacterials

prevention o f respiratory-tract infections a n d overall given as an alternative if isolates have vancomycin MIC mortality in adults receiving intensive care. It found that a values greater than 2 micrograms/mL. linezolid is not combination of topical and systemic prophylactic antibac­ recommended for empirical therapy. 2 1 For empirical treatment of infection thought to be caused by Gram­ terials reduced respiratory-tract infections and overall mortality; treatment based on topical prophylaxis alone negative badlli, a fourth-generation cephalosporin, carba­ penem, or combinations of a beta lactam and beta-lactamase reduced respiratory infections but not mortality. A large, multicentre study' conducted in l 3 ICUs using cluster inhibitor, with or without an arrtinoglycoside is recom­ randomisation showed that the use of either SOD or SDD mended; combination antibacterial treatment should be was associated with improved mortality in critically ill given when multidrug-resistant Gram-negative bacilli (such adults. as Pseudomonas aeruginosa) are suspected in neutropenic or The risk of antibacterial resistance was evaluated in only severely ill patients with sepsis, or in those known to be colonised with such pathogens. 2 1 one study 1 • 10 This prospective, randomised, controlled study Antibacterial treatment can be stopped after 1 0 t o 1 4 of 934 patients admitted to a surgical and medical ICU compared a SDD regimen with a control group receiving days i f a response i s seen within 2 t o 3 days. A longer treatment duration of 4 to 6 weeks is recommended for standard treatment. 10 Colonisation with Gram-negative patients with persistent fungaemia or bacteraemia after bacteria resistant to ceftazidime, dprofloxadn, imipenem, catheter removal, for patients who are found to have colistin, or tobramydn occurred in 1 6 % of SDD patients and in 2 6 % of those in the control group. No patient in either • infective endocarditis or suppurative thrombophlebitis, and group ·was colonised with MRSA, while 1 % of all patients for paediatric patients with osteomyelitis; 6 to 8 weeks of were colonised with vancomycin-resistant enterococcus. treatment are recommended for adults with osteomyelitis." Although SDD reduces hospital-acquired pneumonia, US et a!. guidelines discourage routine antibacterial prophylaxis.'· " especially in hospital settings where there are high levels of antibacterial ·resistance, 7 and particularly in relation to N Engl J prevention of nosocomial pneumonia. " CDC guidelines do, Med 340: ibid.; 341: et al. however, recommend topical oral chlorhexidine gluconate 0. 1 2 % during the perioperative period only for adults BMJ 334: undergoing cardiac surgery .7 Another potential source of infection in intensive care is CUrr Opin Grit Care 8: et al. from the use of intravascular catheters. Catheter-related bloodstream infections occur in 3 to 1 0 % of patients with Intensive Care Med 10: inserted catheters 1 2• 1 3 and are a leading cause of nosocomial et al. bloodstream infection in ICUs." Most serious catheter­ Crit Care related infections are associated with central venous catheters. 1 4 Conditions that compromise host defences Am J Respir (including severe bums and malnutrition), severe sepsis, or Grit Care Med severe and sustained multiple organ dysfunctions are associated with a higher risk of catheter- related bloodstream et al. infections. " Colonisation of the catheter tip due to Am J Respir Grit Care Med migration of skin orgartisms from the insertion site into 173: the cutaneous catheter tract is the most common route of et al. N Eng/ J Med 360: infection for short-term central venous catheters. 1 3• 1 5 For et al. long-term catheters (those staying in place more than 1 5 days) , colonisation i s mainly due t o manipulation o f the Lancet 362: venous line with migration of organisms along the internal lumen of the catheter. 13• 15 The ability of orgartisms to a db ere MM1¥R 53 to host proteins such as fibronectin that commonly build up on catheter tips, makes colonisation easier . 1 3· 1 5 The organisms implicated most often are coagulase-negative et a/. BMJ staphylococd; 13•14 other organisms commonly involved 334: include Staphylococcus aureus, Candida spp., Enterococci, and eta/. Gram-negative bacilli." Grit Care Guidelines for the prevention of infection associated e t al. 1\MfWR with both peripheral intravascular and central venous ibid.; catheterisation have been developed. 14•16·18 Prevention and control of infection involves several interventions, which Curr should be used in combination. 1 3· 1 5· 1 9 Intervention Opin Grit Care 13: measures include: J Hosp Infect 47 • barrier precautions at the time of catheter insertion • disinfection of the skin at the insertion site with chlorhexidine or alternatively povidone-iodine • the use of catheters impregnated with antibacterial (usually rifampicin or minocycline) or antiseptic agents (commonly chlorhexidine or silver sulfadiazine) • use of good aseptic technique and hand hygiene (see ' et al. p. 1 7 3 3. 1 ) when accessing or maintaining the catheter Int J Lab Hematol 2007; 29: system Antibacterial prophylaxis has not been shown to reduce the N Eng! J Med 348: rate of infection when given during catheter insertion, 13•15 et al. but when antibacterials were given with a central venous J Clin catheter in place, risks for catheter colonisation and Onco/ 2005; 23: bloodstream infections were significantly reduced. 1 3 How­ LA, et al. ever, the use of prophylactic antibacterials is discouraged Clin Infect Dis 49: because of concern over the emergence of resistant ibid. SO organisms. 18· 1 9 Antibacterial ointments ( such as badtradn, mupirodn, neomycin, and polymyxin B) or antiseptic ointments applied to catheter-insertion sites increase the rate of catheter colonisation by fungi, promote the emergence of antibacterial-resistant bacteria, and have not Legionella pneumophila is an aerobic, Gram-negative been shown to decrease the rate of infections." Studies bacterium that was first identified in 1 977 as the result of suggest that anticoagulants such as heparin and low­ an outbreak of severe pneumonia at a convention of the molecular-weight heparins are able to decrease fibrin American Legion. Legionnaires' disease is the pneumonic sheath and thrombus formation around the catheter and in form of the infection and is a relatively common cause of so doing reduce catheter-related infections. 1 5•20 Routine community acquired pneumonia ( s e e p. 2 0 2 . 1 ) ; replacement of short-term catheters as a means to reduce non-pneumonic infection (called Pontiac fever) i s a milder, infection rates is not recommended. 1 3• 1 8 usually self-limiting, flu-like illness. Legionellosis has been Guidelines for the diagnosis and management of suggested as a broad term to cover pneumonic and intravascular catheter-related infections have been devel­ non-pneumonic clinical syndromes caused by any Legionella oped by experts in the USA. 21 Antibacterials for catheter­ spp., which may include L. bozemanii, L. micdadei (Pittsburgh related infections are often given empirically and the choice pneumonia agent) , and L. wadsworthii. These bacteria are of drug should take into account local antibacterial found worldwide in the environment and particularly in susceptibility data and the severity of disease, and should warm water and warm damp places. Infection is usually usually cover coagulase-negative staphylococci. Empirical transmitted by aerosolisation or aspiration. Serious out­ therapy with vancomycin is generally recommended where breaks have been associated with infected air-conditioning there is a high prevalence of MRSA. Daptomycin may be systems or water supplies. Older adults, smokers, and

1. Liberati A, Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester; John Wiley; 2009 (accessed 04/05110). 2. Kollef MH. The prevention of ventilator-associated pneumonia. 1999; 627-34. Correction. 294. 3. Chan EY, Oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis. 2007; 889. 4. Krueger WA, Unertl KE. Selective decontamination of the digestive tract. 2002; 139-44. 5. Stoutenbeek CP, The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. 1984; 185-92. 6. Bonten MJM, Selective decontamination of the digestive tract: all questions answered? 2003; 7: 203-5. 7. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. 2005; 171: 388-416. Also available at: http:/!www. thoracic.org/sections/publications/statements/pages/mtpi/guide1-29. htmJ (accessed 25/05/06) 8. Koeman M, Oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia. 2006; 1348-55. 9. de Smet AMGA, Decontamination of the digestive tract and oropharynx in ICU patients. 2009; 20-31. I 0. de Jonge E, Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. 2003; 101 1-6. 11. CDC. Guidelines for preventing health-care-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. 2004; (RR-3): 1-36. Also available at: http://www.cdc.gov/mmwr/PDP/rr/rr5303.pdf (accessed 07/05/10) 12. Bhutta A, Reduction of bloodstream infections associated with catheters in paediatric intensive care unit: stepwise approach. 2007; 362-5. 13. Frasca D, Prevention of central venous catheter-related infection in the intensive care unit. 2010; 14: 212. 14. O'Grady NP, Guidelines for the prevention of intravascular catheter-related infections. 2002; 51(RR-10): 1-29. Correction. 51: 711. Also available at: http://www.cdc.gov/mmwr/PDF/rr/ rr5I IO.pdf (accessed 12/07/04) 15. Timsit JF. Diagnosis and prevention of catheter-related infections. 2007; 563-71. 16. DoH. Guidelines for preventing infections associated with the insertion and maintenance of central venous catheters. 2001; (suppl): S47-S67. Also available at: http://www.dh.gov.uk/en/ Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/ DH_4005481 ?ldcService=GET_FILE&diD=l4080&Rendition=Web (accessed 07/05/10) 17. NICE. Infection control: prevention of healthcare-associated infections in primary and community care (June 2003). Section 5: central venous catheterisation. Available at: http://www.nice.org.uk/nicemedia/pdf/ Infection_controUullguideline.pdf (accessed 07/05110) 18. Bishop L, Guidelines on the insertion and management of central venous access devices in adults. i61-78. 19. McGee DC, Gould MK. Preventing complications of central venous catheterization. 2003; 1123-33. 20. Abdelkefi A. Randomized trial of prevention of catheter-related bloodstream infection by continuous infusion of low-dose unfractio­ nated heparin in patients with hematologic and oncologic disease. 7864-70. 21. Menne! Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. 2009; I-4?. Correction. 2010; 457.

�t3f!_i�n..n..?.!.�e.��.�!�.��� .................................................... .

All cross-references refer to entries in Volume A

immunocompromised people are particularly susceptible to Legionnaires' disease. Symptoms usually begin 2 to 14 days after being exposed to the bacteria and are similar to other forms of pneumonia. The severity of disease ranges from a mild cough to a rapidly progressive pneumortia with respiratory failure, shock, and multi-organ failure. The mortality rate from Legionnaires' disease is dependent on the severity of the disease, the appropriate­ ness of initial antibacterial treatment, the setting where infection was acquired, and host factors. In untreated immunocompromised patients the mortality rate may be 40 to 80%; if treated appropriately this decreases to 5 to 3 0 % . F o r. immunocompetent patients the mortality rate is about 10 to 1 5 % . The usual treatment for mild to moderate Legionella infections is with an oral macrolide, with erythromycin now increasingly replaced by azithromycin;1•2 clarithromydn, roxithromydn, or telithromydn may be further acceptable alternative macrolides. 1•2 Oral fluoroqui­ nolones (such as dprofloxacin, levofloxadn, or moxiflox­ acin) are also increasingly recommended as alternatives to the macrolides. ,., Doxycycline or co-trimoxazole are further altematives.1•2. 4 For severe infections or in immunocom­ promised patients parenteral therapy (if available) with azithromycin, clarithromycin, or a fluoroquinolone is recommended.1·2 Combination intravenous treatment with erythromycin and rifampicin has also been used for severe infections. ' Rifampicin has also been given with fluor­ oquinolones or doxycycline, especially in severe or deteriorating illness or in immunocompromised patients, although this may be of little further benefit -' Generally about 7 to 10 days of treatment should be given to those with mild to moderate infections, while those with more severe infections, multisystem disease, or who are immunocompromised should be treated for up to 2 1 days.1•2 However, patients treated with oral azithromycin may only need 3 to 5 days treatment due to its long half-life and tissue retention. 1•2

1. 2. 3. 4.

Roig J, �ella J. Legionnaires' disease: a rational approach to therapy. J Antimicrob Chemother 2003; 51: 1119-29. Amsden GW. Treatment of Legionnaires' disease. Druas 2005; 65: 60514. Diederen BMW. Legionella spp. and Legionnaires' disease. J Infect 2008; 56: 1-12. Abramowicz M, ed. The choice of antibacterial drugs. In: Handbook of antimicrobial therapy. 19th ed. New Rochelle NY: The Medical Letter, 2011: 70.

��C>.�Y..................................................................................... .

Leprosy (Hansen's disease) is a chronic disease caused by the bacillus, Mycobacterium leprae; it has a prolonged incubation period (years) and slow onset of symptoms. Disease results from bacillary infiltration of the peripheral nervous system, skin, eyes, respiratory mucosa, bones, and testes. It is not highly infectious and transmission requires both prolonged close contact with an infected patient and an inherent immunological susceptibility to the disease in the exposed person. Clinical leprosy may be regarded as a consequence of deficient cell-mediated immunity in susceptible individuals; most individuals are naturally immune, and symptoms are suppressed. The clinical manifestations depend on the bacillary load and the host's immune response to the mycobacterium. Patients with leprosy may be classified as having: • Multibadllary (or lepromatous) leprosy, which occurs when cellular immunity is largely deficient, and includes the sub-groups lepromatous (LL), borderline leproma­ tous (BL), and midborderline leprosy (BB), as well as any other types giving a positive skin smear for add-fast bacilli. Generally the lepromin test (p. 2 5 4 3 . 3 ) is negative. • Paucibadllary (or tuberculoid) leprosy, which results when cellular immunity is only partially deficient, and includes the sub-groups borderline tuberculoid (BT), tuberculoid (TT), and indeterminate leprosy (I) when the skin smear is negative. Generally the lepromin test is positive. For the purpose of treatment, WHO classifies patients with more than 5 skin lesions as having multibacillary leprosy, and those with 1 to 5 skin lesions as having paucibadllary leprosy. The use of this clinical classification avoids the necessity to provide facilities for bacteriological examination of skin smears. C hanges in the hosts immune response to the mycobacteria may result in lepra reactions and unless treated these may lead to severe nerve and tissue damage. 1 Most reactions belong to one of two main types: • Type 1 lepra reactions, or reversal reactions, are caused by spontaneous increases in T -cell reactivity to mycobacterial antigens (type N hypersensitivity) and occur in patients with borderline forms of leprosy. These reactions are characterised by erythema and oedema of the skin and tenderness of peripheral nerves. Prompt treatment with corticosteroids is necessary to prevent permanent nerve damage.2·5 Treatment is usually continued for 3 to 6 months. Adding azathioprine may

Antibacterials permit the use of lower cumulative doses of cortico­ steroid. 6 Methotrexate was found to be effective in treating a patient intolerant to corticosteroids, 7 while ciclosporin is considered to be effective for chronic neuritis.2•8 Prophylactic use of low-dose corticosteroids during the first 4 months of standard multidrug treatment for leprosy has also been investigated, and found to decrease the number of reactional episodes by 7 5 % ; but the protective effect was lost by the end of 1 2 months.9 • Type 2 lepra reactions, also known as erythema nodosum leprosum (ENL ) , represent a systemic inflammatory response (type III hypersensitivity) to dead bacteria and are accompanied by high levels of circulating tumour necrosis factor alpha (TNF a ) . This reaction occurs only in patients with borderline lepromatous or lepromatous leprosy. Mild type 2 reactions may be treated with anti-inflammatories but moderate or severe reactions should be treated with corticosteroids or thalidomide (in males and post menopausal women) .2·4 The incidence and severity of ENL has decreased since the inclusion of clofazimine in multidrug regimens, probably owing to the drug's anti-inflammatory action.2 Clofazimine does not act as rapidly as either corticosteroids or thalidomide, nor is it as effective.2 However, clofazimine may be used with a corticosteroid in patients with severe ENL who are not responding adequately to treatment with corticosteroids alone or when the risk of toxicity with corticosteroids is high; it may be given alone when corticosteroids are contra-indicated.10 Other TNF a inhibiting drugs that have been tried include pentoxifylline5• 1 1 and inllix­ imab . 1 2 Chloroquine has also been used with limited effect . ' Antileprotic drug therapy is generally continued during lepra reactions. Although measures to manage the consequences of nerve damage and lepra reactions are an important part of the management of leprosy, curative antibacterial therapy is the mainstay of treatment. Dapsone monotherapy, long the basis of this, has been replaced since the 1 980s with multidrug oral regimens designed to overcome tbe development of resistance. Dapsone, rifampicin, and clofazimine form the elements of the standard combina­ tions .5·13 Newer alternatives include clarithromycin, mino­ cycline, and fluoroquinolones such as ofloxacin, moxiflox­ acin, and pefloxacin. These may be used as second-line therapy for patients unable to tolerate dapsone or clofazimine. Ethionamide or protionamide have been used in light-skinned patients to avoid clofazimine's tendency to pigment the skin, but are no longer recommended because of their risk of hepatotoxicity. The most widely used multidrug regimens are those reconunended by WH0 10 and in these the choice of drugs and length of treatment are based on the clinical classification outlined above.

substituted with clofazimine 300 mg monthly and 5 0 mg i daily lor 6 months 10 On the basis of a clinical study 16 showing that a single dose each of rifampicin 600 mg, ofloxacin 400 mg, and minocycline 1 00 mg given together is only slightly less effective than standard multidrug treaunent, WHO has suggested that this is a suhable alternative for patients with single-lesion paucibadllary leprosy.3 However, reservations have been expressed about the study, including concerns regarding the short follow-up17 and poor microbiological rationale . 1 8

RELAPSE

, •

1

Relapse after a recommended course of multidrug therapy for multibacillary or paucibacillary leprosy can occur and WHO recommends re-treatment with the initial regimen. 3 . 4 Although the relapse rate after standard multidrug therapy for multibacillary leprosy is generally low, 3•19 there is insufficient information on the long-term efficacy of shorter treatment courses. 14

1 89

19. WHO Leprosy Unit. Risk of relapse in ieprosy. Indian J Lepr 1995; 67: 1326. 20. Smith CM, Smith WCS. Chemoprophylaxis is effective in the prevention endemic countries: a systematic review and meta-analysis. 41: 137-42. 21. Moct FJ, et al. COLEP Study Group. Effectiveness of single dose rifampicin in preventing leprosy in dose contacts of patients with newly diagnosed leprosy: duster randomised controlled trial. BMJ 2008; 336: 761-4.

�f!ptc:spir.'?S.i�.

Leptospirosis is a zoonotic infection caused by serovars of spirochaetes from the genus Leptospira, such as Leptospira interrogans. These are carried by wild, domestic, and farm animals, and can be spread to humans by contact with ; urine, blood, or tissue of infected animals or a contaminated environment. leptospirosis is more common in tropical and subtropical areas, where the climate and greater contact Standard multidrug therapy is safe during pregnancy 4• 5 with infected environments increase the likelihood of Leprosy patients who are pregnant or breast feeding may infection. Occupational groups most at risk include farmers experience clinical deterioration and, in general, ! and agricultural workers, although there have been antileprotic therapy is continued in such patients. outbreaks among participants in water-sports. The organ­ • isms enter the body through broken skin or intact mucous Leprosy is spread from person to person through membranes, can infect any internal organ, and cause respiratory droplets, so household contacts may become 1 damage to the walls of small blood vessels. Many infected infected. A systematic review and meta-analysis20 has people remain asymptomatic and most patients with concluded that prophylaxis, usually with dapsone, in symptoms have a relatively mild course of infection with an some household contacts may prevent disease in this acute !lu-like illness characterised by fever, myalgia, high-risk group. A large randomised placebo-controlled headache, and conjunctival suffusion. A small proportion, study21 found that a single dose of rifampicin given to however, develop severe leptospirosis (Weil's disease), with contacts of new patients with leprosy significantly haemorrhagic complications, jaundice, and renal impair­ reduced the incidence of developing leprosy in the first 2 , ment. years but no difference was noted beyond 2 years. WH03 The routine use of antibacterials to treat leptospirosis is suggests that contacts of newly diagnosed cases should be controversial as most cases are self-limiting, 1 and there is examined for evidence of leprosy and then advised how insufficient evidence to provide clear guidelines for to watch for early signs of the disease; prophylaxis with 1 treatment. However, treatment is usually recommended as rifampicin or other antileprotics is not recommended in soon as the diagnosis of leptospirosis is suspected, l.2 and leprosy control programmes. B C G vaccine appears to be preferably within 5 days of the onset of symptoms 2 protective. Vaccines specifically against leprosy are under Intravenous benzylpenicillin is recommended for severe investigation. leptospirosis .2 Intravenous ceftriaxone,3 cefotaxime, or • doxycycline4 are alternatives. Aminoglycosides such as The multidrug therapy regimens recommended by WHO streptomycin are used in some countries. 5 Oral antibac­ have been widely implemented in recent years raising terials such as amoxicillin, ampicillin, doxycycline, or the possibility of eliminating leprosy as a public health erythromydn may be used in milder infections.2 Jarisch­ problem: that is, reducing the prevalence to less than l Herxheimer reactions may occur after penicillin treatment case per l 0 000 population in endemic areas. Consider­ (see Adverse Effects, under Benzylpenicillin p. 2 3 1 . 2 ) 1 able progress towards this target has been made, and it Preliminary data have suggested that azithromycin may be was announced in 2 0 0 1 that the global level of leprosy effective in mild to moderate leptospirosis; fluoroquinolones had decreased by over 9 0 % . Full control of leprosy, and carbapenems have also shown activity in vitro.5 however, has still not been attained in several countries The incidence of leptospirosis in US soldiers in Panama and continued efforts are necessary. WHO has since was reduced when they were given prophylaxis with developed a global strategy for the further reduction of weekly oral doxycycline throughout the period of the leprosy burden and sustained leprosy control. 22 exposure.6 Prophylaxis has been suggested for travellers at increased risk of infection, beginning 1 to 2 days before and • Br Med 77-78: 1 continuing throughout the period of exposure.' Leptospir­ The standard regimen recommended by WHO for osis vaccines are available in some countries (see p. 2397 . 3 ) . multibacillary leprosy is rifampicin 600 mg and clofaz­ e t al. Tech Rep Ser 874 imine 300 mg both given once a month, with clofazimine Lancet Infect Dis 50 mg and dapsone 1 00 mg both daily. Treatment is continued for 12 months. U 0 Human A 2 -year treatment duration was chosen originally for diagnosis, surveillance and control. because it is highly effective in the majority of cases and Lancet avoids the need to assess response with skin smears. et al. etal. However, such a long treatment duration is an obstacle e t al. An to implementing treatment programmes in areas where Trans R Soc Trop healthcare is inaccessible or the infrastructure is poor. Clin Infect Dis et a!. Ongoing clinical studie� and experience with patients et al. Curr Opin Infect Clin Infect Dis defaulting from treatment have encouraged WHO to Dis er al. et al. now recommend that treatment for 12 months is N Eng/ J Med Lepr Rev 77: adequate 4 Early hopes that reducing duration of Handbook of et al. treatment to as little as one month would be possible antimicrobial therapy. have not been supported by a study using daily rifampicin and ofloxacin. 14 In patients for whom rifampicin is unsuitable because of 1 resistance or intolerance, WHO recommends10 daily treatment with clofazimine 50 mg, o!loxacin 400 mg, and Listeriosis is an infection caused by Listeria monocytogenes, an et at. minocycline I 00 mg for the first 6 months; treatment is anaerobic, food-borne, Gram-positive bacterium that occurs then continued for at least a further 18 months with ubiquitously and is found in soil, water, and vegetation. It is clofazin1ine plus either minocycline or ofloxacin. able to grow in a wide range of temperatures, including If the toxic effects of dapsone are severe, it should be those found under refrigeration. and stopped and treatment continued with rifampicin and Although exposure to L. monocytogenes is inevitable, clofazimine in the standard dosage for 1 2 months. 10 infection is relatively rare in humans. 1 · 3 When it occurs, it et al. Rifampicin 600 mg, ofloxacin 400 mg, and minocycline follows ingestion of food contaminated with a high Antimicrob Agents 1 00 mg (ROM) given once a month for 24 months was i concentration of the bacteria; foods at high risk of Chemother found to be as effective as the WHO standard regimen et al. contamination include processed and unprocessed dairy given for 24 months15 and has been suggested as an products (especially those made with unpasteurised milk), Am J Trop alternative regimen, particularly for those who cannot cold meats, pate, raw vegetables, and salads. The incubation Med Hyg 70: take clofazimine. J, l O period may range from 1 or 2 days up to 3 months. Those • Lepr Rev who are immunocompetent may have a self-limiting The WHO recommended regimen4•10 for paucibacillary gastroenteritis after consumption, 1.2 and a mild cutaneous infection has occurred in those who have directly handled leprosy is rifampicin 600 mg monthly and dapsone Lepr Rev. infected products or animals. u Occasionally invasive 1 0 0 mg daily. Treaunent is continued for 6 months. If 1 disease (listeriosis) occurs, especially in the immunocomLepr Rev there are severe toxic effects with dapsone it should be

MULTIBACILLARY LEPROSY

PREGNANCY

PROPHYLAXIS

ELIMINATION

l. 2. 3.

5. 6.

7. 8.

9.

Walker SC Lockwood DNJ. The clinical and immunological features of leprosy. Bull 2006; 103-21. Britton WJ, Lockwood DNJ. reactions: current and future approaches to management. 1997; 4: 1-23. WHO. WHO expert committee on leprosy. 1998. Also available at: http:/ !libdoc.who.int/trs/WHO_TRS_874.pdf (accessed lst ed. Geneva: at: Guide_Int_E.pdf (accessed 28/06/07) Britton WJ, Lockwood DNJ. Leprosy. 2004; 363: 1209-19. Marlowe SNS, Clinical outcomes in a randomized controlled study comparing azathioprine and prednisolone versus prednisolone alone in the treatment of severe leprosy type l reactions in Nepal. 98: 602-9. Biosca Methotrexate treatment for type 1 (reversal) leprosy rcactiom. 2007; 45: e7--e9. De Sena CBC, Cydosporine A treatment of leprosy patients with chronic neuritis is associated with pain control and reduction in antibodies against nerve factor. 2006; I21-9. Smith WCS, prophylaxis for prevention of nerve function randomised placebo controlled trial (TRIPOD 1).

Geneva: www. who. int!lep/resources/Final_Push_ %20QA.pdf 20112110) Comparison of pe,,toxifylline, 11. Moreira AL, prednisone in the treatment of ENL. 66: 61-5.

at: htq,Hwww.v,ho.in!lle]'/re;outm/M.DT_Full.pdf (accessed 28/06/07) High relapse rate among lepromatous leprosy patients treated with rifampin plus ofloxacin daily for 4 weeks. 1997; 41: 1953-6. 15. Vil\ahermosa LG, Parallel as�essment of 24 monthly doses of rifampin, ofloxacin, and minocycline versus two years of World Health Organization multi-drug therapy for multi-bacillary leprosy. 2004; 197-200. 16. Singlc-leswn Multicentre Trial Group. Efficacy of single-dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. 1997; 68: 341-9. 17. Lockwood DNJ. Rifarnpicin/minocycline and ofloxadn {ROM) for single lesions-what is the evidence? 1997; 68: 299-300. 18. Katoch VM. Is there a microbiological rationale for single-dose treatment of leprosy? 1998; 69: 2-5. 14.

PAUCIBACTLLARY LEPROSY

l. Bharti AR, Peru-United States Leptospirosis Consortium. Leptospirosis: a zoonotic disease of global importance. 2003; 3: 757-71. 2. WHO, International Leptospirosis Society. at: Geneva: WHO, http: 1 fwww. who. intf csr1 don! en/WHO _CD S_C SR_EPH_2002 .2 3. pdf {accessed 151l2/08) with sodium penicillin G for 3. Panaphut T, Ceftriaxone 2003; 36: 1507-13. treatment of severe leptospirosis. 4. Suputtamongkol Y, open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe leptospiro�is. 2004; 39: 1417-24. 5. Griffith ME, Antimicrobial therapy of leptospirosis. 2006; 19: 533-7. 6. Takafuji ET, An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. 1984; 310: 497-500. 7. Abramowicz M. ed. The choice of antibacterial drugs. In: 19th ed. New Rochelle NY: The Medical Letter, 20l l: 357.

Listeriosis

1 90

Antibacterials

promised, the young and elderly, and i n pregnant women and their fetuses and neonates. Listeria! meningitis and bacteraemia are the most common presentations; the latter may lead to endocarditis. u L. monocytogenes may also cause meningoencephalitis, focal CNS infection, and infection of visceral organs, the eye, bones, and joints, and pleural, peritoneal, and pericardia! spaces. t2 Listeriosis is fatal in up to a third of cases. 1.2 .4 Listeria! infection is especially dangerous to the fetus and neonate. Pregnant women are prone to developing listeria} bacteraemia (although CNS involvement is rare ) . The bacteria cross the placenta and infect the fetus; fetal distress, spontaneous abortion, still-birth, or premature delivery may then occur. Maternal deaths are rare but the fetal mortality rate is up to 5 0 % . Infection may also occur during delivery, and perinatal sepsis or meningitis are common. Late-onset illness may develop up to a month after delivery.1•2 The treatment of choice is intravenous ampicillin at high doses, 1 ·4 although penicillin is also active. An aminoglyco­ side, usually gentamicin, is often added for synergy. ' ·' Those with a penicillin allergy may be given co-trimoxazole, U·5 vancomycin, 1 •3 teicoplanin, 1 or erythromycin.5 Reports of the successful use of other antibacterials include listeria! meningitis treated with levofloxacin and meropenem;6 endocarditis in a patient intolerant of standard therapy treated with oral linezolid;3 listerial meningitis and brain abscesses refractory to standard therapy treated with intravenous linezolid and meropenem;4 and rhombence­ phalitis successfully treated with linezolid 7 Rifampicin has also been used but resistance has been reported with monotherapy.5 Cephalosporins, 1•5 fosfomycin, 5 and nali­ dixic acid5 are ineffective. Some fluoroquinolones ( such as ciprofloxacin) show decreased susceptibility, however, the newer fluoroquinolones such as levofloxacin and maxi­ floxacin have strong bactericidal activity against L. monocytogenes. 5 Therapy should continue for 2 weeks in those with bacteraemia, 3 weeks in meningitis, 4 to 6 weeks in endocarditis, and 6 to 8 weeks in brain abscess or encephalitis.

1. 2. 3. 4.

Swaminathan B, Gerner-Smidt P. The epidemiology of human listeriosis. Microbes Infect 2007; 9: 1236---4 3. Ramaswamy V, et al. Listeria�review of epidemiology and pathogenesis. J Microbial Immunol lnfect 2007; 40: 4-13. Muiioz P, et a l . First report of Listeria monocytogenes endocarditis treated with linezolid. Int J Antimicrob Agents 2006; 28: 480-l. Manfredi R, et a ! . Listeria monocytogenes meningitis and multiple brain abscesses in immunocompetent host. Favorable response to combination linezolid-meropenem treatment. J Chemother 2006; 18: 331-3. 5. Allerberger F, Wagner M. Listeriosis: a resurgent foodborne infection. Clin Microbial Infect 2010; 16: 16-23. 6. Viale P, e t al. Major role of levofloxacin in the treatment of a case of Listen"a monocytogenes meningitis. Diagn Microbiol lnfect Dis 2007; 58: 1379. 7. Morosi S, et a!. A case of rhombencephalitis caused by Listeria monocytogenes successfully treated with linezolid. J Infect 2006; 52: e73-e75. em

Lyme disease is a seasonal infectious disease caused by the spirochaete Borrelia burgdorferi and transmitted mainly by Ixodes ticks. I. scapularis, one of the species of ticks that may cause Lyme disease, may also ·be infected with, and transmit, Anaplasma phagocytophilum and/or Babesia microti and therefore the bite from this tick may lead to Lyme disease, human granulocytic anaplasmosis (see Ehrlichiosis, p. 1 79 . 1 ), or babesiosis (p. 9 2 2 . 2 ) as a single infection or as a co-infection. 1 Lyme disease was first recognised in the 1 970s in Lyme, Connecticut, but when the spirochaete responsible was later identified, it was found to occur worldwide with regional variations. Lyme disease is a multisystem disease characterised by inflammatory reactions that mainly affects the skin, nervous system, heart, and joints, and can be divided into 3 stages. In the early stage a characteristic skin lesion (erythema migrans) occurs at the site of the tick bite and may be accompanied by flu-like or meningitis-like symptoms. This may be followed weeks or months later by signs of disseminated infection, including neurological and cardiac abnormalities, and even years later by chronic arthritis and the late skin manifestation acrodermatitis chronica atrophicans, both signs of persistent infection. Appropriate treatment should prove curative, espe­ cially in the early stages. Recommendations for treatment1 -4 give oral tetracyclines (doxycycline or tetracycline) and the beta-lactam antibacterials (amoxicillin, phenoxymethyl­ penicillin, or cefuroxime) as the antibacterials of choice for early Lyme disease in the absence of neurological symptoms or advanced AV block. Treatment is usually for 14 days (range 10 to 2 1 days for doxycycline and 14 to 21 days for amoxicillin or cefuroxime) . The macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) are less effective and should only be used in patients allergic to, or who cannot be given, first-line drugs 2· 3 Young children (usually specified as below 8 years of age in the US and below 12 years in the UK) may be given amoxicillin or All cross-references refer to entries in Volume A

cefuroxime. 1•3 Pregnant women should avoid tetracyclines but may be given any of the other oral regimens. u Adults and children presenting with neurological symptoms. either early or late, should be treated with intravenous ceftriaxone, cefotaxime, or benzylpenicillin for 14 to 28 days. Patients allergic to cephalosporins or penicillins may be given oral doxycycline 200 to 400 mg daily in 2 divided doses.1·3 Early Lyme disease with cardiac complications may be treated with either an oral or intravenous antibacterial for 14 to 21 days. Lyme arthritis can generally be effectively treated with one of the oral regimens given for 28 days. Patients with ongoing or recurrent joint pain after the initial treatment course may be re-treated with either another 4-week course of oral antibacterials or with intravenous ceftriaxone for 2 to 4 weeks. Acrodermatitis chronica atrophicans may be treated with an oral antibacterial for 21 days.3 A small percentage of patients continue to have non-specific symptoms after appropriate treatment of Lyme disease; there is some controversy over whether prolonged treatment is effective in these patients and studies have suggested otherwise.'·' The use of antibac­ terials in patients with chronic (more than 6 months) subjective symptoms after recommended treatment is hotly debated9•1 0 but the Infectious Diseases Society of America (IDSA) does not support such therapy.' Adults and older children co-infected with A. phagocyto­ philum should be treated with doxycycline for 10 days. In the US, reconunended treatment for severely ill children less than 8 years of age is doxycycline for 4 to 5 days followed by amoxicillin or cefuroxime to complete a 14-day course. Patients with mild illness and who cannot be given a tetracycline may be given rifampicin 300 mg twice daily for 7 to 10 days plus amoxicillin or cefuroxime.3 Preventive measures against Lyme disease include the use of tick repellents, physical protection, 3• 1 1 . 1 2 and prompt removal of attached ticks 3 Most guidelines3• 1 1 do not support the use of empirical antibacterial therapy or serologic testing after tick bites as generally the risk of infection is low, 1 3 particularly if the tick is removed promptly. The risk of infection may, however, be greater if the tick has fed to repletion. 1 4 A study" has shown that empirical treatment with a single dose of doxycycline given within 72 hours of a tick bite may be warranted in endemic areas where the probability of infection is high. Although routine antibacterial prophylaxis is not recommended by the ID SA, 3 they recommend that a single dose of doxycycline may be given provided that the tick has been attached for 36 hours or more, prophylaxis can be started within 72 hours of the time of tick removat and the tick species can be identified as I. scapularis. Lyme disease vaccines are available in some countries.

l. 2. 3.

Steere AC. Lyme disease. N Eng! J Med 2001; 345: 115-25. Loewen PS, e t a l . Systematic review of the treatment of early Lyme disease. Drugs 1999; 57: 157-73. Wormser GP, e ta l . The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43: 1089-1134. Also available at: http://www.journals. uchicago.edu/doilpdf/10.1086/508667 (accessed 18/08/08) 4. Wormser GP. Early Lyme disease. N Bngl J Med 2006; 354: 2794-2801. 5. Klempner MS, e t al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001; 345: 85-92. 6. Kaplan RF, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology 2003; 60: 1916-22. 7. Krupp LB, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60: 1923-30. 8. Baker PJ. Perspectives on "chronic Lyme disease�. Am J Med 2008; 121: 562-4. 9. Auwacrter PG. Point: antibiotic therapy is not the answer for patients with persisting symptoms attributable to Iyme disease. Clin Infed Dis 2007; 45: 143-8. 10. Stricker RB. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with lyme disease. Clin Infect Dis 2007; 45: 149-57. 11. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of Lyme disease. Pediatn"cs 2000; 105: 142-7.[Retired October 2003] Also available at: http://aappolicy.aappublications.org/cgi/ content/full/pediatrics; 105/1/142 (accessed 01/09/10) 12. Hayes EB, Piesman J. How can we prevent Lyme disease? N Eng! J Med 2003; 348: 2424-30. 13. Shapiro ED, et a!. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. N Eng! J Med 1992; 327: 1769-73. 14. Matuschka F-R, Spielman A. Risk of infection from and treatment of tick bite. Lancet 1993; 342: 529-30. 15. Nadelman RB, et a!. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Eng! J Med 2001; 345: 79-84.

See under Sexually Transmitted Diseases, p. 207.2.

Melioidosis Melioidosis (or Whitmore's disease ) 1 ·3 is caused by the Gram-negative aerobic bacterium Burkholden·a pseudomallei (Pseudomonas pseudomallei), and naturally occurring infection is common in tropical and sub-tropical regions where it is found in soil, mud, and water; it is endemic in south-east Asia and northern Australia. 1 Its true incidence and

distribution may, however, be much wider than originally thought. B. pseudomallei has some features that makes it a candidate for deliberate release as a bioweapon. Naturally acquired infection usually occurs by inocula­ tion, or sometimes by inhalation or aspiration. Most cases occur in people with some underlying medical condition such as diabetes, chronic kidney or liver disease, or those who are immunocompromised (but HIV infection does not appear to be a major risk factor); person-to-person spread is extremely rare. The incubation period ranges from 1 to 2 1 days and i s thought t o depend o n the size and route o f the inoculum; latent intervals as long as 62 years have been reported. The expected incubation period after deliberate release of aerosol-based biological weapons is 10 to 14 days. Diagnosis is difficult because of the broad range of clinical manifestations. Melioidosis ranges from localised infection to acute pneumonia and fulminant septic infection; any organ or part of the body can become chronically infected. However, most cases present as a febrile illness with severe pneumonia and sepsis. Patients may become overwhelmed by the infection and die from septic shock within 48 hours of developing symptoms. Untreated, the mortality rate for melioidosis with septicaemia approaches 1 00 % , but with optimal treatment this can be reduced: in Thailand melioidosis is associated with a case fatality rate of about 5 0 % , u while in Australia, the rate is about 2 0 % .2 The prognosis of melioidosis is much better in children than in adults, and relapse is rare. 1 Melioidosis is difficult to treat, and response to treatment is often slow despite high -dose parenteral antibacterials being given. B. pseudomallei is also intrinsically resistant to many antibacterials including some third­ generation cephalosporins, penicillins, rifamycins, and aminoglycosides; it shows relative resistance to fluoroqui­ nolones and macrolides. 2 Treatment was based on anecdotal regimens until, in a study from Thailand, 4 intravenous ceftazidime halved the mortality of severe melioidosis when compared with conventional parenteral treatment with high doses of chloramphenicol intravenously, doxycycline, and co-trimoxazole. As a result ceftazidime came to be considered the treatment of choice for the intensive phase of treatment. 1 . 2,5 Alternatives include the carbapenems such as imipenem and meropenem.t2•5 Cefoperazone with sul­ bactam and amoxicillin with clavulanic acid have also proved effective and the latter may be given as empirical treatment for septicaemia in areas where melioidosis is endernical. u Resistance to ceftazidime and amoxicillin­ clavulanic acid has been reported, 6 emphasising the importance of careful monitoring for the emergence of resistance during treatment. Ceftazidime plus co-trim­ oxazole, both given intravenously, has been advocated by some for severe melioidosis, especially in patients with septicaemia.7 High dose parenteral antibacterial treatment should be given for at least 10 to 14 days for systemic infections followed by eradication-phase (or maintenance treatment) with oral antibacterials. Prolonged intensive­ phase parenteral therapy is generally used for deep-seated infections such as osteomyelitis, multiple undrained abscesses, or CNS infection. Granulocyte colony-stimulating factor (G-CSF) has been added to intensive phase therapy (usually meropenem) to decrease early mortality in patients presenting with severe sepsis.2•3 Introduction of G-CSF therapy at one hospital in Australia was reported to decrease the mortality rate from 95 to 1 0 % 8 However, a study in Thailand, reported no significant effect on mottality when G-CSF was given to patients with severe sepsis.9 Oral treatment should only be started when there is clear evidence of clinical improvement . 1 In Thailand, a conventional treatment regimen of chloramphenicol given for the first 8 weeks of oral treatment with doxycycline and co-trimoxazole given for 20 weeks, has been associated with relapse rates of about 1 0 % ; 1.2 this rate increased to nearly 3 0 % if antibacterial treatment was taken for 8 weeks or less. 1 Lower relapse rates have been reported in Australia where co-trimoxazole monotherapy is given for 3 to 6 months.2 A regimen of co-trimoxazole with doxycycline was found to be equivalent to the conventional regimen, as defined by culture-confirmed recurrence, 1 0 and treatment for at least 12 to 20 weeks is recommended by some experts 3 In children and pregnant women high doses of amoxicillin with clavulanic acid may be given. 1•2• 11 Some patients with mild infections, including skin and soft-tissue lesions and parotid abscesses, have been successfully treated with the oral regimens alone . 1 2 Although there is no evidence o f the protective efficacy of postexposure antibacterial prophylaxis in preventing melioidosis, on the basis of animal experiments doxycycline or co-trimoxazole may be given orally for 7 days to those known to have been exposed to heavy contamination. 1 3 I.

2. 3. 4.

White NJ. Melioidosis. Lancet 2003; 3 6 1 : 1715-22. Cheng AC, Currie BJ. Melioidosis: epidemiology, pathophysiology, and management. Clin Microbial Rev 2005; 18: 383-416. Peacock SJ. Melioidosis. Curr Opin Infect Dis 2006; 19: 421-8. White NJ, et a!. Halving of mortality of severe melioidosis by ceftazidime. Lancet 1989; ii: 697-701.

Antibacterials 5. Samuel M, Ti TY. Interventions for treating melioidosis. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2002 (ilCCessed 16/05/05). 6. Dance DAB, e t al. Development of resistance to ceftazidime and co­ amoxidav in Pseudomonas pseudomallei. J Antimicrob Chemother 1991; 2 8 : 321-4. 7. Sookpranee M, et a!. Multicenter prospective randomized trial comparing ceftazidime plm co-trimoxazole vvith chloramphenicol plus doxycycline and co-trimoxazo!e for treatment of severe melioidosis. Antimicrob Agmts Chemother 1992; 36: 158-62. 8. Cheng AC, et a!. Adjunctive granulocyte colony-stimulating factor for treatment of septic shock due to melioidosis. Clin Infect Dis 2004; 38: 327. 9. Cheng AC, et a!. A randomized controlled trial of granulocyte colony­ stimulating factor for the treatment of severe sepsis due to melioidosis in Thailand. Clin Infect Dis 2007; 45: 308-14. 10. Chaowagul W, et al. Open-label randomized trial of oral trimethoprim­ sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis. Antimicrob Agents Chemother 2005; 49: 4020-5. I. l l . Rajchanuvong A et al. A prospective comparison of co-amoxiclav and the combination of chloramphenicoL doxycycline, and co-trimoxazole for the oral maintenance treatment of melioidosis. Trans R Soc Trop Med Hyg 1995; 89: 546-9. 12. Gibney KB, et a!. Cutaneous melioidosis in the tropical Australia: a prospective study and review of the literature. 2008; 47: 603-9. 13. Health Protection Agency. Glander:. and melimdosis: guidelines for action in the event of a deliberate release (issued October 2008). Available at: http://www.hpa.org.uk/wcb/HPAwebFile/HPAweb_C/ 1 194947412449 (accessed 22/03110) Meningitis1 -4 refers to infection of the subarachnoid space and meninges, which may be caused by viruses, bacteria, protozoa, or fungi. The symptoms and signs of meningitis result from the host inflammatory response to infection. Whereas viruses cause the majority of generally mild cases of infectious meningitis, bacterial meningitis is usually a more serious condition. Meningitis may occasionally be a manifestation of non-infectious (auto-immune or neoplas­ tic) disease. This section discusses bacterial meningitis and its management. For reference to fungal meningitis, see p. 5 6 6 . 3 . The bacteria most often found i n adult or childhood meningitis (from 3 months of age) are Neisseria meningitidis (meningococci) and Streptococcus pneumoniae (pneumococ­ ci) . N. meningitidis A, C, and W 1 3 5 are the main subtypes involved in epidemics in the African meningitis belt, whereas B and C subtypes are responsible for outbreaks in Europe and North America. Haemophilus influenzae mening­ itis was a common cause of meningitis in infants and young children before the availability of H. influenzae type b vaccine, and this pathogen is stili found in non-vaccinated young children, particularly in resource-poor countries. In neonates, infants, pregnant women, immunocompromised patients, and the elderly, Listeria monocytogenes and Gram­ negative bacilli may also be encountered, and Str. agalactiae may cause meningitis in neonates and infants. Meningitis after head trauma, neurosurgery, or in the presence of CSF shunts is not infrequently caused by staphylococci (both Staphylococcus aureus and coagulase-negative staphylococci) or Gram-negative bacilli. The bacteria are transmitted from person to person through droplets of respiratory or throat secretions. Infection is spread by prolonged close contact (such as kissing, sneezing and coughing, living in close quarters or dormitories, and sharing eating or drinking utensils ) . The average incubation period is 4 days, ranging between 2 and 10 days. The clinical presentation of acute bacterial meningitis is largely dependent on the patient's age. The classic manifestations of meningitis in older children and adults, including fever, headache, neck stiffness, photo­ phobia, confusion, and vomiting, are rarely present in infants. In general, the younger the patient, the more subtle and atypical are the signs and symptoms. Fatality rates can be as low as 2 % in infants and children, and as high as 20 to 3 0 % in neonates and adults depending on the causative bacteria and patient's age. Brain damage, transient or permanent deafness, or learning disability may occur in up to one-third of survivors. A less common but more severe (often fatal) form of meningococcal disease is meningo­ coccal septicaemia which is characterised by a widespread haemorrhagic rash, acute adrenal insufficiency, and rapid circulatory collapse. (For further information see Meningo­ coccal Infections, p. 1 94. 1 . ) Choice o f treatment. Bacterial meningitis i s a medical emergency and almost universally requires hospitalisation. D eath may occur in a matter of hours if left untreated. If a patient with suspected bacterial meningitis cannot be transferred to hospital urgently, UK guidelines' advise that treatment with parenteral benzylpenicillin should be started before transfer. Alternative antibacterials include a third generation cephalosporin or chloramphenicol. 6 Patients with suspected or confirmed bacterial meningitis should have blood and/or CSF samples taken for culture and receive empirical therapy until the causative organism has been identified and susceptibility patterns have become available�7-9 Empiric antibacterials are given intravenously in relatively high doses, and treatment should be targeted at

specific organisms as soon as the results of blood and/or CSF cultures are known. The choice of empirical therapy depends on the bacterial pathogens (and their antibacterial susceptibility patterns) that are most likely to have caused meningitis and varies with age and the presence of predisposing factors such as trauma or neurosurgery. Guidelines have been published for the UK7•8•10·" and the USA, 9 and country specific guidelines should be consulted where available. • In most countries, a third generation cephalosporin (high -dose ceftriaxone or cefotaxime) is recommended as empirical treatment for bacterial meningitis in adults and children. These drugs are active against N. meningitidis, most Str. pneumoniae strains, and H. influenzae, and penetrate CSF well. • Where ceftriaxone or cefotaxime are not available or are unaffordable, a combination of ampicillin and chloramphenicol or chloramphenicol alone may be used as an alternative . 1 2 For those patients allergic to both penicillins and cephalosporins, a combination of vanco­ mycin and chloramphenicol may be given 7 • In patients over 55 years ampicillin should be added to cover Listeria.8 • Empirical treatment in neonates may also include ampicillin to cover Listeria, and an aminoglycoside to cover Gram-negative organisms. 9' 1 3 • I n the U S A and other areas where penicillin and cephalosporin-resistant pneumococci or meticillin-resis­ tant staphylococci are encountered, vancomycin (with or without rifampicin) should be given with a third­ generation cephalosporin to children or adults with bacterial meningitis.4•7-10 • Vancomycin together with ceftazidime ( or/cefepime or meropenem) should be given to patients with meningitis complicating neurosurgery, head trauma, or CSF shunts. Because of concern of suboptimal CSF penetration, vancomycin should not be used alone in patients with meningitis due to resistant pneumococci or staphylo­ cocci, especially when dexamethasone is given as well. The duration of antibacterial treatment depends on the organism isolated. For Str. pneumoniae I 0 to 14 days of treatment is recommended and for H. influenzae 7 to 14 days. For N. meningitidis 7 days, treatment is sufficient. In L. monocytogenes and group B streptococcal meningitis, antibacterials should be given for a minimum of 14 to 2 1 days while Gram-negative bacilli should b e treated for a minimum of 3 weeks.9,t4 For discussion on a shorter duration of treatment see Meningitis, under Uses and Administration of Ceftriaxone, p. 2 5 6 . 1 . Chloramphenicol i s effective for the treatment of epidemic meningococcal meningitis and ceftriaxone or chloramphenicol are the drugs of choice for patients over 2 years of age in areas with limited health facilities. u s An intramuscular dose of ceftriaxone ( I 00 mg/kg to a maximum of 4 g) was found to be as effective as an intramuscular dose of oily chloramphenicol ( I 00 mg/kg to a maximum of 3 g) for the treatment of meningococcal meningitis during epidemics in resource-poor settings . 1 6 For children under 3 months, intravenous ampicillin plus cefotaxime or gentamicin are recommended to cover probable bacteria for this age group, while for children aged between 3 months and 5 years, intravenous ceftriaxone is recommended. Those older than 5 years of age may be given intravenous ceftriaxone or ampicillin. 1 5 Prophylaxis. Immunisation is the most effective way of preventing bacterial meningitis in children and since the introduction of effective conjugate vaccines against the common meningeal pathogens the epidemiology of bacter­ ial meningitis has changed. In the developed world where these vaccines are routinely given as part of childhood immunisation programmes bacterial meningitis has become a disease of adults rather than of infants and children ' Vaccination is recommended for travellers to areas affected by meningococcal outbreaks and is compulsory for pilgrims going to Saudi Arabia. Several vaccines are available to prevent bacterial meningitis. Unconjugated polysaccharide vaccines against N. meningitidis subtypes A, C, Y, and/ or W 1 3 5, in various combinations, have been available for many years and are recommended for children older than 2 years who are at high risk of infection, such as those with asplenia and with terminal complement deficiencies, and students living in dormitories. A newer conjugated tetravalent ACWY meningococcal vaccine protects against A, C, W l 3 5 and Y meningococcal subtypes and is now a visa requirement for pilgrims to Saudi Arabia. A monovalent conjugate vaccine against N. meningitidis subtype C has recently been licensed in developed countries for use in children and adolescents. This conjugate vaccine produces better protection than unconjugated polysaccharide vaccine, in children under 2 years of age. l. 5 It has been more difficult to develop vaccines against the group B subtype, however, several avenues of research have resulted in the production of an effective vaccine against this subtype. For further information on meningococcal vaccines see, p . 2 40 1 . 3 . The newer conjugate Haemophilus

1 91

vaccines (see p. 2387 . 2 ) are similarly more immunogenic than the polysaccharide vaccine, and universal immuni­ sation of infants with these conjugate vaccines has been associated with more than 99% reduction in invasive H. influenzae type b diseases in developed countries 2 In 2000, a conjugate vaccine, directed against the seven most prevalent invasive pneumococcal strains in the USA, was approved for routine childhood immunisation and since 2009 a 1 3 -valent conjugate vaccine has been available in several countries. Three doses of the 7�valent vacdne, given at 2, 4, and 6 months of age, were assodated with a reduction of more than 90% in invasive pneumococcal infections, including sepsis and meningitis.2 For further information on pneumococcal vaccines see, p. 2410. 1 . • Close contacts of patients infected with meningococcus A, Y, or W l 3 5 should be offered tetravalent meningo­ coccal vaccine; children < 1 year of age should receive 2 doses 1 month apart. 5 • Those exposed to serogroup C infection who are unimmunised or incompletely immunised should be vaccinated with a meningococcal C vaccine. Those who completed a course more than one year before should be offered a booster. 5 • All unimmunised index cases under the age of 25 years should also be offered a meningococcal C vaccine. Cases of confirmed serogroup C disease who have previously been immunised with meningococcal C or tetravalent vaccines should be offered a meningococcal C vaccine before discharge from hospital. 5 Antibacterial treatment does not eliminate nasopharyngeal carriage of N. meningitidis and chemoprophylaxis should be given to close contacts of the index case (irrespective of vaccination status) to reduce the risk of invasive disease.5 A systematic review1 7 found that ceftriaxone, ciprofloxacin, and rifampicin were all effective at eradicating carriage for up to 2 weeks although resistance to rifampicin may occur after prophylactic treatment; penicillin was less effective. • A single oral dose of ciprofloxacin or, alternatively, oral rifampicin twice daily for 2 days should be given to close contacts as soon as possible (preferably within 24 hours) after diagnosis of the index case. For pregnant women, a single oral dose of either ciprofloxacin or azithromycin, or a single parenteral dose of ceftriaxone can be used. 5 • If further cases occur within a group of close contacts within 4 weeks of receiving prophylaxis, then repeat prophylaxis should be with an alternative recommended antibacterial.5 • Index cases (except those whose disease was treated with ceftriaxone) should be given antibacterial prophylaxis before discharge from hospital. 5 Chemoprophylaxis is also recommended for healthcare workers whose mouth or nose is directly exposed to large particle droplets or secretions from the respiratory tract of a probable or confirmed index case of meningococcal disease during acute illness and until 24 hours of systemic antibacterial treatment has been completed. 5 Similarly, treatment of H. influenzae meningitis does not eliminate nasopharyngeal carriage of the organism and rifampicin should be given to index cases for 4 days before discharge from hospital. Anyone who has been in direct or prolonged dose contact with the infected persons should also be given rifampicin for 4 days. Unvaccinated children should be immunised. Chemoprophylaxis is not normally indicated for close contacts of pneumococcal and other types of bacterial meningitis. 7, 14 The WHO recomn1endation for outbreak control is mass vaccination of persons residing in districts in the epidemic phase as well as surrounding districts in an alert phase. It is estimated that a mass immunisation campaign, promptly implemented, can avoid 70% of cases. 1 Adjunctive treatment. Mortality and morbidity, including deafness in children, remain high in meningitis despite effective antibacterial therapy. Endotoxins and other microbial products, released from bacteria after antibacterial treatment, are able to elicit a severe inflamm­ atory response, suggesting that anti-inflammatory drugs may be of benefit. A systematic review18 of adjunctive corticosteroid therapy concluded that corticosteroids reduce mortality, neurological sequelae, and especially the risk of severe hearing loss in both children and adults. This systematic review concludes that corticosteroids should be given before, or with the first dose of antibacterial in adults; the same recommendations apply to children living in high­ income countries. However, results from a study in sub­ Saharan Africa19 did not support the routine use of adjunctive corticosteroids in the treatment of adults with bacterial meningitis in resource�poor countries where Strep. pneumoniae is the main pathogen and where a large number of patients are also likely to have advanced HIV disease. Another study20 of dexamethasone in Vietnamese patients over 14 years of age with suspected bacterial meningitis reported that dexamethasone did not improve survival in all patients; significant benefit was only seen in patients with proven bacterial meningitis, including those given prior

1 92

Antibacterials

treatment with antibacterials. This finding was thought to be due to patients with tuberculosis meningitis in the treatment group. The results of a later systematic review and meta-analysis/1 which included these 2 studies, suggested that in patient populations similar to those seen in high­ income countries and in populations with a low prevalence of HIV, adjunctive treatment with corticosteroids improved survival and neurologic recovery in adults and adolescents. For information on the use of corticosteroids in tuberculous meningitis see Tuberculosis, under Uses of Corticosteroids, p. 1 6 1 4 . 3 . Careful management o f fluid and electrolyte balance may be important in the treatment of meningitis and fluid restriction to prevent cerebral oedema has been widely advocated and used in children.22•23 This practice was based on reports of hyponatraemia which were attributed to inappropriately increased concentrations of antidiuretic hormone. However, subsequent studies have suggested that the raised concentration of antidiuretic hormone may be an appropriate host response to hypovolaemia, and that more liberal use of parenteral fluids may be beneficial.2 A systematic review22 concluded that there is some evidence to support the use of intravenous fluids, in preference to restricted fluid intake, parricularly in the first 48 hours in settings with high mortality rates. However, where children present early and mortality rates are lower, there is probably little benefit and insufficient evidence to guide practice; it has been suggested that fluids should not be restricted in children. 14 The British Infection Society working party7•8 recommends that adult patients with meningitis should not be fluid restricted in an attempt to reduce cerebral oedema.

1. WHO. Meningococcal meningitis. Fact sheet No. 141 November 2012. Available at: http://www.who.int/mediacentre/factsheets/fsl41/en (accessed 04/04/13) 2. Soiez�Ilorens X , McCracken GH. Bacterial meningitis in children. Lancet 2003; 361: 2139-48. 3. Nudelman Y, Tunkel AR. Bacterial meningitis: epidemiology, pathogenesis and management update. Drugs 2009; 69: 2577-96. 4. van de Beek D, et al. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693-702. 5. Health Protection Agency. Guidance for public health management of meningococcal disease in the UK (updated March 2012). Available at: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947389261 (accessed 04/04/13) 6. Sudarsanam T, e t al. Pre·admission antibiotics for suspected cases of meningococcal disease. Available in The Cochrane Database of Systematic Reviews; Issue l. Chichester: John Wiley; 2008 (accessed 29/07/08). 7. Begg N, et al. British Infection Society Working Party. Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults. J Infect 1999; 39: 1-15. 8. British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent adults-second edition (12/04). Available at: http://www. britishinfectionsociety.org/drupal/sites/default/files/MeningitisAlgo­ rithm03.pdf (accessed 04/04/13) 9. Tunkel AR , e t al. Infectious Diseases Society of America. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39: 1267-84. Also available at: http:l/www.joumals.uchicago. edu/doi/pdf/10.1086/425368 (accessed 18/08/08) 10. Heyderman RS; British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent adults-second edition. J Infect 2005; 50: 373-4. 11. NICE. Bacterial meningitis and meningococcal septicaemia: manage­ ment of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care (issued June 2010, revised September 2010). Available at: http://www. nice.org. uk/nicemedia/live/ 1 302 7/493 39/49 3 39. pdf (accessed 16/05/l l ) 1 2 . Prasad K, et al. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2007 (accessed 20/06/08). 13. Heath PT , e t al. Neonatal meningitis. Arch Dis Child Fetal Neonatal Ed 2003; 88: F173-F178. 14. El Bashir lL et a l . Diagnosis and treatment of bacterial meningitis. Arch Dis Child 2003; 88: 615-20. 15. Meded.ns Sans FrontiCres. Clinical guidelines: diagnosis and treatment manual for curative proorammes in hospitals and dispensaries: guidance for prescribing- 2010 edition. Paris: MSF, 2010. 16. Nathan N, et a/. Ceftriaxone as effective as long-acting chloramphenicol in short·course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study. Lancet 2005; 366: 30813. 17. Zalmanovici Trestioreanu A. e t al. Antibiotics for preventing meningo­ coccal infections. Available in The Cochrane Database of Systematic Reviews; Issue 8. Chichester: John Wiley; 201 1 (accessed 08/03112). 18. Brovwer MC, e t a l . Corticosteroids for acute bacterial meningitis. Available in The. Cochrane Database of Systematic Reviews; Issue 9. Chichester: John Wiley; 2010 (accessed 04104/13). 19. Scarborough M.. e t al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007; 357: 2441-50. 20. Nguyen THM, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Eng/ J Med 2007; 357: 2431-40. 21. Assiri AM, et al. Corticosteroid administration and outcome of adolescents and adults with acute bacterial meningitis: a meta·analysis. Mayo Clin Proc 2009; 84: 403-9. 22. Maconochie IK, et al. Fluid therapy for acute bacterial meningitis. Available in The Cochrane Database of Systematic Reviews; Issue l . Chichester: John Wiley; 2008 (accessed 24/03/10). 23. Yogev R, Guzman-Cottrill J. Bacterial meningitis in children: critical review of current concepts. Drugs 2005; 65: 1097-112.

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Meningococcal disease1-3 refers to systemic infection with Neisseria meningitidis and may present clinically either as meningitis or septicaemia, or both. Less common forms of metastatic meningococcal infection include polyarthritis, All cross-references refer to entries in Volume A

pericarditis, pneumonitis, and genito-urinary-tract infec­ tions. N. meningitidis is a Gram-negative bacterium. occurring worldwide, and is classified into several serotypes. Serotypes A. C, and W l 3 5 are responsible for epidemic meningitis in sub-Saharan Africa, while serotypes B and c are the cause of outbreaks in Europe and North America. The number of cases of meningococcal disease due to serotype C has decreased significantly after the introduction of vaccination in developed countries. Infections are more common in young children under 5 years of age and in adolescents. N. meningitidis only infects humans· and about 10 to 2 5 % of the population may be carriers of the organism. The bacteria are carried in the pharynx and may sometimes penetrate the mucosa and spread through the bloodstream causing systemic disease that may rapidly progress to shock and death. Patients with meningococcal disease and asymptomatic nasopharyngeal carriers may spread meningococcal infection via respiratory droplets or throat secretions. Close and prolonged contact such as kissing, sneezing and coughing, living in close quarters, and sharing eating or drinking utensils are established risk factors. ' -2•4 Symptoms and signs during the early stage of meningococcal disease are non -specific and include fever, vomiting, malaise, and lethargy. Most patients with meningococcal septicaemia develop a vasculitic rash (petechiae or purpura) which is often scant or absent in patients with meningitis. Purpuric rash, drowsiness or impaired consciousness, and shock are late presentations and associated with high mortality rates, which may be up to 5 0 % in severe forms. Meningococcal meningitis usually presents with headache, neck stiffness, photophobia, and drowsiness. Mortality from meningo­ coccal meningitis is less than in septicaemia and may be below 5% with prompt treatment. 1•2·' Guidelines for prevention and control of meningococcal disease have been developed for the UK6·8 and the USA. 9•10 Choice of treatment. Mortality is reduced by early recognition of the disease and prompt treatment with antibacterials. In the UK, rapid admission to hospital is considered the highest priority in suspected meningococcal disease; benzylpenicillin should be given parenterally, preferably intravenously, as soon as possible (either before or after transfer) . 1 · '·8 Alternative antibacterials include a third-generation cephalosporin or chloramphenicol.' B oth initial empirical and later treatment may be with benzylpenicillin, ampicillin, chloramphenicol, or third­ generation cephalosporins such as cefotaxime or ceftriax­ one.4·5·7· u · 1 2 However, there a r e concerns about calcium chelation when ceftriaxone is given with parenteral calcium-containing products and therefore some experts advise cefotaxime as the drug of choice.7• 1 3 In infants less than 3 months of age ampicillin (or amoxicillin) should be added to provide cover against listeria! infection. 7 Oily chloramphenicol or ceftriaxone are used during epidemics in Africa and in areas with limited health facilities.• Uncomplicated meningococcal disease usually requires 7 days of antibacterial treatment. For further details of the treatment of meningococcal meningitis, including the treatment of close contacts, see Meningitis, p. 1 9 1 . 1 . Immunisation i s the most effective way o f preventing meningococcal meningitis and several vaccines are available (see Meningococcal Vaccines, p. 240 1 . 3 ) .

1. 2. 3. 4.

Welch SB, Nadel S. Treatment of meningococcal infection. Arch Dis Child 2003; 88: 608-14. Singh J, Arrieta AC. Management of meningococcemia. Indian J Pediatr 2004; 71: 909-13. Stephens DS, e t al. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 2007; 369: 2196-2210. WHO. Meningococcal meningitis. Fact sheet No. 141 2010. Available at: http://www. who.int/mediacentre/factsheets/fs 141 /en (accessed 24/03110) 5. Meningitis Research Foundation. Meningococcal meningitis and septicaemia: guidance notes, diagnosis and treatment in general practice-2008 edition. Available at: http://www.meningitis.org/assets/ xf50631 (accessed 24/03110) 6. Health Protection Agency. Guidance for public health management of meningococcal disease in the UK (updated March 2012). Available at: http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/ 1 194947389261 (accessed 04/04/13) 7. Scottish Intercollegiate Guidelines Network. Management of invasive meningococcal disease in children and young people: a national clinical guideline (issued May 2008). Available at: http://www.sign.ac.uk/pdf/ sign102.pdf (accessed 24/03/10) 8. NICE. Bacterial meningitis and meningococcal septicaemia: manage· ment of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care (issued June 2010, revised September 2010). Available at: http://www. nice .org. uk/nicemedia/live/ 1 302 7/493 39 I 493 39. pdf (accessed 17/05/11) 9. CDC. Recommendations of the Advisory Committee on Immunization Practices (ACIP): prevention and control of meningococcal disease. MM'WR 2013; 62(RR-2): 1-22. Also available at: http://www.cdc.gov/ mmwr/pdf/rr/rr6202.pdi (accessed 04/04/13) 10. American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics 2005; 116: 496-505. Full version: http://pediatrics.aappublicatlons.org/cgi/reprint/ ll6/2/496.pdf (accessed 20/03/06) 1 1 . Meningitis Research Foundation. Management of meningococcal disease in children and young people-seventh edition 10/10. Available at: http://www.meningitis.org/assets/x/50150 (accessed 04/04/13) 12. British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent

adults-second edition (12/04). Available at: http://www. britishinfectionsociety.org/drupal/sites/defaultlfiles/MeningitisAlgo­ rithm03.pdf (accessed 01105/13) 13. Cathie K, e t al. Drug use in acute meningococcal disease. Arch Dis Child Educ Pract Ed 2008; 93: 151-8.

Mouth infections Infections of the mouth include those of dental origin such as dental caries, abscesses, gingivitis, and periodontal infections, and those without a dental origin. Infections arising in the nasal cavity, middle ear, oropharynx, and paranasal sinuses can also affect the oral cavity. Emphasis has· shifted from treatment to prevention of oral diseases 1 This discussion deals mainly with infections of dental origin. The organisms most often found in oral infections are viridans streptococci, a variety of anaerobes, and facultative streptococci. Dental caries2 is a chronic disease caused by the erosion of tooth enamel due to acid produced by bacteria (usually Streptococcus mutans) in plaque. This process is affected by salivary flow and composition, exposure to fluoride, dietary sugar content, and preventative measures such as tooth brushing and flossing. Fluoride in various forms is used in dental caries prophylaxis, where it may promote remineralisation or reduce acid production by plaque bacteria.1•2 For further information on the use of fluoride for dental caries prophylaxis see under Uses and Administration of Sodium Fluoride, p. 2089.2. Sugar-free chewing gum can also help prevent caries by stimulating the production of saliva. 3•4 For further references see Dental Caries under Xylitol, p. 2220.3. Dental caries vaccines have been investigated. The term periodontal disease' refers to conditions affecting the supporting structures around the teeth (periodontium) , including the gingiva, peridontal ligament, cementum, and alveolar bone. Pathogenic bacteria in the plaque, genetic factors, tobacco and alcohol use, diabetes, immunosuppression, and the use of some drugs can contribute to such disease. Gingivitis (or gum disease) is an inflammation of the gums surrounding the teeth in response to bacterial biofilm or plaque that accumulates between the gingiva and the teeth; irritation from plaque causes pockets to develop where the gingiva separates from the tooth. Gingivitis may or may not develop into periodontitis, but periodontitis is always preceded by gingivitis. Periodontitis is an infection of the period­ ontium causing inflammation of the periodontal ligament, gingiva, cementum, and alveolar bone. With ongoing inflammation the periodontal connective tissue breaks down and destruction of the local alveolar bone occurs. Periodontal infections are usually mixed infections6·7 and are associated with an increase in the number of Gram­ negative and anaerobic bacteria. '·• Most gingivitis and periodontitis can be prevented and treated by adequate oral hygiene and plaque removal using mechanical means such as toothbrushing. Mechanical removal of calculus is necessary where the build up is significant. Antiseptics may also help to reduce plaque accumulation and several, but most notably chlorhexidine, have been used. 6•8 Oral antibacterials may be used as an adjunct to scaling, root planing, or drainage in patients with refractory disease, who are immunocompromised, or have signs of systemic illness.'· 7 Antibacterials commonly used include tetracyclines, metronidazole, amoxicillin (with or without clavulanic acid) , ciprofloxacin, and clindamycin.6 Combination therapy with metronidazole and either amoxicillin or ciprofloxacin, or amoxicillin with clavulanic acid followed by doxycycline has also been used. 6 Dentoalveolar abscesses originating from the periodontal tissue (usually caused by anaerobic bacteria) may be treated with metronidazole; clindamycin is an alternative. 7 Those originating from periapical tissues (usually caused by mixed infections) can be treated with amoxicillin, metronidazole, or clindamycin.7 Antibacterial treatment may be stopped once the systemic signs of the infection have resolved (usually after 2 to 3 days of treatment) . 7 In the UK, the BNF advises against the routine use of clindamycin in oral infections, but notes that it can be used for the treatment of dentoalveolar abscess that has not responded to penicillin or metronidazole. Prevotel/a intermedia, fusiform bacteria, and spirochaetes have also been linked with acute necrotising ulcerative gingivitis (ANUG; also called Vincent's infection or trench mouth) . ANUG may result in accelerated destruction of affected tissues, as well as local or systemic spread of infection. Treatment involves debridement and an oral penicillin with metronidazole; clindamycin monotherapy is an alternative. Antibacterials and antiseptics delivered locally to the periodontal pocket may be of value.•

1. WHO. Recent advances in oral health: report of a WHO expert committee. WHO Tech Rep Ser 826 1992. Available at: http:/llibdoc.who. int/trs/WHO_TRS_826.pdf (accessed 18/08/08) 2. Selwitz RH, et al. Dental caries. Lancet 2007; 369: 51-9. 3. Edgar WM. Sugar substitutes, chewing gum and dental caries-a review. Br Dent J 1998; 184: 29-32.

Antibacterials 4. 5. 6. 7.

Van Loveren C. Sugar alcohols: what is the evidence for caries­ preventive and caries-therapeutic effects? Caries Res 2004; 38: 286-93. Pihlstrom BL, et a!. Periodontal diseases. Lancet 2005; 366: 1809-20. Greenwell R Bissada NF. Emerging concepts in periodontal therapy. Drugs 2002; 62: 2581-7. Ellison SJ. The role of phenoxymethylpenicillin, amoxicillin, metronid­ azole and clindamycin in the management of acute dentoalveolar abscesses-a review. Br Dent J 2009; 206: 357-62. 8. Eley BM. Antibacterial agents in the control of supragingival plaque-a review. Br Dent J 1999; 186: 286-96.

MycetomaL2 is a localised infection found worldwide, but most commonly in the tropics and subtropics. Infection mainly results from trauma to the skin, and may spread locally through the lymphatic system to surrounding tissues, progressively destroying connective tissue (fascia) and bone. It is characterised by painless soft-tissue swelling, draining sinus tracts, and discharge of grains composed of large aggregates of filaments (fungal or actinomycete) . The foot is most often affected ( 7 0 to 80% of cases), less often hand ( 1 2 % ) , legs, and knee j oints. The term Madura foot is used for mycetoma affecting the foot. Mycetomas may be caused by various organisms; those caused by fungi such as Madurella mycetomatis are called eumycetomas and are discussed on p. 567. 1 . Those caused by the filamentous bacteria, actinomycetes, are called actinomycetomas: Nocardia brasiliensis is the commonest actinomycete responsible; others include Actinomadura madurae, A. pelletieri, and Streptomyces somaliensis. For details of systemic infections caused by Nocardia spp., see under Nocardiosis, p. 1 95.3. Combined drug treatment i s preferred for actinomyce­ tomas so as to avoid resistance and eradicate residual infection; cures are usually achieved after treatment for 4 to 24 months. t2 The most common regimen is streptomycin and dapsone; co�trimoxazole may replace dapsone in patients who have not responded to initial treatment after a few months and in those who cannot tolerate dapsone. Successful treatment has been reported with amikacin, either as monotherapy or with co-trimoxazole.1 Rifampicin, sulfonamides, or pyrimethamine with sulfadoxine, have been tried in resistant infections and are considered suitable for second-line therapy;1 amoxicillin with clavulanic acid has also been used successfully.' A two-step regimen4 has also been used: intensive therapy with benzylpenicillin, gentamicin, and co-trimoxazole for 5 to 7 weeks is followed by maintenance therapy with amoxicillin and co-trim­ oxazole for 2 to 5 months after clinical remission. More recently, a modified two-step regimen5 has been tried, omitting benzylpenicillin and giving gentamicin and co­ trimoxazole for 4 weeks followed by maintenance therapy with doxycycline and co-trimoxazole for 5 to 6 months after remission. Surgery is indicated for patients with infections resistant to drug therapy, deep or extensive infections, or infections with bone involvement that will not respond to long-term conventional therapy; amputation may be required in some cases. 1'2 I.

2. 3. 4. 5.

Fahal AH. Mycetoma: a thorn in the flesh. Trans R Soc Trop Med Hyg 2004; 98: 3-11. Lichon V, Khachemoune A. Mycetoma: a review. A m J Clin Dermatol 2006; 7: 315-21. Bonifaz A e t al. Treatment of actinomycetoma due to Nocardia spp. with amoxicillin-davulanate. Br 1 Dermatol 2007; 156: 308-1 1. Ramam M, et a!. A two-step schedule for the treatment of actinomycotic mycetomas. Acta Derm Venereol 2000; 80: 378-80. Ramam M, et al. A modified two-step treatment for actinomycetoma. Indian J Dermatol Venereal Leprol 2007; 73: 235-9.

���r.'?ti.si�.fi!..��-��O.�?.J.iti� .......................... ..

See p . 1 8 5 . 1 .

are necessary until infection is controlled. Intravenous antibacterial therapy is given as an adjunct and should be continued until no further debridements are needed. 1•5 Antibacterial treatment regimens should cover Gram­ positive, Gram-negative, and anaerobic organisms. The possibility of infection with group A Streptococcus or Clostridium species should also be considered. Possible treatment regimens for mixed infections include monother­ apy with ertapenem, imipenem, meropenem, piperacillin­ tazobactam, or tigecycline.4 Multidrug regimens for mixed infections include: • benzylpenicillin and clindamycin plus a fluoroquinolone or an aminoglycoside4 • benzylpenicillin and gentamicin plus metronidazole or clindamycin 1 • ampicillin-sulbactam and clindamycin plus ciproflox­ acin2 • patients known to be hypersensitive to penicillins may be given clindamycin or metronidazole with an aminogly­ coside or fluoroquinolone2 If group A Streptococcus or Clostridium is the likely cause, a combination of clindamycin and benzylpenicillin should be used.2 Until meticillin-resistant staphylococcal infedion has been ruled out, treatment regimens should also include vanco­ mycin, daptomycin, linezolid, or quinupristin/dalfopris­ tin.4·5 Hyperbaric oxygen therapy has also been beneficial although prospective controlled studies are lacking. 1 . 3·6 Intravenous normal immunoglobulins have also been tried in patients with staphylococcal or streptococcal necrotising fasciitis but further study is considered warranted.2 - 5 I. Hasham S, et al. Necrotising fasciitis. BM1 2005; 330: 830-3. Correction. ibid.; 1 143. 2. Stevens DL, et a l . Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005; 41: 1373-1406. Corrections. ibid.; 1830 and ibid. 2006; 42: 1219. [dose error] Also available at: http://www. joumals.uchicago.edu/doifpdf/10.1086/497143 (accessed 15/12/08) 3. Kihiczak GG, et al. Necrotizing fasciitis: a deadly infection. 1 Bur Acad Dermatol Venereol 2006; 20: 365-9. 4. Anaya DA. Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis 2007; 44: 705-10. 5. Sarani B, et a!. Necrotizing fasditis: current concepts and review of the literature. J Am Col! Sur,q 2009; 208: 279-88. 6. Jallali N, et al. Hyperbaric oxygen as adjuvant therapy in the management of necrotizing fasciitis. Am J Surg 2005; 189: 462-6.

chlamydia! infection than gonococcal infection' and erythromycin ointment has also been unreliable.6 Silver nitrate is generally considered ineffective, 1 despite an unexpected reduction in the incidence of chlamydia! conjunctivitis in one study. 5 The CDC4 does not recommend prophylactic antibacterial treatment for infants born to mothers with untreated chlamydia! infection. Screening and treatment of pregnant women for C. trachomatis infection may be a more effective method of control than ocular prophylaxis -' , 7 This approach also tackles the more serious problem of pneumonia.8 Neonatal conjunctivitis continues to cause blindness, especially in developing countries. Povidone-iodine is less expensive and perhaps more readily available in such countries than silver nitrate or erythromycin. In a study in Kenya involving more than 3000 infants' a 2 . 5 % ophthalmic solution o f povidone-iodine appeared t o b e a more effective prophylactic than either a I % ophthaimic solution of silver nitrate or erythromycin 0 . 5 % eye ointment. In particular, there were fewer cases of chlamydia! conjunctivitis with povidone-iodine.

TREATMENT

All cases of neonatal conjunctivitis should be treated for both N. gonorrhoeae and C. trachoma/is because of the possibility of mixed infection. 3 Gonococcal neonatal conjunctivitis must be treated systemically . WH03 recommends ceftriaxone 5 0 mg/kg by intramuscular injection as a single dose (to a maximum of 1 2 5 mg) or, if ceftriaxone is not available, spectinomycin 25 mg/kg (to a maximum of 7 5 mg) or kanamycin 2 5 mg/kg (to a maximum of 75 mg) by intramuscular injection as a single dose. In the USA, CDC4 recommends a single intravenous or intramuscular injection of ceftriaxone 25 to 50 mg/kg (up to 1 2 5 mg) when there is no evidence of disseminated infection. See also under Gonorrhoea (p. 2 0 6 . 2 ) for the treatment of infants exposed to gonorrhoea at birth or with established gonococcal infection at any site. For nongonococcal neonatal conjunctivitis WH03 and CDC4 recommend erythromycin 5 0 mg/kg daily in 4 divided doses orally for 14 days; WH03 recommend co­ trimoxazole 240 mg twice daily for 1 4 days as an alternative. There is no indication that topical therapy is of additional benefit. 3 .4

I . WHO. Conjunctivitis of the newborn: prevention and treatment at the primary health care level. Geneva: WHO, 1986. 2. Laga M, et a ! . Epidemiology and control of gonococcal ophthalmia neonatorum. Bull WHO 1989; 67: 471-8. 3. WHO. Guidelines for the management of sexually transmitted infections. Geneva: WHO, 2003. Also available at: http://whqlibdoc. who.intlpublications/2003/9241546263.pdf (accessed 22/06/04) 4. CDC. Sexually transmitted diseases treatment guidelines, 2010. MM WR 2010; 59 (RR-12): 1-1 10. Also available at: http:llwww.cdc.gov/STD/ treatment/2010/STD-Treatment-2010-RR5912.pdf (accessed 08/01/ l l ) Correction. ibid. 2011; 60: 1 8 . [dose} 5. Laga M, et a!. Prophylaxis of gonococcal and chlamydia} ophthalmia neonatorum: a comparison of silver nitrate and tetracycline. N Eng! 1 Med 1988; 318: 653-7. 6. Black-Payne C. et al. Failure of erythromycin ointment for post natal ocular prophylaxis of chlamydia} conjunctivitis. Pediatr Infect Dis J 1989; 8: 491-5. 7. Hammerschlag MR, et a!. Efficacy of neonatal ocular prophylaxis for the prevention of chlamydia! and gonococcal conjunctivitis. N Engl J Med 1989; 320: 769-72. 8. Schachter J. Why we need a program for the control of Chlamydia trachomatis. N Eng! J Med 1989; 320: 802--4. 9. Isenberg SJ, et a!. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Bngl 1 Med 1995; 332: 562--6.

Conjunctivitis of the newborn, also known as ophthalmia neonatorum, is defined as any conjunctivitis with discharge occurring during the first 28 days of life . 1 That due to Neisseria gonorrhoeae is the most serious; it usually appears by the third day after birth and can rapidly result in blindness; systemic infections, especially severe septicaemia, may occur. Chlamydia trachomatis is another major cause of neonatal conjunctivitis (inclusion conjunctivitis); it char­ acteristically occurs 5 to 14 days after birth and is less threatening to sight than gonococcal infection, but may also infect the nasopharynx and can cause pneumonia. Chlamydia! conjunctivitis is more common than gonococcal conjunctivitis in developed countries. Both organisms are sexually transmitted and the infants of mothers with such I genital-tract infections are infected during their passage 1 through the birth canal. Other less serious bacterial causes of neonatal conjunctivitis include Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus spp ., and Pseudomonas spp.; they are often hospital-acquired . ' The management of gonococcal and chlamydia! neonatal conjunctivitis varies from country to country depending on Nocardia spp. are Gram-positive aerobic branching bacteria the prevalence of gonorrhoea and C. trachomatis infection that cause systemic or localised infection. The principal and on bacterial resistance. pathogenic species in man is N. asteroides; others include N. • brasiliensis, N. pseudobrasiliensis, and N. caviae. Localised The ideal method of prophylaxis is to treat the infected chronic infection or actinomycetoma is described under mother during pregnancy, but this is not always possible. Mycetoma (above ) . Systemic nocardiosis is mainly a lung Where the risk of gonococcal infection is high, ocular infection and often involves abscess formation; it occurs prophylaxis at birth is particularly important because of especially in immunocompromised patients and may be the rapid onset of conjunctivitis and its potential disseminated with abscesses in the brain and subcutaneous seriousness and is preferable to early diagnosis and tissues. treatment of the neonate .2 Cleansing of the neonate's The treatment of choice has been a sulfonamide such as eyes immediately after birth followed by the topical sulfadiazine or co-trimoxazole, 1·5 although a study in vitro application of either tetracycline 1 % eye ointment, 3 indicated that the fixed ratio of trimethoprim:sulfamethox­ erythromycin 0 . 5 % eye ointment,4 or silver nitrate l % azole in co-trimoxazole might contain too little trimetho­ eye drops i s advised3 and i s sometimes required by law.4 prim for optimal activity.' Sulfafurazole" has been used Silver nitrate1 is active against all strains of N. gonorrhoeae successfully. There have been reports of the effective regardless of their susceptibility to antibacterials; it is treatment of nocardiosis with amikacin,8•9 linezolid, 1 0, 1 1 inexpensive and widely available, but may cause minocycline, 1 2 • 1 3 or ciprofloxacin with doxycycline . 1 4 chemical conjunctivitis and has been ineffective in preventing chlamydia! conjunctivitis (see below ) . Tetra­ Imipenem may also b e used, 1 5 and i s most active when combined with amikacin; the combination is considered by cycline has been reported to be as effective as silver some to be the best choice for initial therapy when nitrate in protecting against gonococcal conjunctivitis parenteral antibacterials are required.16•17 Other suggested caused by multiresistant strains5 and WHO now lists both alternatives include meropenem, 1 5 • 1 6 cefuroxime, 16 cefo� drugs as the drugs of choice 3 taxime, 1 6 and ceftriaxone;15•16 due to their relatively low The value of prophylaxis against chlamydia/ neonatal toxicity and excellent CSF penetration, these antibacterials conjunctivitis is less certain. Tetracycline ointment has been reported to be less effective in preventing may be particularly useful in cerebral nocardiosis. 16

Nocardiosis

PROPHYLAXIS

Necrotising fasciitis1 - 5 i s an uncommon but severe soft­ tissue infection resulting in necrosis of the subcutaneous tissue and adjacent fascia, together with severe systemic illness, and is associated with high morbidity and mortality rates. Type I infections are caused by a mixture of aerobic and anaerobic organisms, whereas type II are mono­ microbial infections due to group A streptococci or staphylococci and may be associated with a toxic shock syndrome (p. 2 1 1 . 3 ) . Some definitions recognise type III infections due to Vibrio vulnificus, mainly occurring in patients with liver disease and often rapidly progressive and fatal. Necrotising fasciitis can affect any part of the body but is most common on the extremities, the perineum, and the trunk. (The term Fournier's gangrene has been used to describe rapidly progressive necrotising fasciitis of the perineum and genitals.) Necrotising fasciitis usually follows trauma, and most patients have pre�existing conditions that predispose to infection, such as diabetes mellitus, chronic renal failure, peripheral vascular disease, or parenteral drug abuse. C omplete debridement of the infected tissue is considered essential for treatment; repeated debridements

•

1 93

1 94 Antibacterials Treatment of nocardiosis needs t o be prolonged a n d may continue for at least 6 to 1 2 months, depending on the site of infection and the immune status of the patient.5•16

1. 2. 3. 4.

Abdi EA. et a l . Nocardia infection in splenectomized patients: case reports and a review of the literature. Postgrad Med J 1 987; 63: 455--8. Smego RA. et. a/. Treatment of systemic nocardiosis. Lancet 1 987; i: 456. Filice GA. Treatment of nocardiosis. Lancet 1 987; i: 1261-2. Varghese GK, et al. Nocardia brasiliensis meningitis. Postgrad Med J 1992; 68: 986. 5. Agterof MJ , et al. Nocardiosis: a case series and a mini review of clinical and microbiological features. Neth J Med 2007; 65: 199-202. 6. Bennett JE, Jennings AE. Factors influencing susceptibility of Nocardia spedes to trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother 197 8; 13: 624-7. 7. Poland GA, et al. Nocardia asteroides pericarditis: report of a case and review of the literature. Mayo Clin Proc 1990; 65: 819-24. 8. Goldstein FW, et al. Amikadn·containing regimens for treatment of nocardiosis in immuncicompromized patients. Bur J Clin Microbiol 1 987; 6: 198-200. 9. Meier B, et al. Successful treannent of a pancreatic Nocardia asteroides abscess with amikacin and surgical drainage. Antimicrob Aoents Chemother 1986; 29: 1 50- 1 . 10. Moylett ElL et al. Clinical experience with linezolid for the treatment of Nocardia infection. Clin Infect Dis 2003; 36: 3 1 3- 1 8 . 11. Jodlowski TZ, e t a l . Linezolid for the treatment of Nocardia spp. infections. Ann Pharmacother 2007; 41: 1694-9. 12. Petersen EA. et al. Minocycline treatment of pulmonary nocardiosis. JAMA 1 98 3 ; 250: 930-2. 13. Naka W, et al. Unusually located lymphocutaneous nocardiosis caused by Nocardia brasiliensis. Br J Dermato1 1 995; 132: 609-13. 14. Bath PMW, e t a l . Treatment of multiple subcutaneous Nocardia asteroides abscesses with dprofloxadn and doxycycline. Postgrad Med J 1989; 65: 190-1. 15. Abramowia M, ed. Th e choice of antibacterial drugs. In: Handbook of antimicrobial therapy. 19th ed. New Rochelle NY: The Medical Letter, 201 1: 7 3 . 16. Corti ME, Villafafie Fioti MF. Nocardiosis: a review. Int J Infect Dis 2003; 7: 243-50. 17. Ameen M, et al. Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulfonamides. J Am Acad Dermatol 20 I 0; 62: 239-46.

�����.c:�!.�.��. .l!!r:oJ�.':'��C!?./..!�.'�t!.�.��...........

Environmental mycobacteria are widespread, and many species other than those responsible for leprosy (p. 1 8 8 . 3 ) and tuberculosis (p. 2 1 2 . 2 ) a r e facultative parasites capable of producing disease in man. These organisms, which have been referred to as atypical, nontuberculous (NTM), tuberculoid, opportunistic, or MOTI (mycobacteria other than tuberculous), are rarely, if ever, transntitted from person to person but are acquired from the environment. Symptomatic infections are usually associated with focal or generalised defects in the host's immune system. The diseases produced include localised skin and soft tissue lesions, pulmonary infections, lymphadenitis, and dis senti­ nated infections. Cutaneous disease may follow traumatic inoculation with Mycobacterium marinum ( 'swinuning pool' or 'fish-tank' granuloma) , M. ulcerans (Buruli ulcer) , M. chelonae (M. chelonei), M. abscessus (formerly M. chelonae subspecies ) , or M. fortuitum. Ulcerated lesions due to M. haemophilum have been described mainly in immunocomprontised patients. Pulmonary disease may be clinically indistinguishable from pulmonary tuberculosis, and has most frequently been attributed to the M. avium complex (MA C ) , which includes M. avium and M. avium-intracellulare, or to M. kansasii, and to a lesser extent M. xenopi; less common causes include M. abscessus, M. asiaticum, M. celatum, M. chelonae, M. fortuitum, M. malmoense, M. scrofulaceum, M. simiae, and M. szulgai. Lymphadenitis, which is usually self-lintiting and occurs particularly in children under 5 years of age, may be caused by many species but the great majority of cases are due to M. avium complex, M. genavense, M. malmoense, and M. scrofulaceum (sometimes collectively known as the MAIS complex) . Dissemination o f opportunistic mycobacterial infections may occur rapidiy in immunocompromised patients. The majority of cases have been attributed to the M. avium complex; other species implicated include M. abscessus, M. celatum, M. chelonae, M. genavense, M. haemophilum, M. kansasii, M. malmoense, M. scrofulaceum, and M. simiae. The treatment depends on the site and nature of the infection and whether immunodeficiency is present. Both HIV -negative and HIV -positive patients may be affected and the possibility of drug interactions should be borne in ntind in patients receiving antiretroviral therapy.

•

MYCOBACTERIUM AVIUM COMPLEX (MAC).

U S guidelinesl . 2 produced b y the C D C , National Institutes of Health, HIV Medicine Association, and Infectious Diseases Society of America recommend that the treatment of HIV·positive patients with MAC should consist of at least 2 antimycobacterial drugs. Clarithromycin is the preferred first drug (with azithro­ mycin as an alternative) and is given with ethambutol. Use of a third, and possibly, fourth, drug should be considered in patients with advanced immunosuppres� sian ( CD4+ T lymphocyte count less than 5 0 cells/ nticrolitre), high mycobacterial loads, or if the patient is not taking effective HAART. Rifabutin is often used as the third drug, while a fluoroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin) or aminoglycoside

All croSs�references refer to entries in Volume A

(antikacin or streptomycin) can be considered when a fourth drug is needed or rifabutin cannot be used. In

disseminated disease, patients who are not taking

HAART should generally delay starting antiretroviral treatment until after at least 2 weeks of treatment for MAC has been completed. in order to reduce the risk of significant drug interactions or complications due to immune reconstitution syndrome. Those aiready on HAART should continue this treatment if possible. Earlier UK guidelines from the British Thoracic Society ( 1 999, not subsequently updated)' for treatment of HIV­ positive patients with MAC broadly concur with the US recommendations. Rifampicin or rifabutin, ethambutol. and clarithromycin or azithromycin were recommended. A fluoroquinolone such as dprofloxadn, or even antikacin, might be added for patients who were intolerant of first-line drugs or who failed to respond. UK guidelines recommended lifelong treatment; the US considers that treatment may be stopped in selected patients (see Chemoprophylaxis, below ) . In dissemi­ nated disease, the same treatment should be given and continued indefinitely. A prospective, randomised study4 undertaken to compare 3 regimens (clarithromycin and ethambutol. clarithromycin and rifabutin, and all 3 drugs) for the treatment of disseminated MAC in patients with AIDS found that all regimens appeared to provide effective treatment and the differences were not statistically significant. However, patients taking the 3-drug regimen had greater overall clinical efficacy, a lower relapse rate, and a lower risk of death. The 1 999 British Thoracic Society guidelines' state that treatment for HIV-negative patients with MAC pulmonary disease should consist of rifampicin and ethambutol for 24 months, with or without isoniazid. In extrapulmonary disease affecting lymph nodes, surgical excision of the nodes should be undertaken; chemo­ therapy with rifampicin, ethambutol. and clarithromycin for up to 2 years should be considered if disease recurred or where exdsion was incomplete or impossible. In sites other than lymph nodes, chemotherapy should be given for 18 to 24 months. US guidelines' from the American Thoracic Society and the Infectious Diseases Society of America suggest that for ntild nodular or bronchiectatic pulmonary disease, an intermittent regimen of clarithro­ mycin (or azithromycin) , rifampicin, and ethambutol three times weekly is usually sufficient; therapy should be continued until sputum cultures have been negative for 12 months. For severe pulmonary disease or in previously treated patients, a daily regimen should be used; addition of interntittent amikacin or streptomycin for the first few months of therapy can also be considered. Prophylactic treatment is used to reduce the incidence of disseminated MAC disease in patients with IDV infection. There appears to be a tendency to delay starting prophylaxis until later in the disease process; US guidelines2•5 recommend starting prophylaxis in adults and adolescents at a CD4+ T lymphocyte count of less than 50 cells/nticrolitre with either azithromycin or clarithromycin. If these drugs cannot be tolerated then rifabutin may be given as an alternative. Combination therapy with one of the macrolides and rifabutin is not recommended. US guidelines state that prophylaxis need not be lifelong in patients responding to HAART; specifically, primary prophylaxis may be stopped in adults and adolescents whose CD4+ T lymphocyte count has increased to more than 1 00 cells/microlitre for 3 months or more, but should be restarted if the CD4+ count falls to below 5 0 to 100 cells/nticrolitre again. Observational data from a large cohort of patients in the USA found no evidence of increased risk of MAC in patients who had stopped primary prophylaxis in accordance with these guidelines.• US guidelines2•5 also state that it may be possible to stop secondary prophylaxis (chronic maintenance therapy) in HIV -infected adults and adolescents who have completed at least 12 months of treatment for MAC, who remain asymptomatic with respect to MAC, and who have . a sustained response to HAART ( CD4+ T lymphocyte count greater than 1 0 0 cells/nticrolitre for more than 6 months) . Secondary prophylaxis should be restarted if CD4+ T lymphocyte count falls below 1 00 cells/ microlitre. In children, CD4+ T lymphocyte count thresholds for starting, stopping, or resunting prophy­ laxis vary depending on the age of the child. 1 In the UK. however, the earlier British Thoracic Society guidelines noted there was no general agreement about when prophylaxis should be used. If prophylaxis were to be given to patients with a CD4+ T lymphocyte count below 50 cells/microlitre the first drug of choice would be azithromycin; clarithromycin was an alternative and azithromycin with rifabutin would be a third choice. 3 These guidelines, partly based on studies which predate

•

•

the wide use of HAART, recommended that prophylaxis be continued indefinitely. '

MYCOBACTERIUM KANSASII INFECTION.

UK guidelines stated that infections with M. kansasii ntight be treated with rifampicin (or rifabutin) and ethambutol . ' Pulmonary disease in IllY -negative patients was usually treated for 9 months whereas HIV­ positive patients should receive therapy for 2 years or until the sputum has been negative for 12 months. For disseminated infection in HIV -positive patients, clarithromycin should be added and possibly also isoniazid. The place of macrolides and fluoroquinolones in pulmonary or dissentinated M. kansasii infection remained to be established. In extrapulmonary disease in HIV -negative patients, chemotherapy with rifampicin and ethambutol might be used before excision of an infected lymph node. In other extrapulmonary disease the guidelines stated that the data were insufficient to make recommendations, but considered that rifampicin and ethambutol for 9 months appeared sensible, with the addition of protionantide and streptomycin and/or a macrolide if the condition is not responding. 3 US guidelines' suggest the use of rifampicin, ethambutol, and isoniazid for M. kansasii pulmonary infection; treatment should be continued until sputum cultures have been negative for 12 months. For disseminated disease in immunocompromised patients, indefinite treatment may be required until sufficient recovery of immune status occurs.

OTHER OPPORTUNISTIC MYCOBACTERIA.

In M. malmoense and M. xenupi pulmonary disease, UK guidelines have recommended that rifampicin and ethambutol should be given for 2 years in HIV -negative patients. Extrapulmonary M. malmoense infections should be treated in the same manner as extrapulmonary MAC or M. kansasii infections. M. malmoense infection rarely occurs in AIDS patients, but if necessary, treatment with rifampicin, ethambutol. and clarithromycin, and possibly isoniazid should be used. For M. xenopi in IDV -positive patients the guidelines stated that there was no evidence on which to base recommendations; treatment as for pulmonary or disseminated MAC infection was suggested. 3 For pulmonary disease due to rapidly growing bacteria (M. abscessus, M. chelonae, M. fortuitum, and M. gordonae) and other species (M. genavense, M. haemophilum, M. simiae, M. szulgai, and M. ulcerans) surgery should be used if possible. Drug therapy should probably include rifampicin, ethambutol, and clarithromycin. Amikacin, cefoxitin, intipenem, quinolones, and sulfonantides ntight have a place in treatment. For extrapulmonary disease due to these organisms, there had been several anecdotal reports outlining treatment but there was no evidence from controlled clinical studies.' Successful treatment of M. simiae infection in patients with AIDS was reported with clarithromycin, ethambutol. and ciprofloxacin. 7 Surgical treatment and intensive antibac­ terial regimens have been used for M. scrofulaceum infections • Symptomatic improvement was achieved in an AIDS patient with M. celatum infection with a regimen of isoniazid, rifampicin, and ethambutol? For cutaneous infections due to M. marinum (swim­ nting-pool granuloma or fish-tank granuloma) many antibacterial regimens have been used, 1 0 including rifampicin with ethambutol' ' or isoniazid, rifabutin with ciprofloxadn, 1 2 minocydine with co�trimoxazole, 1 3 clarithromydn with rifabutin 14 o r dprofloxadn 12 or ethambutol. " Monotherapy with clarithromycin, ntino­ cycline, doxycycline, or co-trimoxazole have each been tried, mainly in small series of patients. US guidelines' suggest that for treatment of M. marinum infection, the use of 2 active antimycobacterials until 1 to 2 months after symptoms of infection have resolved may be a reasonable approach. Buruli ulcer, due to M. ulcerans, is difficult to treat and usually requires surgery; responses to antimycobacterial monotherapies have been generally disappointing. However, recent evidence suggests that combination antibacterial therapy may reduce the healing time and recurrence rates of ulcers, and minimise or avoid the need fpr surgery . " Treatment of nodules and plaques of early Buruli ulcers with rifampicin and streptomycin for up to 12 weeks, showed inhibition of growth 4 weeks after starting treatment . 1 6 Furthermore, no lesions enlarged during the treatment period. WHO therefore recommends the use of rifampicin and streptomycin or amikacin for 8 weeks . 1 7 Consensus recommendations issued by practitioners in Victoria, Australia 18 consider surgery to be the best treatment for Buruli ulcer, with antibacterial therapy bejng indicated for more extensive disease. Use of antibacterials may also possibly allow more conservative resection and reduce the risk of relapse. The recommended oral regimens were: at least 3 months of rifampicin given with clarithromycin, cipro­ floxadn, or moxifloxadn. For more severe or extensive

Antibacterials disease patients may also require intravenous arnikacin for 4 to 8 weeks in addition to oral therapy. Reports of other therapies include a beneficial response vvith topical nitrogen oxides in a small pilot study of 3 7 patients with Buruli ulcer, 1 9 and healing after local application of phenytoin. 20 Cutaneous disease due to M. haemophilum infection has been treated with an initial treatment course of rifabutin, ciprofloxacin, and clarithromycin, followed by clarithro­ mycin for 2 years. 21 M. chelonae was successfully treated with clarithromycin and linezolid for one month, followed by a further 5 months of treatment with 1 clarithromycin.22

CDC. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: reconunen­ dations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. .Ml\.fVVR 2009; 58 (RR-11): 1 166. Also available at: http://www.cdc.gov/ mmwr/PDF/rr/rr5811.pdf (accessed 05/02/10) 2. CDC. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR 2009; 58: (RR-4): 1-207. Also available at: http://wwvv.cdc.gov/mmwr/pdflrr/ rr5804.pdf (accessed 05/02110) 3. Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunist mycobacterial infections: Joint Tuberculosis Committee guidelines 1999. Thorax 2000; 55: 210-18. Also available at: http://www.brit-thoracic.org.uk/Portals/O/Clinical% 20lnformation/Opportunist%20Mycobacteria/Guidelines/OppMyco. pdf {accessed 18/08/08) 4. Benson CA, et al. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired inununodeficiency syndrome. Clin Infec:t Dis 2003; 37: 1234-43. 5. American Thoracic Society. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Cn't Care Med 2007; 175: 367-416. Correction. ibid.; 744-5. [dme] Also available at: http:/ /ajrccm.atsjournals.org/cgilreprint/175/4/ 367 (accessed 05/02110) 6. Brooks JT, et a l . Discontinuation of primary prophylaxis against Mycobacterium avium complex infection in IDV-infected persons receiving antirctroviral therapy: observations from a large national cohort in the United States, 1992-2002. Clin Infect Dis 2005; 41: 549-53. 7. Barzilai A, et a l . Successful treatment of disseminated Mycobacterium simiae infection in AIDS patients. 1998; 30: 143-6. disease. Chest 1983; 84: 8. Bailey WC. Treatment of atypical 625-8. 9. Piersimoni C, et al. Disseminated infection due to Mycobacterium celatum in patient vvith AIDS. Lancet 1994; 344: 332. 10. Aubry A, et a l . Sixty-three cases of Mycobacterium marinum infection: clinical features, treatment, and antibiotic susceptibility of causative isolates. Arch Intern Med 2002; 162: 1746-52. 11. Donta ST, et a!. Therapy of Mycobacterium marinum infections: use of tetracyclines vs rifampin. Arch Intern Med 1986; 146: 902-4. 12. Laing RBS, et al. Antimicrobial treatment of fish tank granuloma. J Hand Surg (Br) 1997; 22B: 135-7. 13. Gray SF, et al. Fish tank granuloma. BMJ 1990; 300: 1069-70. 14. Laing RBS, et al. New antimicrobials against Mycobacterium marinum infection. Br J Dermatol 1 994; 131: 914. 15. Sizaire V, et a!. Mycobacterium ulcerans infection: control, diagnosis, and treatment. Lancet Infect Dis 2006; 6: 288-96. 16. Etuaful S, et al. Efficacy of the combination rifampin-streptomyctn in preventing growth of Mycobacterium ulcerans in early lesions of Bumli ulcer in humans. Antimicrob Agents Chemother 2005; 49: 3182-6. 17. WHO. Provisional guidance on the role ofspecific antibiotics in the management My 9 0 % susceptibility to fluoroquinolones . 1 4 F o r patients with only mild or moderate community­ acquired infection, drugs with the broadest spectrum of Gram-negative and Gram-positive coverage ( such as ertapenem and tigecycline) have no advantage and may contribute to the emergence of more resistant organisms. Similarly, aminoglycosides are not routinely recommended due to their potential toxicity, although empirical use may be warranted in patients with healthcare-associated infection or intolerance to beta-lactam or fluoroquino­ lone-based regimens.14 The intravenous route is generally preferred, and therapy should be tailored to culture and susceptibility reports when available. Treatment is generally continued until clinical signs of infection and gastrointestinal function have returned to normal; where source control has been adequate, about 5 to 7 days has been suggested 1 5 For reference to the prevention of postoperative iufection, see under Surgical Infection, p . 2 1 1 . 1 . P D peritonitis. Peritonitis i s the main complication of peritoneal dialysis (PD ) . Like primary, and, uulike secondary peritonitis, above, a single infecting organism is often responsible. The most common infections have usually been due to Gram-positive organisms, especially staphylococci, but infections with Gram-negative bacteria (typically Enterobacteriaceae) are becoming more common, and fungi are an increasingly important cause of peritonitis in PD . 1 The origin of infection is often contamination of the dialysis catheter or the exit site. The International Society for Peritoneal Dialysis recommends 18 that the choice of antibacterial for empirical treatment be based on the history of sensitivities of organisms causing peritonitis in the particular hospital or centre involved, and be active against both Gram-positive and Gram-negative organisms. In many cases, first­ generation cephalosporins such as cefazolin or cefalotin provide adequate Gram-positive coverage, but in centres All cross-references refer to entries in Volume A

with high rates of meticillin-resistant infection empirical vancomycin may be needed. Drugs for Gram-negative coverage should possess activity against Ps. aeruginosa and may include the aminoglycosides, ceftazidime, cefepime, a carbapenem, or aztreonam. Fluoroquinolones are only appropriate for Gram-negative coverage if local suscept­ ibility is shown. Intraperitoneal dosage, by mixing the antibacterials with the dialysate, has been shown to be more effective than intravenous use. For many antibacterials, once-daily iutermittent dosing regimens (in a single dialysate exchange) are appropriate and as effective as continuous regimens. 1 9 Intermittent doses of vancomycin are generally given once every 5 to 7 days. 1 8 Once the infecting organism is identified, an appropriate narrow-spectrum antibacterial can be substituted. Treatment is generally continued for 1 4 days i n patients who have a clinical response. Treatment should be extended to 2 1 days in patients with severe infections ( such as Staph. aureus, Gram-negative, or enterococcal peritonitis ) . Exit-site infections can b e treated with a n oral penicillinase-resistant penicillin, a first-generation cepha­ losporin such as cefalexin, or co-trimoxazole for Gram­ positive infections. Vancomycin should be avoided for routine use but may be needed if there is meticillin resistance. Rifampicin may be added in severe Staph. aureus infections. An oral fluoroquinolone such as ciprofloxacin may be used for Gram-negative infections. 1 8 Intraperitoneal ceftazidime may be added in cases of pseudomonal infection where resolution of infection is slow or where there is recurrence. Long-term antibacterial prophylaxis is not generally effective, but intermittent use has been advocated in situations associated with higher risk of infection. Perioperative intravenous antibacterial prophylaxis during PD catheter insertion is recommended, 18 and has been shown to significantly reduce the risk of peritonitis in the first month after surgery. 20 Staph. aureus nasal carriage is associated with increased risk of exit -site infections and intranasal or exit-site mupirocin (cream, as ointment may damage the catheter) or exit-site gentamicin cream have been used to reduce them . 18 The results of a systematic review suggest that treating carriers with intranasal mupirocin significantly decreases overall rates of exit -site infections, although there does not appear to be an associated reduction in risk of peritonitis.20 Dramatic reductions in peritonitis rates have been achieved with programmes based on stringent aseptic wound care and on minimising contact of the PD system with domestic water. 2 1

1. 2. 3. 4.

Johnson CC, e t a!. Peritonitis: update on pathophysiology, clinical manifestations, and management. Clin Infect Dis 1997; 24: 1035-47. Rimula A, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000; 32: 142-53. Koulaouzidis A, e t a l . Spontaneous bacterial peritonitis. World J Gastroenterol 2009; 15: 1042-9. Chavez-Tapia NC, et al. Antibiotics for spontaneous bacterial peritonitis in cirrhotic patients. Available in The Cochrane Database of Systematic Reviews; Issue l. Chichester: John Wiley; 2009 (accessed 15!04/09). 5. Gilbert JA, Kamath PS. Spontaneous bacterial peritonitis: an update. Mayo Clin Proc 1995; 70: 365-70. 6. Runyon BA, et al. Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis: a randomized controlled study of 100 patients. Gastroenterology 1991; 100: 1737-42. 7. Gines P, et a!. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990; 12: 716-24. 8. Saab S, et al. Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis. Am J Gastromterol 2009; 104: 993-1001. 9. Singh N, e t a l . Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995; 122: 595-8. I 0. Frazee LA, et al. Long-term prophylaxis of spontaneous bacterial peritonitis in patients with cirrhosis. Ann Pharmacother 2005; 39: 908-12. 11. Cohen MJ, et a l . Antibiotic prophylaxis for spontaneous bacterial peritonitis in cirrhotic patients with ascites, without gastro-intestinal bleeding. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2009 (accessed 13/04/10). 12. Bernard B, e t a l . Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta­ analysis. Hepatology 1999; 29: 1655-61. 13. Soares-Weiser K, et a!. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2002 (accessed 15/04/09). 14. Solomkin JS, et a l . Diagnosis and management of complicated intra­ abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50: 133-64. Also published inSurg Infect (Larchmt) 2010; 1 1 : 79-109. Also available at: http://wvvw.idsociety.org/WorkArea/ linkit.aspx?Linkldentifiero:oid<emiD==1 5966 (accessed 04/05/10) 1 5. Blot S, De Waele JJ. Critical issues in the clinical management of complicated intra-abdominal infections. Drugs 2005; 6 5 : 161 1-20. 16. Harbarth S, Uckay I. Are there patients with peritonitis who require empiric therapy for enterococcus? Bur J Clin Microbial Infect Dis 2004; 23: 73-7. 17. Wong PF, et al. Antibiotic regimens for secondary peritonitis of gastrointestinal origin in adults. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2005 (accessed 15/04/09). 18. Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int 2005; 25: 107-31. Also available at: http:// www.ispd.org/guidelines/03Piraino42371SPD%20with%20watermark. pdf (accessed 27106106)

19. Wiggins KJ, et al. Treatment for peritoneal dialysis-associated peritonitis. Available in The Cochrane Database of Systematic Reviews; Issue l . Chichester: John Wiley; 2008 (accessed 15/04/09). 20. Strippoli GF, e t a l . Antimicrobial agents for preventing peritonitis in peritoneal dialysis patients. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2004 (accessed 15/04/09). 21. Ludlam H, et a l . Prevention of peritonitis in continuous ambulatory peritoneal dialysis. Lancet 1990; 335: 1 161.

Pertussis Pertussis or whooping cough 1 is caused by infection with the respiratory pathogen Bordete/la pertussis, a Gram­ negative aerobic bacterium. The related species B. parapertussis causes a similar but generally milder illness. Pertussis is very infectious and occurs most frequently in children, but may be more common in adults than once thought. The incidence of pertussis has been greatly reduced by the active immunisation of infants (see under Pertussis Vaccines, p . 2408 . 3 ) and effective prevention by the adequate uptake of vaccine remains the ultimate objective. Erythromycin has been the autibacterial of choice, but the newer macrolides, clarithromycin and azithromycin, have similar efficacy and are also recommended for the treatment of pertussis. 1 ·� Once infection has occurred antibacterial therapy is thought to reuder the patient non-infectious by eliminating nasopharyngeal carriage of B. pertussis. Such treatment is unlikely to affect the clinical course of pertussis because diagnosis is difficult until the paroxysmal stage, hy which time the bacteria have already damaged the respiratory tract and released their toxins. Effective regimens include:2'3 • oral azithromycin 500 mg daily on the first day of treatment then 2 5 0 rng daily for 4 days; infants and children may be given oral azithromycin !0 mg/kg daily for 3 to 5 days, or I 0 mg/kg daily on the first day of treatment then 5 rng/kg daily for 4 days • oral clarithromycin 500 mg twice daily for 7 days; infants aud children may be giveu oral clarithromycin 7. 5 mg/kg twice daily for 7 days • oral erythromyciu 500 mg four times daily for 14 days; infants and children may be given oral erythromycin 40 to 50 mg/kg daily in 3 to 4 divided doses for 7 to I 4 days, or 60 mg/kg daily in 3 divided doses for 14 days Oral co-trimoxazole for 7 to I 4 days may he given as an alternative treatment for patients unable to tolerate macrolides. Oxytetracycline or chloramphenicol are not recommended because of their potential adverse effects. Macrolide antibacterials, given in the same doses as for treatment and within 3 weeks of onset of cough in the index patients, may also be given prophylactically to close contacts.2 However, protection is limited and a systematic review3 concluded there was insufficient evidence to determine the benefit of prophylactic treatment of healthy pertussis contacts. I. Crowcroft NS, Pebody RG. Recent developments in pertussis. Lancet 2006; 367: 1926-36. 2. CDC. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR 2005; 54 (RR-14): l-16. Also available at: http:/lwww.cdc.gov/mmwr/ PDF/rr/rr5414.pdf (accessed 18/08/08) 3. Altunaiji S, et al. Antibiotics for whooping cough (pertussis). Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2007 (accessed 27/06/08).

P.�.CI'Y�git!s

Pharyngitis and tonsillitis are upper respiratory-tract infections with similar causes and occur especially in children. Acute pharyugitis is an inflammatory syndrome of the oropharynx that n1ay include the tonsils whereas tonsillitis is, strictly speaking, a more localised infection. The commonest causes are viral and a sore throat is often a symptom of the common cold as well as influenza and infectious mononucleosis. For further details of these viral infections, see under Choice of Antiviral. p. 9 5 3 . 1 . The most important bacterial cause of acute pharyngitis and tonsillitis is the group A beta-haemolytic streptococcus, Streptococcus pyogenes. Au erythrogenic toxin-producing strain causes pharyngitis and tonsillitis in scarlet fever. In view of the prevalence of a viral cause, opinions have differed over whether and when to treat pharyugitis with antimicrobial drugs. Some have advocated waiting until a definite diagnosis of Str. pyogenes infection is made, but others treat immediately if streptococcal pharyngitis is suspected because of the risk of longer term complications such as rheumatic fever and the need to eradicate Str. pyogenes from the throat . 1 ·3 The incidence of rheumatic fever has heen low for many years in developed countries, but there was evidence of a resurgence in parts of the USA in the mid- I 980s. Thus, in addition to shortening the illness and interrupting transmission, the antibacterial treatment of streptococcal pharyngitis also serves as primary prevention of rheumatic fever (see below). However, in countries in which the incidence of rheumatic fever remains low the routine use of antibacterials for the management of sore throats is discouraged.4'5

Penicillin is the standard treatment for streptococcal pharyngitis or tonsillitis,6�8 generally as phenoxymethyl­ penicillin orally for lO days or a single intramuscular injection of benzathine benzylpenicillin. Both options are advocated by WH07 and the American Heart Association8 for the primary prevention of rheumatic fever (see under Rheumatic Fever, p. 204.3 ), the latter particularly where compliance with a I OM day course of oral penicillin is unlikely. Oral amoxicillin is also effective7·9 and a further treatment option for confirmed streptococcal pharyngitis;8 however, some suggest that empirical use of aminopeniM cillins (including amoxicillin and ampicillin) should probably be avoided because of the risk of maculopapular rash if the patient proves to have infectious mononucleoM sis . 1 0 Erythromycin or another macrolide may be given to penicillin-allergic patients, except where there is evidence of significant resistance, 7•8 as in some parts of Europe, 7 the USA, 1 1 Japan, 1 2 and Finland; 1 3 it may also be a better choice than penicillin if there is a likelihood of infection with Arcanabacterium haemolyticum ( Corynebacterium haemolyti­ cum) , but should be avoided if there is risk of infection with Fusobacterium necrophorum (see below ) . Clindamycin may also be used. 8 Oral cephalosporins are another alternative, and a meta-analysis14 has shown that the likelihood of treatment failure with oral cephalosporins may be about half that with penicillin; first-generation cephalosporins appear no less effective than later generations, 14 and are generally preferred due to their narrower antibacterial spectrum. 8· 14 Despite the general efficacy of penicillin a trend of increasing numbers of relapses and recurrent infections has been noted. 1 5 Some treatment failures have been attributed to poor patient compliance with a 1 0-day course of penicillin and attempts to overcome this have included giving fewer daily doses or shortening the length of treatment. Meta-analysis of studies supports the use of twice-daily dosing of pbenoxymethylpenicillin which appears to be as effective as doses three or four times daily, 16 but a single daily dose is less effective. Courses of phenoxymethylpenicillin shorter than I 0 days have not proved effective.17·1 8 There is some evidence that shorter courses may be possible with other antibacterials. 1 9 Courses of 5 days or Jess of erythromycin, 20 amoxicillin with davulanic add, 2 1 azithromycin,22·23 clarithromycin,24 j osa­ mydn,25 telithromydn, 26 or cephalosporins27 have been given as alternatives to a I 0-day course of phenoxymethyl­ penicillin. However, definitive studies have not been done, and the broader spectrum and higher cost of these regimens are drawbacks. 6 Penicillin resistance in Str. pyogenes remains rare. In addition to poor compliance, treatment failures with penicillin, leading to recurrent infection, might be explained by the presence of beta-lactamase-producing oropharyngeal bacteria that are able to protect Str. pyogenes against penicillin, 28 although this theory was not supported by a study in 462 children. 29 Antibacterials less susceptible to beta lactamase have been effective, sometimes more so than phenoxymethylpenicillin. They include the oral cephalo­ sporins cefaclor,30 cefuroxime axetil, 3 1 cefixime,32 cefpro­ zil, 33 and cefadroxil34 and the combined preparation amoxicillin with clavulanic acid35·36 (however, see above regarding the risk of rash with aminopenicillins) . Clinda­ mycin has eradicated Str. pyogenes and beta-Jactamase­ producing bacteria in children aged 12 years and under with recurrent tonsillitis, but might be less effective in older patients.37 It was also effective where penicillin and erythromycin had failed in an outbreak of streptococcal pharyngitis. 38 Pharyngeal carriage of Str. pyogenes is common, especially in primary-school children and thus its presence does not necessarily reflect acute infection. Eradication is generally unnecessary'·' but may be beneficial in selected cases and has been achieved by a single intramuscular injection of benzathine benzylpenicillin together with a 4-day course of oral rifampicin;39 a 1OM day course of oral clindamycin has also been effective.40 In order to ensure that outbreaks of Str. pyogenes are prevented in closely confined populations, some have recommended prophylactic antibacterials for all members of these populations, without exception.41 Other bacterial causes of pharyngitis include Arcanobac­ terium haemolyticum (Corynebacterium haemolyticum), Chlamy­ dophila pneumoniae ( Chlamydia pneumoniae), Corynebacterium diphtheriae (see under Diphtheria, p. 1 78.3 ), Fusobacterium necrophorum, Neisseria gonorrhoeae (see under Gonorrhoea, p. 2 0 6 . 2 ) , groups C and G beta-haemolytic streptococci, and anaerobic bacteria. A. haemolyticum is thought to be an important cause of pharyngitis in adolescents and young adults; there is often an accompanying scarlatiniform rash. It has been reported to respond to a single injection of benzathine benzylpeni­ cillin or a I 0-day course of oral erythromycin, but not to phenoxymethylpenicillin. 6 F. necrophorum is also common in adolescents and young adults, and is thought to cause about 1 0 % of acute pharyngitis within this age group.42 Of particular concern is

its association with Lemierre syndrome, a life-threatening condition characterised by bacteraemia, metastatic infec­ tions, and suppurative thrombophlebitis of the internal jugular vein. Although susceptible to penicillins and cephalosporins, F. necrophorum does not respond to treatment with macrolides; it has therefore been suggested that empirical use of macrolides be avoided in adolescents and young adults with acute pharyngitis.42 For pharyngitis associated with C. pneumoniae infection, tetracycline or erythromycin are effective antibacterials. 43 Systemic corticosteroids have been tried for the symptomatic relief of acute pharyngitis and in a meta­ analysis,44 patients with severe or exudative sore throat who took corticosteroids in addition to antibacterials were 3 times more likely to have complete resolution of pain at 24 hours than those who did not. However, it remains unclear whether corticosteroids offer additional benefits over simple analgesics, or if they are safe for use in pharyngitis not requiring antibacterial therapy.

32. Kiani R et al. Comparative, multicenter studies of cefixime and amoxicillin in the treatment of respiratory tract infections. Am J Med 1988; 85 (suppl 3A): 6-13. 33. Milatovic D, e t a l . Cefprozil versus penicillin V in treatment of streptococcal tonsillopharyngitis. Antimicrob Agents Chemother 1993; 37: 1620-3. 34. Milatovic D, Knauer J. Cefadroxil versus penicillin in the treatment of streptococcal tonsillopharyngitis. Bur J Clin Microbial Infect Dis 1989; 8: 282-8. 35. Brook I. Treatment of patients with acute recurrent tonsillitis due to group A !3 -haemolytic streptococci: a prospective randomized study comparing penicillin and amoxycillin/clavulanate potassium. J Antimicrob Chemother 1989; 24: 227-33. 36. Dykhuizen RS, e t a l . Phenoxymethyl penicillin versus co�amoxiclav in the treatment of acute streptococcal pharyngitis, and rhe role of !3 lactamase activity in saliva. J Antimicrob Chemother 1996; 37: 133-8. 37. Foote PA, Brook I. Penicillin and clindamycin therapy in recurrent tonsillitis: effect of microbial flora. Arch Otolaryngol Head Neck Surg 1989; liS: 856-9. 38. Raz R, eta!. Clindamydn in the treatment of an outbreak of streptococcal pharyngitis in a kibbutz due to beta-lactamase producing organisms. J Chemother 1990; 2: 182-4. 39. Tanz RR, et al. Penicillin plus rifampin eradicates pharyngeal carriage of group A streptococci. J Pediatr 1985; 106: 876-80. 40. Tanz RR, et al. Clindamycin treatment of chronic pharyngeal carriage of group A streptococci. J Pediatr 1991; ll9: 123-8. 41. Gray GC, et al. Hyperendemic Streptococcus pyogenes infection despite prophylaxis with penicillin G benzathine. N Eng! J Med 1991; 325: 92-7. 42. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med 2009; 151: 812-15. 43. Grayston JT, e t a l . A new respiratory tract pathogen: Chlamydia pneumoniae strain TWAR. J Infect Dis 1990; 161: 618-25. 44. Hayward G, e t al. Corticosteroids for pain relief in sore throat: systematic review and meta-analysis. Abridged version: BMJ 2009; 339: 488-90. Full version: http://www.bmj.com/cgi/reprint/339/aug06_2/b2976 (accessed 02/03/10)

Anonymous. Bacterial pharyngitis. Lancet 1987; i: 1241-2. Marcovitch H. Sore throats. Arch Dis Child 1990; 65: 249-50. Lang SDR, Singh K. The sore throat: when to investigate and when to prescribe. Drugs 1990; 40: 854-62. Little P, et a!. Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising effect of prescribing antibiotics. BMJ 1997; 315: 350-2. 5. Del Mar CB. et al. Antibiotics for sore throat. Available in The Cochrane Database of Systematic Reviews; Issue 4. Chichester: John Wiley; 2006 (accessed 18/08/08). 6. Bisno AL Acute pharyngitis. N Eng! J Med 2001; 344: 205-1 1. 7. WHO. Rheumatic fever and rheumatic heart disease. WH O Tech Rep Ser 923 2004. Also available at: http://www.who.int/cardiovascutar_ diseases/resources/en/cvd_trs923.pdf (accessed 02/03/1 0) Pinta 8. Gerber MA, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from See Syphilis, p. 207.2. the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and f.ICJ.f!.l'.e .................... ............................. . Translational Biology, and the Interdisciplinary Council on Quality of Plague1 . 2 is caused by the Gram-negative bacillus Yersinia Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2009; ll9: 1541-51. Also available at: http://circ. pestis ( Yersinia pseudotuberculosis subsp. pestis) and is usually ahajoumals.org/cgi/reprint/1 19/11/ 1541 (accessed 02/03/10) transmitted to man via rodents and their infected fleas. It 9. Lennon DR e t al. Once-daily amoxicillin versus twice-daily penicillin V has occurred as worldwide pandemics, for example, the in group A fl -haemolytic streptococcal pharyngitis. Arch Dis Child 2008; Black Death in Europe in the Middle Ages. In the 1 980s the 93: 474-8. largest numbers of cases reported were in Tanzania, I 0. Scottish Intercollegiate Guidelines Network. Management of sore throat and indications for tonsillectomy: a national clinical guideline (issued Vietnam, Brazil, Peru and more recently in Madagascar. January 1999). Available at: http://www.sign.ac.uk/pdf/sign34.pdf Plague may take several forms of which bubonic plague is (accessed 02/03/10) most common; others include pneumonic, septicaemic, 11. Martin JM, e t a l . Erythromycin-resistant group A streptococci in the and meningitic plague. Streptomycin, tetracycline, and schoolchildren in Pittsburgh. N Eng! J Med 2002; 346: 1200-6. 12. Maruyama S, et al. Sensitivity of group A streptococci to antibiotics: chloramphenicol have traditionally been used in the prevalence of resistance to erythromycin in Japan. Am J Dis Child 1979; treatment of plague' with streptomycin being the treatment 133: 1143-5. of choice, although the possibility of a Jarisch-Herxheimer 13. Seppala H, et al. Resistance to erythromycin in group A streptococci. N reaction resulting from the bactericidal effect of strepto­ En_ql J Med 1992; 326: 292-7. 14. Casey JR, Pichichero ME. Meta-analysis of cephalosporins versus mycin must be borne in mind; it is also contra-indicated in penicillin for treatment of group A streptococcal tonsillopharyngitis in pregnancy. Success has also been reported with amino­ adults. Clin Infect Dis 2004; 38: 1526-34. glycosides such as gentamicin and kanamycin. Although 15. Dillon HC. Streptococcal pharyngitis in the 1980s. Pediatr Infect Dis J there is no clinical experience with fluoroquinolones, inM 1987; 6: 123-30. 16. Lao AJ. et al. The impact of dosing frequency on the efficacy of 10-day vitro susceptibilities and animal studies suggest that they penicillin or amoxicillin therapy for streptococcal tonsillopharyngitis: a would be effective 3 meta-analysis. Abstract: Pediatrics 2000; 105: 414. Full version: http:f/ In the UK. the recommended treatment for adults is pediatrics.aappublications.org/ cgi/ content/full/1 05/2/ e 19 (accessed gentamicin (first choice in pregnancy); ciprofloxacin or 20/05/04) doxycycline may be used if aminoglycosides are unsuitable l 7. Gerber MA, et al. Five vs ten days of penicillin V therapy for streptococcal and may also be used for first-line therapy in children, but pharyngitis. Am J Dis Child 1987; 141: 224-7. 18. StrOmberg A, et al. Five versus ten days treatment of group A doxycycline is oniy suitable for children over 8 years of age. streptococcal pharyngotonsillitis: a randomized controlled clinical trial If plague meningitis is suspected chloramphenicol should be with phenoxymethylpenidllin and cefadroxil. Scand J Infect Dis 1988; 20: used as it crosses the blood-brain barrier.3 Similar 37-46. 19. Altamimi S, et a!. Short versus standard duration antibiotic therapy for information is provided by WH0,4 with sulfonamides acute streptococcal pharyngitis in children. Available in The Cochrane being mentioned as alternatives. European guidelines5 Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2009 consider either streptomycin or gentamicin to be appro­ (accessed 03/03110). priate for first-line treatment of plague in both adults and 20. Adam D, e t a l . Five days of erythromycin estolate versus ten days of children, and suggest that ofloxacin and levofloxacin may penicillin V in the treatment of group A streptococcal tonsillopharyngitis be appropriate alternatives to ciprofloxacin for second-line in children. Bur J Clin Microbial Infect Dis 1996; 15: 712-17. 21. Syrogiannopoulos GA, et a!. Two dosages of clarithromycin for five days, treatment in adults. amoxicillin/clavulanate for five days or penicillin V for ten days in acute In UK guidelines' ciprofloxacin is considered to be the group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J 2004; 23: drug of choice for prophylaxis in adults and children 857-65. 22. O'Doherty B, e t a l . Azithromydn versus penicillin V in the treatment of ( considered to be at risk after close contact with cases of paediatric patients with acute streptococcal pharyngitis/tonsillitis. Eur J pneumonic disease or after a deliberate release of Y. pestis; Clin Microbial Infect Dis 1996; 15: 718-24. doxycycline may be used as an alternative in those over 1 2 23. Hooton TM. A comparison of azithromycin and penicillin V for the years o f age. European guidelines5 offer similar advice, but treatment of streptococcal pharyngitis. Am J Med 1991; 91 (suppl 3A): consider levofloxacin and ofloxacin as possible options for 23S-26S. 24. Portier H, et al. Five day clarithromycin modified release versus 10 day prophylaxis in adults. Other suggested antibacterials include penicillin V for group A streptococcal pharyngitis: a multi-centre, open­ coMtrimoxazole,3•5 chloramphenicol, 3•5 and sulfadiazine.5 label, randomized study. J Antimicrob Chemother 2002; 49: 337-44. Commenting on the plague epidemic that occurred in 25. Portier H, et a!. Groupe d'etude de pathologic infectieuse pediatrique. India in 1 994, workers from the US CDC6 considered that Traitement des angines aigues a streptocoque beta-hemolytique du prophylaxis should be given to those who have had face-to­ groupe A chez !'enfant par lajosamycine pendant cinqjours. Arch Pediatr face contact or who have occupied a closed space with 2001; 8: 700-6. 26. Norrby SR, et al. Evaluation of 5-day therapy with telithromycin, a novel someone who has pneumonic plague. For prophylaxis, ketolide antibacteriaL for the treatment of tonsillopharyngitis. Clin tetracycline could be given to adults and older children or Microbial Infect 2004; 10: 615-23. sulfonamides to children of 8 years or Jess; chloramphenicol 27. Pichichero M, Casey J. Comparison of European and U.S. results for was also effective. 6 cephalosporin versus penicillin treatment of group A streptococcal Infection with a strain of Y. pestis resistant to all the drugs tonsillopharyngitis. Bur J Clin Microbiol lnfect Dis 2006; 25: 354-64. 28. Brook I. The role of !3 -lactarnase-producing bacteria in the persistence usually effective against plague identified in a patient from of streptococcal tonsillar infection. Rev Infect Dis 1984; 6: 601-7. responded to treatment with coMtrimoxazole 29. Gerber MA, et al. Potential mechanisms for failure to eradicate group A Madagascar7 and streptomycin. streptococci from the pharynx. Pediatrics 1999; 104: 911-17. A vaccine is available for active immunisation. 30. Stillerman M. Comparison of oral cephalosporins with penicillin therapy for group A streptococcal pharyngitis. Pediatr Infect Dis 1986; 5: 649-54. l. Prentice MB , Rahalison L. Plague. Lancet 2007; 369: 1196-1207. 31. Gooch WM, et al. Efficacy of cefuroxime axetil suspension compared 2. Butler T. Plague into the 21st century. Clin Infect Dis 2009; 49: 736-42. with that of penicillin V suspension in children with group A 3. Health Protection Agency. Guidelines for action in the event of a deliberate release: plague (issued April 2007). Available at: http://www. streptococcal pharyngitis. Antimicrob Agents Chemother 1993; 37: 159-63. l.

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Antibacterials

hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947396073 (accessed 18/08/08) 4. WHO. Plague manual: epidemiology, distribution, surveillance and rontrol. Available at: http://www.who.int/csr/resources/publications/plague/ WHO_CDS_CSR_EDC_99_2_EN/en/ (accessed 27/06/06) 5, Bossi P, et al. Task Force on Biological and Chemical Agent Threats of the European Commission. BICHAT guidelines for the clinical management of plague and bioterrorism·related plague. Bur Surveill 2004; 9: 1-6. Also available at: http://www.eurosurveillance.org/images/dynamic/em/ v09nl2/0912-230.pdf (accessed 04/02/10) 6. Campbell GL, Hughes JM. Plague in India: a new warning from an old nemesis. Ann Intern Med 1995; Ill: 151-3. 7. Galimand M, et al. Multidrug resistance in Yers:inia pestis mediated by a transferable plasmid. N Engl J Med 1997; 337: 677-80.

Pneumonia Pneumonia 1 is a respiratory disease characterised by inflammation of the lung parenchyma with congestion. It is mostly due to bacterial or viral infection, but may be caused by fungi in immunocompromised patients or by the aspiration of chemical irritants. Pneumonia is a common illness occurring in all age groups and throughout the world; it is a major cause of death among the elderly and those who are chronically and/ or terminally ill. Symptoms and signs of pneumonia include chills, cough, dyspnoea, fever, head­ ache, myalgia, pleuritic chest pain, and sputum production. Treatment of pneumonia relies on prompt use of antibacterials and identification of the infecting organisms and their sensitivity to antibacterials. Cases of pneumonia are usually classified as community-acquired or hospital­ acquired (nosocomial) pneumonia. Cases of community­ acquired pneumonia can also be further sub-divided into those who can be treated in an ambulatory (outpatient) setting and those that need hospitalisation. Patients who need hospitalisation are generally infected with unusual pathogens and/or have more severe disease. Pneumonia occurring in long-term-care facilities can be treated as either community-acquired or hospital-acquired pneumonia. Cases of hospital-acquired pneumonia are generally classified according to the time of onset after hospital admission. These categories also provide a rough guide as to the likely pathogen and severity of the disease. Other types of pneumonia include aspiration pneumonia and the various forms of interstitial pneumonia or pneumonitis (see also Aspiration Syndromes, p. 1 807.2, and Interstitial Lung Disease, p. 1 607. 1 ) . Interstitial pneumonitis is a common complication in cancer patients and has also been associated with certain drugs, for example amiodarone, bleomycin, and nitrofurantoin. Community-acquired pneumonia. In community­ acquired pneumonia ( CAP)H the commonest pathogen in previously healthy subjects is Streptococcus pneumoniae (pneumococcus) . Other common pathogens include Haemo­ philus injluenzae and atypical pathogens such as Chlamydo­ phila pneumoniae ( Chlamydia pneumoniae) , Mycoplasma pneumoniae, and Legionella pneumophila (see Legionnaires' Disease, p. 1 8 8 . 2 ) . 2 • 5 Less common causes include Staphylococcus aureus, which usually occurs as a secondary bacterial infection after influenza and is associated with high mortality; Moraxella catarrhalis (Branhamella catarrhalis) occurs especially in patients with chronic lung disease; Gram-negative e�teric bacilli; Pseudomonas aeruginosa; Chlamydophila psittad (Chlamydia psittad) (see Psittacosis, p. 204. 1 ) ; and Coxiella bumetii (see Q Fever, p. 204. 1 ) . Gram­ negative bacilli rarely cause pneumonia in the community, especially in previously healthy patients, although the frequency of such infections is increasing.• Anaerobic bacteria are associated with aspiration pneumonia. Viruses are the commonest pathogens in young children. Pneumococcal pneumonia usually develops over several days and in elderly patients onset may be insidious. Str. pneumoniae has usually been considered to be sensitive to penicillins (benzylpenicillin, amoxicillin, or ampicillin) , cephalosporins, erythromycin, or co-trimoxazole, b u t there is increasing prevalence of global resistance although there are marked geographical differences.9• 1 0 However, in clinical practice pneumococcal pneumonia frequently responds to high doses of penicillins or cephalosporins and the routine use of penicillin for CAP may still be reasonable in many countries. The treatment of CAP is complicated by the increasing spectrum of causative organisms and prevalence of antibacterial resistance. Furthermore, since the causative pathogen is often unknown, initial antibacterial therapy is usually empirical. Guidelines for the treatment of pneu­ monia have been issued by bodies in many countries.8• 1 1 - 18 Although common principles can be identified. recommen­ dations must be localised because of differences in patterns of infection . and drug resistance, variations in the availability of antibacterials and local policies for their use, and differences in medical practice. Countries also vary in the degree to which such guidelines are accepted in practice. These guidelines generally give advice for differences associated with age, the severity of the infection, and the presence or · absence of underlying or co-existent disorders. In the UK, guidelines for the management of CAP have been produced by the British Thoracic Society (BTS ) . 8 For All cross-references refer to entries in Volume A

initial empirical treatment in the community oral amoxicillin is usually preferred. Alternatives in penicillin­ allergic patients include doxycycline and the macrolides clarithromycin and erythromycin; clarithromycin is gen­ erally preferred to erythromycin due to better tolerance and more convenient dosing. The approach to treatment is similar for patients hospitalised with low-severity CAP, many of whom are admitted to hospital for non-clinical reasons such as old age, family preference, inadequate home care, or adverse social circumstances; when oral therapy cannot be used in these patients, intravenous amoxicillin, benzylpenicillin, or clarithromycin are suitable alternatives. In those patients hospitalised with moderately-severe CAP there is an increased likelihood of infection with atypical pathogens, or with Legionella spp.; consequently, combined empirical treatment orally with amoxicillin plus either erythromycin or clarithromycin is preferred.8 When oral therapy is inappropriate, intravenous ampicillin or benzylpenicillin is given, with intravenous clarithromycin. For those intolerant of beta lactams and macrolides, oral doxycycline, levofloxacin, or moxifloxacin can be con­ sidered; intravenous alternatives include either mono­ therapy with levofloxacin, or the combination of a second­ or third-generation cephalosporin (such as cefuroxime, cefotaxime, or ceftriaxone) with clarithromycin. 8 Patients hospitalised with severe CAP should receive parenteral empirical treatment regardiess of their ability to take oral medication. Since CAP caused by Legionella spp. is more likely to result in severe disease, the initial empirical regimen should include appropriate therapy. Current recommendations8 are for combined intravenous treatment with a broad-spectrum beta-lactamase-stable antibacterial such as amoxicillin with clavulanic acid or a second- or third-generation cephalosporin such as cefuroxime, cefo­ taxime, or ceftriaxone, together with a macrolide (preferably clarithromycin) . For life-threatening infection where Legionella is suspected, the further addition of levofloxacin should be considered. As an alternative to the above regimens, benzylpenicillin with either levofloxacin or ciprofloxacin can also be used.8 The following treatments are recommended in the UK." along with local microbiological advice, for the minority of patients with CAP in whom the causative organism has been identified, usually in hospital: Str. pneumoniae: preferred treatment, oral amoxidllin or intravenous benzylpenicillin; alternatives, oral clarithro­ mycin, or intravenous cefuroxime, cefotaxime, or ceftriaxone M_ pneumoniae or C. pneumoniae: preferred treatment, oral or intravenous clarithromycin; alternatives, oral dox­ ycycline or an oral or intravenous fluoroquinolone C. psittaci or C. bumetii: preferred treatment, oral doxycycline; alternatives, oral or intravenous clarithro­ mycin Ugionella spp . : preferred treatment, an oral or intra­ venous fluoroquinolone; alternatives, oral or intra­ venous clarithromycin (or azithromycin, if necessary) H. injluenzae (non-beta-lactamase-producing) : preferred treatment, oral or intravenous amoxicillin; alternatives, intravenous cefuroxime, cefotaxime, or ceftriaxone, or an oral or intravenous fluoroquinolone H. injluenzae (beta-lactamase-producing) : preferred treatment, oral or intravenous amoxidllin with clavu­ lanic add; alternatives, intravenous cefuroxime, cefo­ taxime, or ceftriaxone, or an oral or intravenous fluoroquinolone • Gram-negative enteric bacilli: preferred treatment, intravenous cefuroxime, cefotaxime, or ceftriaxone; alternatives, intravenous fluoroquinolone, imipenem, or meropenem • Ps. aeruginosa: preferred treatment, intravenous ceft­ azidime plus either gentamicin or tobramycin; alter­ natives, intravenous dprofloxacin or piperacillin plus either gentamicin or tobramycin • Staph. aureus (non-meticillin-resistant) : preferred treat­ ment, intravenous flucloxadllin with or without oral or intravenous rifampicin; alternatives, intravenous vanco­ mycin, linezolid, or teicoplanin with or without oral or intravenous rifampicin Staph. aureus (meticillin-resistant) : preferred treatment, intravenous vancomycin, linezolid, or teicoplanin with or without oral or intravenous rifampicin In the USA. guidelines for the management of CAP in adults have been jointly produced by the Infectious Diseases Society of America (ID SA) and by the American Thoracic Society (ATS ) . 1 2 For previously healthy outpatients with no risk factors for drug-resistant Str. pneumoniae (DRSP) infection they recommend a macrolide ( such as erythro­ mycin, azithromycin, or clarithromycin); doxycycline may be given as an alternative. In those with co-existing cardiopulmonary disease and/ or other complicating factors ( such as renal disease, diabetes mellitus, alcoholism, malignancies, or asplenia) , taking immunosuppressive drugs, those who have received antibacterial therapy

• • • • • •

within the previous 3 months, or those with other risks for DRSP infection a 'respiratory fluoroquinolone' (gemiflox­ acin, levofloxacin, or moxifloxacin) is recommended. Alternatively a beta-lactam (high-dose amoxicillin with or without clavulanic acid, or ceftriaxone, cefpodoxime, or cefuroxime) plus a macrolide (or doxycycline) may be given. In hospitalised patients who are not in intensive care the preferred treatment is a beta lactam ( cefotaxime, ceftriaxone, ampicillin, or ertapenem) plus a macrolide (or doxycycline) . In penicillin-allergic patients a respiratory fluoroquinolone is recommended. In hospitalised patients who are in intensive care the preferred treatment is a beta lactam (cefotaxime, ceftriaxone, or ampicillin/sulbactam) plus either azithromycin or a respiratory fluoroquinolone. In penicillin-allergic.patients a respiratory fluoroquinolone and aztreonam are recommended. For Pseudomonas infection, an antipneumococcal, antipseudomonal beta lactam (such as piperacillin/tazobactam, cefepime, imi­ penem, or meropenem) plus either ciprofloxacin or levofloxacin are recommended. Alternative regimens include an antipneumococcal. antipseudomonal beta lactam plus an aminoglycoside and azithromycin, or an antipneumococcal, antipseudomonal beta lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone. In penicillin-allergic patients aztreonam should be used in place of the beta lactam. For community- acquired meticillin-resistant Staph. aureus (MRSA) infection, vanco­ mycin or linezolid should be added. In children pneumonia is caused by a wider spectrum of organisms than in adults. Viruses, especially RSV, are very common pathogens in infants and children up to 4 years of age and. as in adults, pneumococci are very common bacterial pathogens. Guidelines for the management of CAP in children have been produced by the BTS . 1 1 Amoxicillin is considered the antibacterial of first choice for empirical oral therapy in children under 5 years of age because it is effective against the majority of causative organisms. Alternatives are amoxicillin with clavulanic acid, cefaclor, erythromycin, clarithromycin, or azithromycin. Macrolides should be given as first-line empirical therapy in children over 5 years since M. pneumoniae pneumonia is more prevalent in older children. Macrolides should also be used in children of any age if either M. pneumoniae or C. pneumoniae are suspected. Amoxicillin should be used as first-line treatment at any age if Str. pneumoniae is thought to be the likely pathogen. If Staph. aureus is suspected then a macrolide or a combination of flucloxacillin with amoxicillin is appropriate. Intravenous therapy should be given in severe infection or when the child is unable to absorb oral antibacterials, for example due to vomiting; appropriate intravenous drugs for severe pneumonia include amoxicillin with clavulanic acid, cefuroxime, or cefotaxime. If the causative organism is known to be Str. pneumoniae a penicillin may be used alone. Chlamydia trachomatis is another common cause in infants up to 3 months of age for which erythromycin may be used or, alternatively, sulfafurazole. Pneumonia in neonates is usually due to organisms acquired from the mother's genital tract, especially group B streptococci, Escherichia coli, and Klebsiella pneumoniae; initial treatment with gentamicin and benzylpenicillin or ampi­ cillin has been suggested. For prophylaxis against group B streptococci in neonates, see under Perinatal Streptococcal Infections, p. 1 97 . 2 . Similar guidelines for the empirical management of CAP in children have been developed in South Africa . ! ' Additional recommendations have been made t o take into account the high prevalence of mv infection. The drug of choice is amoxicillin; although standard doses of amoxicillin will treat most cases of pneumococcal pneumonia the use of high-dose amoxicillin ( 3 0 mg/kg given 3 times daily) is recommended in order to overcome and limit the emergence of resistant pneumococci, and to successfully treat those few children with high-level pneumococcal resistance the following additional factors should be considered: children younger than 2 months have more Gram­ negative infections and therefore need an intravenous aminoglycoside or an intravenous cephalosporin, while children older than 5 years have more infections caused by M. pneumoniae and C. pneumoniae and need a macrolide (erythromycin, clarithromycin, or azithro­ mycin) mv -infected children requiring hospitalisation and those with a high risk of being IITV-infected or who have symptomatic HIV disease or who are s everely malnourished should be given an aminoglycoside plus their empirical antibacterial regimen; alternatively they may be given a regimen that provides effective treatment against Gram-negative bacteria if pneumocystis pneumonia is suspected, co-tiimoxazole should be added. All hospitalised mv -exposed children less than 6 months of age should be treated empirically with co-trimoxazole, unless HIV infection status is

•

•

• I

I

•

negative and the child is not being breast-fed. Empirical treatment with co-trimoxazole plus amoxicillin and an aminoglycoside should also be given to older HIV­ infected children wHh features of AIDS who are not on co-trimoxazole prophylaxis • when Staph. aureus is suspected, cloxacillin is the drug of choice . In HIV-infected children, about 6 0 % of community-acquired Staph. aureus may be resistant to cloxacillin and vancomycin should be given For the prevention of CAP. pneumococcal (p. 2410. 1 ) and influenza (p. 2 3 9 3 . 3 ) vaccines are generally recommended for active immunisation of individuals considered to be at high risk of pneumonia-related complications.8· 12 However, a meta-analysis19 of pneumococcal vaccination in adults (with unconjugated vaccine) has suggested that the practice may not effectively prevent pneumonia, even in high-risk populations. The role of influenza vaccination in reducing the risk of CAP in elderly, immunocompetent patients has also been questioned.2o Hospital-acquired and healthcare-associated pneumonia. Pneumonia occurring at least 48 hours after hospital admission that was not incubating at initial presentation is termed nosocomial or hospital-acquired pneumonia (HAP ) . Ventilator-associated pneumonia (VAP) is a specific subtype of HAP defined as pneumonia occurring at least 48 hours after endotracheal intubation and/or mechanical ventilation, usually resulting from aspiration of pathogenic material that colonises the oropharynx. While early-onset HAP (occurring within the first 4 days of hospital admission) is usually caused by typical community organisms, late-onset infection can be caused by a wide spectrum of possible pathogens, many of which may be resistant to multiple antibacterials; these can include opportunistic Gram-negative badlli such as Ps. aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Burkholderia cepacia, and the Enterobacteriaceae, as well as Staph. aureus. More recently, an increased incidence of these potentially drug-resistant bacteria among patients with early-onset pneumonia, thought to be a consequence of previous hospital stays or antibacterial use, has Jed to the concept of healthcare-associated pneumonia (HCAP) . This is pneu­ mania occurring in any patient who has been hospitalised for at least 2 days in the previous 3 months, lives in a long­ term care or nursing facility, has received intravenous antibacterials, chemotherapy, or wound care in the previous month, or attends a hospital or haemodialysis clinic.21·22 The spectrum of bacteria causing HCAP is similar to late-onset HAP, and patients are considered to be at high risk of multidrug-resistant infection. Other risk factors for multidrug-resistant pneumonia include immunosuppres­ sive disease or therapy, and high frequency of antibacterial resistance within the community or specific hospital unit. Broad spectrum antibacterial therapy is essential for treatment of HAP and HCAP, and most initial therapy is empirical. As in the treatment of CAP, selection of antibacterials must be localised. For initial empirical treatment of early-onset HAP or YAP in patients with no known risk factors for multidrug-resistant pathogens, and any disease severity, ATS recommends21 the following drugs: ceftriaxone; levofloxacin, moxifloxacin, or cipro£lox­ acin; ampicillin/sulbactam; or ertapenem. Where there is late -onset infection or risk factors for multidrug resistance (including possible HCAP) the following are recommended: an antipseudomonal cephalosporin ( cefepime or ceft­ azidime) or an antipseudomonal carbapenem (imipenem or meropenem) or piperadllin-tazobactam together with an antipseudornonal fluoroquinolone (ciprofloxacin or levo­ floxacin) or an aminoglycoside (amikacin, gentamicin, or tobramycin); if MRSA is likely then linezolid or vancomycin should also be used. Intravenous therapy should be given to all patients initially, and changed to the oral or enteral route as soon as possible. Efforts should be made to shorten the duration of therapy from the traditional 14 to 2 1 days to as little as 7 days provided Ps. aeruginosa is absent and that the patient shows a good clinical response. Guidelines for the management of HAP, VAP, and HCAP have also been issued in the UK, 22 and emphasise the need to choose initial antibacterial therapy based on patient-specific factors ( such as previous antibacterial use, length of hospital stay, and comorbidities) as well as local microbiology and resistance patterns. For intensive care patients requiring mechanical ventilation for 48 hours or more, selective decontamination of the digestive tract (see under Intensive Care, p. 1 8 7 . 3 ) is recommended to reduce the risk of VAP. Immunocompromised patients. Immunosuppressed patients are at increased risk of pneumonia. In addition to the bacteria mentioned above they are susceptible to opportunistic infections with Mycobacterium tuberculosis (see Tuberculosis, p. 2 1 2 . 2 ) ; viruses such as CMV and fungi, in particular Pneumocystisjirovecii (see p . 5 6 7 . 2 ) , are also causes of pneumonia in these patients. Aspiration pneumonia. Aspiration of organisms present in the upper respiratory tract into the lungs, often as a result of loss of consciousness or difficulty in swallowing, can cause aspiration pneumonia.23 When

community acquired the organisms responsible are mainly j ' anaerobes, but in hospital-acquired aspiration pneumonia For infections associated specifically with see Gram-negative bacilli and Staph. aureus are also found. Endometritis (p. 1 80 . 3 ) , Perinatal Streptococcal Infections Confusion has arisen over the term 'aspiration pneumonia' (p. 1 97 . 2 ) , and Premature Labour (p. 203 . 3 ) . because it has also been applied more generally to aspiration, tor example, of gastric acid (Mendelson's syndrome ), resulting in chemical pneumonitis and not associated with bacterial infection. Lung abscess generally Preterm birth, with or without rupture of membranes, characterises late-stage aspiration pneumonia involving causes significant perinatal morbidity and mortality. There anaerobic bacteria. The aetiology is rarely established, but is evidence that infection appears to have an important role specific anaerobic bacteria involved include Peptostreptococ­ in the cause or as a consequence of ruptured membranesU cus, Prevotella melaninogenica (Bacteroides melaninogenicus) , and as many as 50% of spontaneous preterm births are due and Fusobacterium nucleatum. Nearly all patients with to infection, with Mycoplasma spp. being the most commonly anaerobic pulmonary infections are treated empirically. isolated organisms from the amniotic cavity. 3 Other bacteria Some23 workers have expressed the view that penicillin and that have been implicated include group B streptococci, clindamycin are inadequate and that antibacterials with Chlamydia trachomatis, and those associated with bacterial activity against Gram-negative organisms, such as third­ vaginosis. The role of antibacterial treatment has been generation cephalosporins, fluoroquinolones, and pipera­ evaluated. However, it is possible that maternal antibac­ cillin are usually required even in community-acquired terial treatment may suppress the stimulation of labour aspiration pneumonia. Most patients with lung abscess without effectively treating fetal infection2 and concerns receive parenteral therapy until they become afebrile and have been expressed that delaying delivery in the presence show clinical improvement; oral therapy may then continue of a subclinical infection may not produce the best outcome for weeks or months if necessary. for the neonate.4 I. A meta-analysis5 and a systematic review1 of studies of BMJ the routine use of antibacterials as adjuncts in the Lancet management of premature labour in women with intact membranes have failed to show an overall improvement in e t al. neonatal morbidity; indeed, an increase in neonatal Am Pam Physician mortality was actually noted.5 Furthermore, a long-term Drugs follow-up study6 indicated an increased rate of functional impairment among 7 -year-olds whose mothers had e t al. received erythromycin for spontaneous preterm labour; an Am increased incidence of cerebral palsy was also noted among Chest children exposed to either erythromycin or amoxicillin with Lancet clavulanic acid. In women with preterm premature rupture ofmembranes, et a!. meta-analyses7,8 and a systematic review2 have shown that antibacterials could delay delivery, and reduce both horax 64 maternal morbidity ( chorioamnionitis and postpartum infections) and some aspects of neonatal morbidity (sepsis, pneumonia, and intraventricular haemorrhage ) . No effects Lancet on neonatal mortality or gestational age-related morbidity were noted, 2,8 and a long-term follow-up study found no et al_ evidence of negative health effects on the child. 9 However, an increased incidence of neonatal necrotising enterocolitis J Antimicrob Chemother has been found after maternal use of amoxicillin with clavulanic acid specifically and it is considered best avoided Thorax in women at risk of premature delivery; erythromycin may be the antibacterial of choice.2 A systematic review and meta-analysis3 evaluated the effect of antibacterials on the et al. rate of preterm births when given in the second trimester of pregnancy to women at risk of preterm births. Giving Clin Infed D1�· macrolides or clindamycin was associated with a lower rate of preterm delivery, whereas giving metronidazole alone in et al. the second trimester was associated with a greater risk of preterm delivery in a high-risk population. Bur Respir J Clinical infections of the genito-urinary tract during pregnancy are a cause of significant morbidity in the et al. neonate and antimicrobial treatment is necessary (see S Afr Med J Bacterial Vaginosis, p. 1 74. 1 , Chlamydia! Infections, 96: p. 1 7 7 . 1 , and Perinatal Streptococcal Infections, p. 1 9 7 .2 ) .

�regnancy and t?e. .�e.?.�.Cite

���-������,

Premature labour

Hoare Z. Lim WS. Pneumonia: update on diagnosis and management. 2006; 332: 1077-9. File TM. Community-acquired pneumonia. 2003; 362: I99l2001. Ostapchuk M, Community-acquired pneumonia in infants and children. 2004; 70: 899-908. Epstein BJ, Gums JG. Optimal pharmacological therapy for community­ acquired pneumonia: the role of dual antibacterial therapy. 2005; 65: 1949-71. and treatment of community-acquired 5. lutfiyya MN, pneumonia. 2006; 73: 442-50. 6. Niedennan MS. Recent advances in community-acquired pneumonia: inpatient and outpatient. 2007; 131: 120'5-15. 7. Garau J. Calbo E. Community-acquired pneumonia. 2008; 371: 455--8. 8. Lim WS, Pneumonia Guidelines Committee of the British Thoracic Society Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. T 2009; (suppl 3): iii1-iii55. Also available at: http://www. brit-thoracic.org.uk/Portals/0/Clinical%20Information/Pneumonia/ Guidelines/CAPGuideline-full.pdf (accessed 24/02/1 0) 9. Garau J. Treatment of drug-resistant pneumococcal pneumonia. 2: 404-15. D, Increa�ing prevalence of antimicrobial resistance 10. among of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. 2002; 50 (suppl Sl): 25-37. 11. British Thoracic Society. BTS Guidelines for the management of community acquired pneumonia in childhood. 2002; 57 (suppl l): il-124. Also ;;1Vailable at: http://www.brit-thoracic.org.uk/ponals/O/ Clinicai%20Information/Pneumonia/Guidelines/paediatriccap.pdf (accessed 18/08/08) 12. Mandell LA, Infectious Diseases Society of America/American con�ensus guidelines on the management of ron,rrumuv·acau 2 kg: 1 5 mg/kg every 12 to 24 hours l.

American Academy of Pediatrics. 2012 Red Book: Repott of the Committee on Infectious Diseases, 29th ed. Elk Grove Village, illinois, USA: American Academy of Pediatrics, 2 0 1 2 .

Adverse Effects, Treatment, and Precautions ..... . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

As f o r Gentamicin Sulfate, p . 3 0 8 . 2 . P e a k plasma concentrations of amikacin greater than 30 to 35 micro­ grams/mL or trough concentrations greater than 5 to I 0 micrograms/mL should be avoided. Comparisons with equipotent doses found that amikacin affects auditory (cochlear) function to about the same extent as gentamicin.

Effects on the eyes. A report of retinal damage after intra­ vitreal injection of amikacin. 1 l.

Jackson TL, Williamson TH. Amikadn retinal toxicity. B r J Ophthalmol 1 999;

83: 1 1 99-1200.

Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAP O S ) and the Porphyria Centre Sweden, classifies amikacin as not porphyrinogenic; it may be used as a drug of first choice and no precautions are needed. 1 I.

The Drug Database for Acute Porphyria. Available at: http:ffwww. drugs-porphyria.org (accessed 041 1 0 / l l )

Interactions As for Gentamicin Sulfate, p. 309.2.

Antimicrobial Action As for Gentamicin Sulfate, p. 309.2. Amikacin is active against a similar range of organisms although it is also reported to have some activity against Nocardia asteroides, Mycobacterium tuberculosis, and some atypical mycobacterial

Acediasul f one strains. Amikacin is not degraded by many of the common enzymes often responsible for acquired aminoglycoside resistance. In consequence, cross-resistance with genta­ micin and other aminoglycosides is infrequent and amikacin may be effective against strains resistant to other aminoglycosides. However, resistant strains of Gram­ negative bacteria and staphylococci have been reported, and it is generally reserved for infections resistant to other aminoglycosides, although reports differ as to the extent and speed of the development of amikacin resistance where it has been widely used. References. l.

Ho YTI, et al. In-vitro activities of aminoglycoside-aminocyditols against mycobacteria. J Antimicrob Chemother 1997; 40: 27-32.

Pharmacokinetics As for Gentamicin Sulfate, p. 3 0 9 . 3 . On intramuscular injection, peak plasma- amikacin concentrations of about 20 micrograms/mL occur I hour after a 500-mg dose, reducing to about 2 micrograms/mL 1 0 hours after injection. A plasma concentration o f 38 micro­ grams/mL has been reported after the intravenous infusion of 500 mg over 30 minutes, reducing to 18 micrograms/mL I hour later. Amikadn has been detected in body tissues and fluids after injection; it crosses the placenta but does not readily penetrate into the C SF, although substantial penetration of the blood-brain barrier has been reported in children with meningitis. A plasma half-life of about 2 to 3 hours has been reported in patients with normal renal function. Most of a dose is excreted by glomerular filtration in the urine within 24 hours. References.

l. Vanhaeverbeek M, et al. Pharmacokinetics of once-daily amikadn in elderly patients. J Antimicrob Chemother 1993; 31: 185-7. 2. Gaillard J-L, et a!. Cerebrospinal fluid penetration of amikadn in children with community-acquired bacterial meningitis. Antimicrob Agents Chemother 1995; 39: 253-5. 3. Bressolle F, et a!. Population pharmacokinetics of amikacin in critically ill patients. Antimicrob Agents Chemother 1996; 40: 1682-9. 4. Canis F, et al. Pharmacokinetics and bronchial diffusion of single daily dose amikacin in cystic fibrosis patients. 1 Antimicrob Chemother 1997; 39: 431-3. 5. Tod M, et a!. Population pharmacokinetic study of amikacin adminbtered once or twice daily to febrile, severely neutropenic adults. Antimicrob Agents Chemother 1998; 42: 849-56. 6. Treluyer JM, et a!. Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children. Antimicrob Agents Chemother 2002; 46: 1381-7. 7. Okusanya 00, et a!. Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infection. Antimicrob Agents Chemother 2009; 53: 3847-54.

P..r�P.�.r�ti c:>n.� ....... ................................... .

Proprietary Preparations (details are given in Volume B) Single-ingredient Preparations. Arg.: Biklint; Greini; Riklinak; Austral.: Amikint; Austria: Biklin; Belg. : Amukin; Braz.: Ami­ cHon; Klebicil; Novamin; China: Mi Li Xian U�F!N5t); Mi Ying lie l*�:!:i); Cz.: Amikin; Fin.: Biklin; Fr.: Amiklint; Ger.: Bik­ lint; Gr. : Amicagel; Amicasil; Amikan; Biorisan; Briklin; Bruce­ lin; Cinegel; Consumonit; Durocin; Farcyclin; Flexelite; Fro­ mentyl; Kancin-Gap; Lanomycin; Lifermycin; Likacin; Medilen; Micalpha; Orlobin; Remikin; Rovericlin; Selaxa; Uzix; Xylanal; Hong Kong: Amikin; Hung.: Amikint; Likacin; India: Acil; Afcin; Alkanit; Alnamik; Amcin; Amexel; Amiact; Amibiotic; Arnie; Amicaba; Amicin; Amicip; Amicom; Amijet; Amikable; Amikas; Amikater; Amikavel; Amikcin; Amikef; Amikin; Ami­ lab; Amimac; Amimax; Aminocin; Arniron; Amistar; Amister; Amisulf; Amitax; Amivir; Amiz; Amiza; AMK; Amoka; Amri­ cin; Amtop; Amzo; Anamika; Antinag; Arimic; Atmika; Avika­ cin; Avmik; Axcin; Bekacin; Blocin; Cadicin; Cinamica; Cinas; Coskacin; Curesin; D-Cin; Elcin; Elmik; Emcin; Emica; Emka; Endocin; Erkacin; Erocin; Erymik; Estacin; Eumik; Fokin; Fymika; Gabacin; Gekacin; Gemka; Glomika; GJykacin; Hosik; Icin; Ideg; Ikacin; Ikka; Inkacin; Ivimicin; Jyomik; Kadna; Kam; Kamsa; Kasino; Kawacin; Lemicin; Lexcin; Litomik; Lupamik; M-Cinn; Malaracin; MBKacin; Medcin; Megamica; Mepcin; Mica; Micare; Micin; Mikabit; Mikacin; Mikafine; Mikaject; Mikaphar; Mikastar; Mikatax; Miker; Mikif; Mikka; Mini; Mishacin; MKCN; Narish; NBCin; Nicin; Niksin; Nimicin; Nimika; Niskacin; Nosomik; Orkacin; Osin; Indon. : Alostil; Amikint; Glybotic; Mikasin; Irl. : Amikin; Ital.: Amicasil; Amikt; Amikan; BB-KSt; Chemacin; Dramigel; Likacin; Luka­ din; Mediamik; Migracin; Mikan; Mikavirt; Nekacin; Malaysia: Apalin; Mex. : Agnicin; Akacin; Amicina; Amikafur; Amikalemt; Amikasons; Amikavi; Arnikayect; Amikin; Amiyec; AMK; Bera­ mikin; Biclin; Biokacin; Gamikal; Kafrant; Kana; Karmikin; Libamic; Lisobac; Mikazult; Oprad; Plokimt; Sermicina; Tetra­ lin; Yectamidt; NZ: Amikint; Philipp. : Amikacide; Amikint; Amitax; Cidacid; Cinmik; Kamin; Kormakin; Mikasul; Nica; Panmikin; Pol.: Amikin; Biodacyna; Port. : Arnie; Biclint; Kami­ na; Rus.: Amikozit (AMHK03HT)t; Chemacin (XeMaU:HH) ; Selemy­ cin (CeJieMHUHH); S.Afr. : Amikin; Kacinth-At; Spain: Biclint; Swed. : Biklin; Switz.: Amikin; Thai. : Akacin; Akicin; Amikint; Anbikint; Siamik; Tipkin; Tybikin; Turk.: Amijeksin; Amike­ temt; Amiklin; Amikozit; Mikasint; UAE: Mikacin; UK: Amikin; Ukr.: Amici} (AMHUIDI); USA: Amikint; Venez. : Amika­ vax; Behkacin; Biklin; Likacin. The symbol

Multi-ingredient Prepara�ons.

India: Mikapime; Nicpime-AM;

Ukr.: Inflarax (llH>t�of)1loni .Su!fas; Fqriif1')icin · A $\.IIPhatE:f K�-l070; S.ulfatq . Qe. · a:strol))iCinJfl -7'- 89'f4M234E5.

Pharmacopoeias. In Eur. (see p . vii ), Tnt., and US.

Ph. Eur. 8: (Bacitracin Zinc) . The zinc complex of bacitracin.

The potency is not less than 60 units/mg, calculated with reference to the dried substance. A white or light-yellowish­ grey hygroscopic powder. Slightly soluble in water and in alcohol. The filtrate of a saturated solution has a pH of 6 . 0 to 7 . 5 . Store in airtight containers.

USP 36: (Bacitracin Zinc ) . The zinc complex of bacitracin,

which consists of a mixture of antimicrobial polypeptides, the main components being bacitracins A, B I, B2, and B 3 . It has a potency of not less than 65 units/mg, calculated with reference to the dried substance. It contains not less than

226

Antibacterials

4% and not more than 6 % of zinc, calculated with reference to the dried substance. A white or pale tan, hygroscopic powder, odourless or having a slight odour. Sparingly soluble in water. pH of a saturated solution in water is between 6.0 and 7 . 5 . Store in airtight containers at a temperature of 8 degrees to 1 5 degrees.

Incompatibility. Bacitracin was slowly inactivated in bases

containing stearyl alcohol. cholesterol. polyoxyethylene derivatives, and sodium laurilsulfate, and was rapidly inac­ tivated in bases containing water, macrogols, propylene glycol. glycerol. cetylpyridinium chloride, benzalkonium chloride, ichthammol. phenol. and tannic acid. 1 l.

Plaxco JM, Husa WJ. The effect of various substances on the antibacterial activity of bacitracin in ointments. 1 Am Pharm Assoc (Sci) 1 9 5 6; 45: 141-5.

Bacitracin zinc was more stable than bacitracin and could be stored for 18 months at temperatures up to 40 degrees without appreciable loss of activity. Lozenges of bacitracin zinc and ointments and tablets containing bacitracin zinc with neomycin were more stable than the corresponding bacitracin preparations. Bacitracin zinc was less bitter than bacitracin and the taste was more readily disguised. 1

Stability.

1.

Gross HM, et a!. Zinc bacitracin in pharmaceutical preparations. Drng Cosmet Ind 1 954; 75: 6 1 2- 1 3 .

Units The second International Standard Preparation ( 1 964) of bacitracin zinc contains 7 4 units/mg.

Uses and Administration Bacitracin and bacitracin zinc are applied topically (as a cream, ointment, dusting powder, or ophthalmic ointment), often with other antibacterials such as neomycin and polymyxin B, and sometimes with corticosteroids, in the treatment of local infections due to susceptible organisms. Typical concentrations of bacitracin or bacitracin zinc in such products are 400 to 500 units/g. Absorption from open wounds and from the bladder or peritoneal cavity may lead to adverse effects, although the dose-limiting toxicity of combined preparations is considered to be due to neomycin. Parenteral use of bacitracin is usually avoided because of nephrotoxicity but it may be given intramuscularly for the treatment of infants with staphylococcal pneumonia and empyema due to susceptible organisms. For details of doses in children, see p. 228. 1 . Bacitracin has been given orally in the treatment of antibiotic-associated colitis due to Clostridium difficile.

Administration in children. In the USA. bacitracin may be given intramuscularly for the treatment of infants with staphylococcal pneumonia and empyema due to suscepti­ ble organisms. Infants weigbing less than 2 . 5 kg may be given a dose of 900 units/kg daily in 2 or 3 divided doses; those weighing more than 2.5 kg may be given l 000 units/kg daily in 2 or 3 divided doses.

Adverse Effects and Precautions Systemic bacitracin may produce severe nephrotoxicity, resulting in renal failure due to tubular and glomerular necrosis. Renal function should be determined before, and daily during, therapy. Fluid intake and urinary output should be maintained to avoid kidney toxicity. If renal toxicity occurs, bacitracin should be stopped. Use with other nephrotoxic drugs should be avoided (see Interactions, p. 228. 1 ) . Nausea and vomiting may occur, a s well a s pain a t the site of injection. Hypersensitivity reactions, including rashes and anaphylaxis, have occurred with systemic, and more rarely with topical. use.

Hypersensitivity. References1-6 to hypersensitivity reac· tions to bacitracin, including anaphylaxis. L

2. 3.

4. 5.

6.

Sood A, Taylor JS. Bacitracin: allergen of the year. Am J Contact Dennat 2003; 14: 3--4. Jacob SE, James WD. From road rash to top allergen in a flash: bacitracin. Dennatol Surg 2004; 30: 52 1--4. Freiler JF, et a!. Intraoperative anaphylaxis to bacitracin during pacemaker change and laser lead extraction. Ann Allergy Asthma Immunol 2005; 95: 389-9 3 . Greenberg K . et a l . Anaphylaxis to topical bacitracin ointment. Am J Emerg Med 2007; 25: 95-6. Greenberg SB, et al. Successful resuscitation of a patient who developed cardiac arrest from pulsed saline bacitracin lavage during thoracic laminectomy and fusion. J Clin Anesth 2008; 20: 294--6. Cronin H. Mowad C. Anaphylactic reaction to bacitracin ointment. Cutis 2009; 83: 1 27-9.

Interactions Additive nephrotoxicity would be anticipated if bacitracin were given systemically with other nephrotoxic drugs, particularly colistin, kanamycin, neomycin, polymyxin B, and streptomycin; such use should be avoided. Bacitracin is All cross-references refer to entries in Volume A

reported to enhance the neuromuscular blocking action of certain drugs, such as neuromuscular blockers and anaesthetics, if given during surgery or postoperatively.

Antimicrobial Action Bacitracin interferes with bacterial cell wall synthesis by blocking the function of the lipid carrier molecule that transfers cell wall subunits across the cell membrane. It is active against many Gram-positive bacteria including staphylococci, streptococci (particularly group A strepto­ cocci), corynebacteria, and clostridia. It is also active against Actinomyces, Treponema pallidum, and some Gram-negative species such as Neisseria ,and Haemophilus influenzae, although most Gram-negative organisms are resistant. Acquired bacterial resistance to bacitracin rarely Occurs, but resistant strains of staphylococci have been detected.

Neomycin and Polymyxin B Sulfates, Bacitracin, and Hydro­ cortisone Acetate Ointment; Neomycin and Polymyxin B Sulfates, Bacitracin, and Hydrocortisone Acetate Ophthalmic Ointment; Neomycin and Polymyxin B Sulfates, Bacitracin, and Lidocaine Ointment; Neomycin Sulfate and Bacitracin Ointment; Neomycin Sulfate and Bacitracin Zinc Ointment; Polymyxin B Sulfate and Bacitracin Zinc Topical Aerosol; Polymyxin B Sulfate and Bacitracin Zinc Topical Powder.

Pharmacokinetics Bacitracin is not appreciably absorbed from the gastro­ intestinal tract or from intact or denuded skin, wounds, or mucous membranes; however, systemic absorption has been reported after peritoneal lavage. It is rapidly absorbed when given by intramuscular injection. BaCitracin readily diffuses into pleural and ascitic fluids but little passes into the CSF. About 10 to 40% of a single inj ected dose is excreted slowly by glomerular filtration and appears in the urine within 24 hours.

l.

Alksne L. Balofloxacin Choongwae. Curr Opin Investig Drugs 2003; 4: 224-9.

Prepa rations .. ................................. ... ..

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. China: Heng Jie ('tll!Jit ) ; Tiantong

P..r�p(l_r(l_li()_n. S. ....... ................................... ................... .

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Canad. : Baciject; Bacitin;

Balofloxacin is a fluoroquinolone antibacterial used in the treatment of urinary-tract infections.

USA:

Bad-IM; Venez. : Baciderm.

Multi-ingredient Preparations. Arg. : Biotaer an Caramelos; Bio­ taer Nebulizable; Butimerin; Carnot Colutorio; Cicatrex Biotic; Austral.: Cicatrint; Nemdyn; Neosporint; Austria: Baneocin; Eucillin; Nebacetin; Belg. : Neobacitracine; Neobacitracine; Braz. : Anaseptil; Bacidennina; Bacigen; Bacina; Bactoderm; Cicatrene; Cutidermt; Dermase; Epicitrin; Ferid; Kindcetint; Nebacetin; Nebaciderme; Nebacimed; Neobacipan; Neocetrin; Neotopt; Neotricin; Polysporint; Teutomicin; Canad.: Antibio­ tic Ointment; Antibiotique Onguentt; Bacimyxin; Band-Aid Antibiotic Adhesive Bandages plus Antibiotic; Bioderm; Cicatrint; Complete Antibiotic Ointment; Cortimyxin; Cortis­ porin; Diosporin; Neosporin; Optimyxin; Ozonol Antibiotic Plus; Polyderm; Polysporin Complete; Polysporin Triple Antibiotic; Polysporin; Polytopic; Triple Antibiotic Ointment; Chile: Anbiotop; Bacitopic Compuestot; Banedif Oftalmico con Prednisolonat; Banedif Oftalmicot; Banedif ZN; Banedift; Der· mabiotico; Monticina; Nasomin; Oftabiotico; Pensulan; Rinoba­ nedif; Unguento Derrnico Antibioticot; Cz.: Framykoin; Ophthalmo-Framykoin Compositum; Ophthalmo-Framykoin; Pamycon; Fin. : Bacibact; Fr. : Badcoline; Ger.: Nebacetint; Neobact; Polyspectran HC; Polyspectran; Gr. : Apobacyn; Lyse­ paine; Nebacetin; Sopain-Plus; Vioplex-T; Hong Kong: Baci­ myxint; Polydnt; Polyspectrant; Hung.: Baneocin; Bivacynt; India: Derbec-N; Nebasulf; Neosporin-H; Neosporin; Neotop; Indon. : Liposin; N B; Nebacetin; Netracint; Scanderma Plus; Tigalin; Tracetin; Irl. : Cicatrint; Polyfax; Israel: Bamyxin; Ital. : Bimixin; Cicatrene; Cicatrene; Enterostop; Orobicin; Malaysia: Bacitracin-N; Baneod.n; Mex. : Nebacetina; Neosporin; Polixin; Soxaron; Tribiot; Neth.: Badcoline-B; Norw. : Bacimycin; Phi­ lipp. : BNP Ointment; Terramycin Plus; Trimycin-H; Trimycin; Pol.: Baneocin; Bivacynt; Maxibiotic; Multibiotic; Neotopict; Scaldex; Tribiotic; Port.: Baciderma; Bacitracina Zimaia; Cicatrin; Dimicina; Distopt; Polisulfade; Rus.: Baneocin (Erureou.nH); S.Afr. : Cicatrint; Polysporint; Singapore: Baneo­ cin; Batramycin; Fast Powdert; Polybamycin; Spain: Bacispor­ int; Banedift; Dermisone Tri Antibiotic; Dermo Rubber; Edifar­ ingent; Lizipaina; Neo Bacitrint; Phonal; Pomada Antibiotica; Rinobanedif; Tulgrasum Antibiotico; Switz.: Baneopolt; Batra­ mycint; Cicatrex; Lysopainet; Neotracin; Thai.: Bacal; Bano­ cin; Banocin; Basina; Citacin; Genquin; Izac; Lobacin; Medcint; My-B; Mybadn Dermic; Mybacin; Novacin; Thrody; Turk.: Thiocilline; UK: Polyfax; Ukr.: Baneocin (EaHeOII,HH); USA: Ak­ Poly-Bac; Ak-Sporet; Bacitraycin Plus; Cortimycin; Neocin; Neosporin + Pain Relief; Neotricin HCt; Ocu- Spor-B; Ocutricin; Polycin-B; Polymycin; Polysporin; Polytracin; ProCoMycin; Tri­ Biozene; Venez. : Dermabiotic.

(7\:i;IC); Kor. : Q-Roxin.

Bambermycin (BAN, p!NNJ

� [fl

B�rnbrm,idna( B�ftib?rfnJICinJ(�ipurJj; ffayof)h()spholiJX)I; &a,M�Ill\IH ne>rE!Oll'V'JiX�); Maxipime (.l?iJt!i-'1'); Pai Nai Xin (l!OC*!iX); Shi Rui Ping (±Jlffl -'1' ); Xian Ke Nuo (j\;liJi.t\'); XinLiWei (m:h�); Ying Lan (��); Cz.: Maxipime; Fin.: Maxi­ pimet; Fr. : Axepim; Ger.: Maxipime; Gr.: Anticepim; Gencef; Maxinject; Maxipime; Verapime; Zefipime; Hong Kong: Maxi­ pime; Hung.: Maxipime; India: Adpime; Biopime; C-Pime; Cadpime; Calpime; Ceficad; Cefpime; Cefudix; Cepime; Chase; Effimax; Forpar; lnpime; Insipim; Ipacare; lvipime; Kampi; Kef­ age; Kingcef; KPM; Leepime; Mapime; Maxicef; Maxipime; Megapime; Micropime; Neutrapime; Nitipime; Novapime; Orpime; Indon. : Actacef; Biocepime; Caprifim; Celorim; Emax; Exepime; Interpim; Macef; Maxicef; Maxilan; Maximer; Maxi­ pimet; Procepim; Rapime; Rirnax; Sandocef; Sopime; Vipime; Ital. : Cepim; Cepimex; Maxipime; Malaysia : Maxipime; Mega­ pime; Mex.: Imation; Maxef; Maxipime; NZ: Maxipime; Phi­ lipp. : Axera; Cepimax; Dimipra; Hapimax; Medipime; Pimcep; Pozineg; Sanpime; Vipefime; Zepim; Zepime; Pol.: Maxipime; Port: Maxipime; Bus. : Cepim (QeiiHM); Efepim (3cj>HIIHM); Max­ ipime (MaKcHIIHM); Maxycef (MilKCHI1ecJ>); Movizar (MOBI13AP); S.Afr.: Maxipime; Singapore: Maxipime; Spain: Maxipime; Swed. : Maxipimet; Thai. : Cefamax; Maxipime; Megapime; Orpimet; Pime; Sefpime; Turk.: Ekipim; Maxipime; Unisel; UAE: Qpime; Ukr.: Cebopime (Qe6oiiHM); Efipime (3cj>HTIHM); Maxinort (Mari); Kui Ke ()1!!31: ) ; Li Jian Ke (J'z:iJJt 5/: ); Luo Wei Ke (iilf1l5/:); Ou Jian ( i!XiJJt ) ; Qi An (J:J('!i'); Qin Ke Ao (!li!J"l'l:i:ii ) ; Qing Ke Yi (wjjJ�); She Er (%$); Shi Rui Ke (±Jilij"J'I:); Si Li Jie (CfJ)JJif); Suprax (il!-llr!f- 1 : Te Pu Ning ('i'!f-l!'"J'); Xin Fu Su ( l'ili:ffi! * ) : Xindaxin (l'iliit!fX); Yan Ling (?"J'Z); Yan Yi (?"�); Yu Shu ('lit:l'r); Zai Wo (f!f!£); Cz.: Suprax; Fr.: Oroken; Ger.:

Profile Cefmenoxime is a third-generation cephalosporin antibac­ terial with actions and uses similar to those of cefotaxime (p. 246. 1 ) . It has been given as the hydrochloride by intramuscular injection, or intravenously by injection or infusion in the treatment of susceptible infections. Like cefamandole (p. 2 3 6 . 2 ) , cefmenoxime has an N­ methylthiotetrazole side-chain and coagulopathy and a disulfiram-like interaction with alcohol have been reported rarely. Cefmenoxime hydrochloride is also given as eye drops for the treatment of eye infections.

Cephoral; InfectoOpticef; Supraxt; Uro�Cephoral; Gr.: Ceftoral; Covocef�N; Hung.: Suprax; India: AB -CEF; Aelxim; Afixim; Almocef; Arcef; Aricef; Aroxim; Asicef; Astute; Atocef; Avcif; Axim; Axiom-OR; Belfix; Bestocef; Biotax�O; Bixigard; Brufix; C-Fix; C-FX; C -Tax-0; Cadifix; Canbicef; Candycef; Carcef; Cas­ xim; Cebay; Cefaden-0; Cefcem; Cefcon; Cefesym; Cefexy; Cefi; Cefia; Cefiact; Ceficacy; Cefidn; Cefigard; Cefigo; Cefi­ gram; Cefikab; Cefime; Cefimed; Cefimo; Cefinar; Cefind; Cefine; Cefio; Cefisym; Cefit; Cefiwel; Cefix; Cefiza; Ceflim; Cefnij; Cefo; Cefocef-LB; Cefox; Cefrub; Cefspan; Ceftas; Cefti­ win; Cefupop; Cefvel; Cefxi-0; Celitol; C emax-0; Cemaxin; Ceme; Cevidm; Cexim; Cexime; Cifgen; Cifilac; Cifivar; Cif­ zone; Cinxim; Civic; Claferon-0; Clomid; Cocef; Daczim; Dot­ cef; E-Fix; Eden; Efoxim; Elce; Elcef; Elfi; Emtax; Esfix; Eurox; Evacef 0; Excef; Extacef-P; Extacef; Femcef; Fevorit; Fexim; Fexitage; Fimi; Fixcef; Fixi; Fixsana; Fixsav; Fixtrim; Fixx; Focime-L; Formic-0; Gramocef-0; Halixim; Hifen-DS; Hifen; Hofim; I�M-Safe; Incef; Ind(ef; JmKef; Jidox; Kapdux CL; Kefix; Kxime; L-Cef; Labocef; Laximo; Laycef; LBCef; Letix; Lexime; Logcef; Magnexim; Mahacef; Medicip; Micfox; Mili­ xim; Mintocef; Mytax-0; Nayafix; NBCef; Nitaxim-0; Nizocef; Novacef; Novafex; Nuclear; Nufix; 0-Powercef; Oflomix; Omnapil; Omnatax-0; Orcef; Orfix; Oritaxim�O; Pancef-0; Si� Fixim; Xim; Ziprax; Indon. : Anfix; Cefacef; Cefarox; Cefika; Cefila; Cefspan; Ceptik; Comsporin; Ethifix; Fixacep; Fixam; Fixef; Fixiphar; Lanfix; Maxpro; Nucef; Opixime; Profim; Pyx­ ime; Simcef; Sofix; Spanceft; Spaxim; Sporetik; Starcef; Taxime; Tocef; Trixim; Urticef; Yafix; Irl.: Suprax; Israel: Suprant; Ital. : Cefixoral; Stadium; Supracef; Suprax; Unixime; Jpn: Cefspan; Malaysia: Cefix; Cefixycin; Ixime; Minixime; Mex. : Denvar; Philipp.: Actimax; Aeruxim; Axetef; C -Tax P; Cefixmycin; Cifacure; Ezcef; Fix�A; Fixcef; Fixxx; Refixime; Saveceft; Septipan; Synmex; Taxocef; Tergecef; Ultraxime; Zefral; Pol.: Suprax; Port.: Bonoceft; Cefimix; Cefiton; Cefizel; Neocef; Tricef; Rus.: Ceforal (ll;e¥ ; : . · · ._ .• • (ZJP:!2-t2-Am1ooth�zot4:.Y!hl·metho)()llrninqacetamidol3-(1-pyrindin!orm�t. [1Yil�3:iepfl'em+c\'lrbo¥llte stttphate · C21H10N�OsS,,H2SQ4061l::ll . . _ • . · ·• · _ . . ·

lHH); Hizone (Xlnou); Ificef (M�e.p); Lenda­ cin (Jlel\llllU HH); Lifaxon (liHRKcou); Loraxone (JiopiiKcou); Medaxone (MeiUUpaMIIKc); Rocepherin (PmwepHH); Rocepbin (PolleHH); Stericef (Crep�e4J) ; Tercel (Teplle); Torocef (Topo11e); Triaxone (TpHIIKCOH); S.Afr. : Kocef; Medaxone; Ofrarnax; Rocepbin; Rociject; Triaphin; Triaxipbin; Singapore: Antibacin; Cefaxone; Ceftriphine; Ofra­ max; Rocephin; Trexofin; Triaxone; Tricefin; Trizon; Spain: Rocefalint; Swed.: Cefonovat; Rocephalin; Switz.: Rocepbin; Thai.: CEF-3; Cef-Zone; Ceftrex; Ceftriphin; Gomcepbin; Ofra­ max; Rinxofayt; Rocephin; Sedalin; Triacelt; Tricepbint; Trix­ one; Trixophin; Utofin; Zefaxone; Turk.: Armaseft; Baktisef; Cefaday; Cefridem; Cephaxon; Desefin; Equiceft; Forse!; lese!; Nevakson; Novosef; Rocephin; Triaxon; Unacefin; UAE: Triax­ one; UK: Rocephin; Ukr.: Cefaxone (lle4JaxcoH); Cefogram (lle4Jorp!1M); Lendacin (JleHJIRiliiH ) t; Noraxon (HopiiKCOH); Ofra­ max (OPaMRKc); Parcel (IIaplle)t; USA: Rocepbin; Venez. : Bioceftrax; Cefin; Cefix; Ceftrialin; Ciplacef; Eftrival; Megion; Rocepbin; Strixone; Tricefi.

Multi-ingredient Preparations.

China: Xin Junbizhi (gjl;Et�' itt ) ; India: Acticef-SB; Adesul; Afzone-S; Alitax-S; Alkaceff-S; Alna­ cef-S; Alnacef-T; Amceft-S; Arixon-SB; Arixon-TZB; Augtaz; Avcef-S; Avcef-TZ; Axocare-S; Axocare-T; Axon-SB; Axone-SB; Axtrum-S; Bactosul; Big-Tum; Broadcef-S; Broadcef-T; C-Fort; C -Tab-SB; C-Tum; Cadizone-S; Cadizone-XP; Cafage-S; Cameo­ S; Cearium; Cebactum; Cef-S; Cefa-T Kit; Cefaday-S; Cefaday­ TZ; Cefcin-SB; Cefcin-TJ; Cefirone T; Cefirone-V; Cefj oy; Cef­ mol-SF; Cefmol-TZ; Cefritz-TZ; Cefrose-S; Cefs-T; Cefset-S; Cef­ set-TX; Cefsine-S; Cefsine-TZ; Ceftichek; Ceftraset-S; Ceftril-S; Ceftrimax; Ceftrol-S; Cefurin; Cefwon-S; Cefzone-S; Cefzox-SF; Cefzox-TZ; Cepoxit-S; Cesafe-TZ; Cetriax-S; Cetzone-S; Cet­ zone-TZ; Cezone Plus; Champione-S; Chuncif-S; Corcef-SB; Cotyx-S; Crucef; CSI-S; CT Ce!! SM; CT Ceff-TZ; CTMor-TZ; CTrisana-SB; CTX-TZ; Cucef-S; Cuxone-SL; Deczone-S; Dec­ zone-T; Deczone-TP; Dewcef-S; Dibact; Eftanu-S; Ekcef-S; Emtri-S; Estxone-SB; Extacef-Tazo; Extacef-XL; Finecef-T; Fine­ triax-S; Formic; Forone-SB; Geminate Plus; Glen-SB; Glen-TZB; Glicef-S; Glicef-T; Gloriax-SB; Gramocef-S; Ificef-T; Hocef-S; Hocef-T; Ifytrox-SB; Ifytrox-TB; Incef-SB; Incef-TZ; Indocef-SB; Indoxone-S; Infoxon-S; Infoxon-T; Kali-S; Kafi-TBZ; Keftra· gard; Kexone Plus; Kxone-SL; Labxone-SB; Lezone-S; Lezone­ XP; Lifecare-A; Lifecare-C; Lifecare-SB; Lifecare-T; Lisel-S; Lisel-TBZ; Lyceft Plus; Mahacef-SB; Mat-CS; Mepef-S; Mintrax­ S; Mocef-S; Mocef-TZ; Monobact; Montaz; Nexef-SB; Nexef­ TBZ; Nizotrax-S; NKCef+S; Novaceft-S; Nutracip-SB; Oframax Forte; Onbact; Opticef-S; Oritiz; Oxy-S; Pancef-S.

Phormocopoeial Preparations

BP 20 14: Ceftriaxone Injection; USP 36: Ceftriaxone for Injection; Ceftriaxone Injection.

Cefuroxime

!BAN, usAN. riNNJ

Pharmacopoeias. In Chin., Bur. (see p. vii), Jpn, and US.

Ph. Eur. 8: (Cefuroxime Axetil) . A white or almost white

powder. Slightly soluble in water and in alcohol; soluble in

The symbol t denotes a preparation no longer actively marketed

255

acetone, in ethyl acetate, and in methyl alcohol. Store in airtight containers. Protect from light.

USP 3 6 : ( C efuroxime Axetil ) . A mixture of the diastereoisomers of cefuroxime axetil. A white or almost white powder. The amorphous form is insoluble in water and in ether; slightly soluble in dehydrated alcohol; freely soluble in acetone; soluble in chloroform, in ethyl acetate, and in methyl alcohol. The crystalline form is insoluble in water and in ether; slightly soluble in dehydrated alcohol; freely soluble in acetone; sparingiy soluble in chloroform, in ethyl acetate, and in methyl alcohol. Store in airtight containers.

Cefuroxime Sodium (BANM, rfNNMI

Pharmacopoeias. In Chin., Bur. (see p . vii) , Jpn, and US.

Ph. Eur. 8: ( Cefuroxirne Sodium ) . A white or almost white

slightly hygroscopic powder. Freely soluble in water; very slightly soluble in alcohol. A I % solution in water has a pH of 5.5 to 8 . 5 . Store in airtight containers.

USP 36: ( Ceforoxime Sodium ) . A white or faintly yellow

powder. Freely soluble in water; very slightly soluble in alcohol, in chloroform, in ether, and in ethyl acetate; soluble in methyl alcohol. pH of a ! 0 % solution in water is between 6.0 and 8 . 5 . Store in airtight containers.

Incompatibility and stability.

Cefuroxime sodium may be incompatible with aminoglycosides.

References. 1.

Barnes AR. Chemical stabilities of cefuro:xime sodium and metronid­

2.

Stiles ML, et al. Stability of ceftazidime (with arginine) and of cefuroxime

azole in an admixture for intravenous infusion. 15:

J Clin Pharm Ther 1 990;

1 87-96.

sodium in infusion-pump reservoirs. Am J Hosp Pharm 1 992; 49: 276 1-4. 3. Hebron B, Scott H. Shelf life of cefuro:xime eye-drops when dispensed in artificial tear preparations. Int J Pharm Pract 1 993; 2: 1 63-7.

Uses and Administration Ceforoxirne is a second-generation cephalosporin antibac­ terial used in the treatment of infections caused by susceptible Gram-positive and Gram-negative bacteria, including infections of the bones and joints, CNS, skin and skin structures, respiratory tract, genito-urinary tract (including gonorrhoea) , and Lyme disease. It is also used for surgical infection prophylaxis. For details of these infections and their treatment, see under Choice of Antibacterial, p. 1 7 2 . 2 . Cefuroxime i s given orally as t h e acetoxyethyl ester, cefuroxirne axetil, in the form of tablets or suspension with or after food, or by injection as the sodium salt. Cefuroxirne sodium may be given by deep intramuscular injection, by slow intravenous injection over 3 to 5 minutes, or by intermittent or continuous intravenous infusion; it can also be given by intracameral injection. Doses of cefuroxime axetil and cefuroxime sodium are expressed in terms of the equivalent amount of cefuroxime; 1 . 20 g of cefuroxime axetil and I . OS g of ceforoxime sodium are each equivalent to about 1 g of ceforoxime. The usual oral dose is 2 5 0 mg twice daily; for uncomplicated urinary-tract infections I 2 5 mg twice daily may be adequate and for respiratory-tract infections 2 5 0 to 500 mg twice daily is recommended. For Lyme disease an oral dose of 500 mg is given twice daily for 2 0 days. By injection the usual dose is 750 mg of cefuroxime every 8 hours but in more severe infections 1 . 5 g may be given intravenously every 8, or in some cases every 6 hours. Those with pneumonia or with acute exacerbations of chronic bronchitis may respond to sequential therapy with parenteral cefuroxime 1 . 5 g twice daily or 7 5 0 mg twice daily respectively, followed by oral cefuroxime 500 mg twice daily in each case. For the treatment of meningitis due to sensitive strains of bacteria, cefuroxime is given intravenously in doses of 3 g every 8 hours. In the treatment of gonorrhoea, a single dose of I. 5 g by intramuscular injection, divided between 2 injection sites, has been used. A single I -g oral dose of cefuroxime has been given for uncomplicated gonorrhoea. In each case an oral dose of probenecid I g may be given with cefuroxirne. For surgical infection prophylaxis, the usual dose is I . 5 g of ceforoxirne intravenously before the procedure; this may be supplemented by 7 5 0 mg intramuscularly every 8 hours for up to 24 to 48 hours depending upon the procedure. For

256

Antibacterials

total joint replacement, 1 . 5 g o f cefuroxime powder may be mixed with the methylmethacrylate cement. Cefuroxime may be given by intracameral injection for the prophylaxis of postoperative endophthalmitis; a dose of l mg is slowly injected into the anterior chamber of the eye at the end of cataract surgery. The dose of cefuroxime may need to be reduced in patients with renal impairment, see p. 2 5 8 . 1 . For details of doses in children, see also p . 2 5 8 . 1 .

Reviews. I.

Perry CM, Brogden RN. Cefuroxime axetil: a review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.

2. 3.

Drugs 1 996; 52: 1 2 5-58. et a!. Cefuroxime axetil: an updated review of its use in the management of bacterial infections. Drugs 2 0 0 1 ; 61: 1455-1 500. Scott LJ,

Keating GM. Intracameral cefuroxime: prophylaxis of postoperative endophthalmitis after cataract surgery.

Drugs 2 0 1 3 ; 73: 1 7 9-86.

Administration in children.

Cefuroxime may be given to neonates and children for the treatment of infections caused by susceptible Gram-positive and Gram-negative bacteria and for surgical prophylaxis. It is given orally as cefuroxime axetil; the sodium salt is given parenterally either by intramuscular injection or intravenously, by slow injection over 3 to 5 minutes, or intermittent or con­ tinuous infusion. The BNFC suggests the following treatment doses for cefuroxime: given orally • children 3 months to 2 years of age: 1 0 mg/kg (to a maximum dose of 1 2 5 mg) twice daily • those over 2 years of age: 1 5 mg/kg (to a maximum dose of 2 5 0 mg) twice daily, or given parenterally • neonates under 7 days of age: 2 5 mg/kg every 1 2 hours • neonates 7 to 21 days of age: 2 5 mg/kg every 8 hours • neonate 21 to 28 days of age: 2 5 mg/kg every 6 hours • these doses may be doubled in neonates with severe infections, but should be given intravenously • children from I month of age: 20 mg/kg (to a maximum dose of 7 5 0 mg) every 8 hours; this dose may be increased to 50 to 60 mg/kg (to a maximum dose of 1 . 5 g) every 6 or 8 hours in severe infection and cystic fibrosis For surgical prophylaxis the BNFC suggests that children from the age of I month may be given a dose of 50 mg/kg (to a maximum dose of I . 5 g) intravenously before the procedure; this may be supplemented by up to 3 further doses of 3 0 mgikg (to a maximum dose of 7 5 0 mg) intramuscularly or intravenously at 8-hour intervals for high-risk procedures. In the USA, the American Academy of Pediatrics1 suggests the following doses: orally • children I month and older: 20 to 3 0 mg/kg daily in 2 divided doses (to a maximum daily dose of 0 . 5 to I g) for mild to moderate infections intravenously or intramuscularly • for neonates aged � 7 days (irrespective of body weight) : 50 mg/kg every 1 2 hours • for neonates aged 8 to 28 days and weighing � 2 kg: 50 mg/kg every 8 to 12 hours; a dosing interval of 1 2 hours may b e used until 2 weeks o f life i n extremely low birth-weight neonates (weighing less than I kg) • for neonates aged 8 to 28 days and weighing > 2 kg: 50 mg/kg every 8 hours • children I month and older: 7 5 to 100 mg/kg daily in 3 divided doses (to a maximum daily dose of 2 . 2 5 to 4.5 g) for mild to moderate infections, or 1 00 to 200 mg/kg daily in 3 or 4 divided doses (to a maximum daily dose of 3 to 6 g) in severe infections 1.

American Academy of Pediatrics.

2012 Red Book: Report of the Committee

29th ed. Elk Grove Village, Illinois, USA: American of Pediatrics, 2 0 1 2 .

Administration in renal impairment.

Parenteral doses of cefuroxime may need to be reduced in renal impairment. Licensed product information suggests the following doses based on creatinine clearance ( C C ) : • C C 1 0 t o 20 mL/minute: 7 5 0 m g twice daily • CC less than I O mL/minute: 750 mg once daily Patients undergoing haemodialysis should receive an additional 7 5 0 -mg dose following each dialysis; those undergoing continuous peritoneal dialysis may be given 7 5 0 mg twice daily.

Adverse Effects and Precautions As for Cefalotin Sodium, p. 2 3 5 .2 . Gastrointestinal disturbances, including diarrhoea, nausea, and vomiting, have occurred in some patients receiving cefuroxime axetil. There have been rare reports of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Mild to moderate hearing loss has been reported in some children given cefuroxime for the treatment of meningitis. All cross-references refer to entries in Volume A

Antibiotic-associated colitis.

For reports of pseudo­ membranous colitis associated with cefuroxime axetil, see Cefalotin, p . 2 3 5 . 2 .

Hypersensitivity. A report1 of a serum sickness-like reac­ tion to cefuroxime. Similar reactions have occurred with cefaclor (p. 2 3 3 . 1 ) , although it is unclear whether they represent a class effect. A patient who developed a type- ! hypersensitivity reaction to cefuroxime, charaCterised by itchy maculopap­ ular rash, exhibited cross-sensitivity to cefotaxime and ceftriaxone on patch testing, possibly because of similarities in the side-chain; 2 no cross-sensitivity to cefazolin, cefepime, cefoxitin, or ceftazidime, or to various penicillins, was seen on testing and the patient subsequently tolerated doses of amoxicillin and ceftazidime. The authors noted that cefuroxime had been found in another study to be the most frequent cause of immediate-type hypersensitivity reactions to cephalosporins.

P.r.�P.�.r£a); Kaidixin (i'V\'i'il'JiX); Ku Xin (�JiX); Li Fu Xin (Bil jji(JiX); Li Jian Xin (iL1lUJi); Lifurox ( JJ 'Iii: Jt ) ; Monacef ( f!il ilJ !iX); Pai Wei Xin (l!RiliiG JiX ); Rui Fu Xin (lii\i i!Kf�): Sipeiding (RJ � JE ) ; Supero (!if 91ii"r); X i Lu Xin (l\tjj!j}il'f); Xin L i Xin (il'fJl:JiX); Xin Lu Xin (JiXJi!j}il'f); Xinfuxin (!/ilit/lili;l(); Yaxing (j]E.!ll_ ) ; Youlex­ in (iltlt!/ili); Yun Tai (1!;:$); Zinacef (iffi JJJiX); Cz. : Axetine; Medoxin; Miksor; Xorimax; Zinacef; Zinnat; Zinoximet; Denm.: Zinacef; Zinnat; Fin.: Aprokam; Zinacef; Zinnat; Fr.: Cepazinet; Zinnat; Ger.: Cefuhexalt; Cefuro-Purent; Cefurox-Wolfft; Cefuroxt; Elobact; Zinnatt; Gr.: Anaptivan; Cefoprim; Cefur;

Cefuretil; Cefuroprol; Cerofene; Ceruxim; Cupax; Ecoline; Fea­ cef; Foucacillin; Fredyr; Furaxil; Galemin; Genephoxal; Gonif; Helatocil; Interbion; Lyprovir; Medoxem; Mevecan; Mosalan; 2 . Varela Losada S, et a!. Immediate-type allergic reaction to cefuroxime: Nelabocin; Nipogalin; Normafenac; Receant; Saxetil; Sedopan; cross-reactivity with other cephalosporins, and good tolerance to Vekfazolin; Yokel; Zagorine; Zetagal; Zilisten; Zinacef; Zinadol; ceftazidime. J lnvestig Allergol Clin Immunol 2009; 19: 1 64-5. Hong Kong: Axacef; Axim; Ceflour; Quali-Cefumat; Sefuxim; Xorimax; Zinacef; Zinnat; Hung.: Cefurint; Ceroxim; Xorim; Porphyria. The Drug Database for Acute Porphyria, com­ Xorimax; Zinacef; Zinnat; India: Actum; Adexim; Altacef; Altum; Anorex; Arixime; Atom; Aucee; Axacef; Axeptil; Axeris; piled by the Norwegian Porphyria Centre (NAPOS) and Axetim; Axtl; Bacticef; Barocef; Bencef; Bigcef; Biocef; Bullcef; the Porphyria Centre Sweden, classifies cefuroxime as C-Furo; C-Tri-T; Cascef; Ceax; Cef-Vepan; Cefakind; Cefam; probably not porphyrinogenic; it may be used as a drug of Cefar; Cefasyn; Cefexl; Cefies; Cefking; Ceflet; Cefob; Cefogen; first choice and no precautions are needed.1 Cefoprim; Ceforim; Ceforox; Cefos; Cefoxim; Cefpil; Cefta; Cef­ l . T h e D r u g Database f o r Acute Porphyria. Available a t : http://www. tab; Ceftal; Ceftra; Ceftum; Cefu; Cefubir; Cefucin; Cefucos; drugs-porphyria.org (accessed 1 5 / 1 0/ 1 1 ) Cefunis; Cefupet; Cefurin; Cefusym; Cefutab-0; Cefuvik; Cefyr­ ex; Cefzim; Ceplex; Cepokem; Cerom; Ceroxitum; Cesai; Cetil; Sodium content. Each g o f cefuroxime sodium contains Ceurox; Cilixern; CTrox; Curoxim; Cutil; Cuxim; Daltum; Deri­ cef; Difu; Duxim; Edrucef; Ethicef; Evercef; Exeption; Exime; about 2.2 mmol of sodium. Flamicef; Forcef; Forcez; Forex; Forkem; Fucef; Furion; Furo­ bid; Furomax; Furome; Furox; Furoxil; Fydoroxim; Glyph·ZM; Gocef; 1-M-Sure; Iflacef; Insifu; Intracef; Iviroxime; Jaxe; Joxcy; Kaircef; Kaxitel; Kefstar; Kefuel; Kern; Kincef; Klime; L-Tum; Probenecid reduces the renal clearance of cefuroxime. Lazocin; Luroxime; Magna; Magnacef; Martec; Maxim; MaxI tum; Metump; Milcef; Neftum-AXT; Neroxim; Nifoxime; Novaroxim; Ocef; Omnix:im; Oruf; Supacef; Indon. : Anbacim; Cefuroxt; Celocid; Cethixim; Kalcef; Kenaceft; Oxtercid; Roxbit; Sharox; Soxime; Zinaceft; Zinnat; Irl.: Ceftal; Zinacef; Cefuroxime is bactericidal and has a similar spectrum of Zinnat; Israel: Cefurax; Ceroximt; Kefurim; Pan-Cefuroxime; antimicrobial action and pattern of resistance to those of Zinacef; Zinnat; Ital. : Biociclint; Cefoprimt; Cefurin; Curoxim; cefamandole (p. 2 3 7 . 1 ) . It is more resistant to hydrolysis by Duxima; Itorex; Lafurext; Oraxim; Supero; Tilexim; Zinnat; beta-lactamases than cefamandole, and therefore may be Zinocep; Zoref; Malaysia: Altacef; Anikef; Ceflour; Efurox; Fur­ more active against beta-lactamase-produdng strains of, for oxime; Vaxcel Cefuroxime; Xorimax; Xylid; Zinacef; Zinnat; example, Haemophilus influenzae and Neisseria gonorrhoeae. Zocef; Mex.: Cefabiot; Cefagen; Cefuracet; Cetoxil; Froxal; However, treatment failures have occurred in patients with Fucerox; Furobioxin; Magnaspor; Novador; Ximaken; Xorufec; H. influenzae meningitis given cefuroxime and might be Zinnat; Neth. : Aprokam; Zinacef; Zinnat; Norw.: Zinacef; NZ: associated with a relatively high minimum bactericidal Axetine; Zinacef; Zinnat; Philipp.: Aeruginox; Altacef; Ambix­ concentration when compared with the minimum ime; Axet; Axurocef; Bactipoz; Betcef; C-Tri T; Cefogen; Ceftil; inhibitory concentration or with a significant inoculum Cefucilt; Cefumax; Cefurex; Cefuzime; Cervin; Cesavess; Cido­ effect. Reduced affinity of penicillin-binding proteins for kez; Cimex; Clovixime; Curecef; Darcef; Ecocef; Educef; Elix­ cefuroxime has also been reported to be responsible for ime; Emixor; Eoroxime; Eroxmit; Eurimax; Finax; Fubaxynt; resistance in a beta-lactamase-negative strain of H. Furocef; Furocem; Furomax; Furoximt; Furoxy; Harox; Ifurax; Infekor; Jectocef; Kaftax; Kefezy; Kefox; Kefstar; Kefsyn; Kefur­ influenzae. ox; Keunzef; Lasuzef; Laxinat; Loxatrelt; Medxil; Medxime; References. Medzyme; Microzef; Panaxim; Panjecxime; Pheoronex; Plero­ 1. Arditi M, et a!. Cefuroxime treatment failure and Haemophilus zef; Profurex; Rexofen; Rezafil; Robisef; Rocef; Romicef; Rovix; influenzae meningitis: case report and review of literature. Pediatrics Roxetil; Roxicef; Roxime; Roxymt; Rucef; Ruxim; Sharoxt; 1 989; 84: 1 32-5. Shincef; Teikeden; Unoximed; Vitaroxima; Xorimax; Zefcid; 2 . Mendelman PM, et al. Cefuroxime treatment failure of nontypable Zefsur; Zefur; Zefuxim; Zegen; Zenoxim; Zinacef; Zinaf; Zinnat; Haemophilus influenzae meningitis associated with alteration of Zoltax; Zurenix; Pol.: Biofuroksym; Bioracef; Ceroxim; Novocef; penicillin-binding proteins. 1 Infect Dis 1 990; 162: 1 1 1 8-23. 3 . Brown NM, et al. Cefuroxime resistance in Haemophilus influenzae. Plixymt; Tarsime; Xelacef; Xorimt; Xorimax; Zamur; Zinacef; Lancet 1 992; 340: 5 5 2 . Zinnat; Zinoxx; Port.: Antibioxime; Axacef; Cefofixt; Condro­ nac; Curoxime; Famicef; Lusoceft; Saracef; Zipos; Zoref; Rus.: Antibioxim (AHrn6HOKCHM); Axetine (AKcenm); Cefurabol (I\erpypa6on); Cefurus (l(erpypyc); Cetyl (l(erHn) ; Kefstar (Kerpcmp); Ketocef (Kerouerp): Proxime (!IpoKCHM); Supero Cefuroxime axetil is absorbed from the gastrointestinal tract (Cynepo); Xorim (KcopHM); Zinacef (3HHau;e¢); Zinnat (3HHHaT); and is rapidiy hydrolysed in the intestinal mucosa and blood S.Afr. : Auroxime; Betaroxime; Cefasyn; Cefu-Hexal; Ceroxim; to cefuroxime; absorption is enhanced in the presence of Cipofix; CuroAx; Intraceft; Medaxime; Zefroxe; Zefurime; food. Peak plasma concentrations occur about 2 to 3 hours Zinacef; Zinnat; Zinoxime; Singapore: Bearce£; Ceftil; Cefxin; after an oral dose. The sodium salt is given by intramuscular Shincef; Xorimax; Zinacef; Zinnat; Spain: Curoximat; Niva­ or intravenous injection. Peak plasma concentrations of dort; Selant; Zinnat; Swed.: Zinacef; Zinnatt; Switz. : Cefurim; about � 7 micrograms/mL have been achieved 45 minutes Zinacef; Zinat; Thai.: Axuroceft; C-Tri T; Cefamart; Cefurim; after an intramuscular dose of 7 5 0 mg with measurable Farmacef; Furoxime; Magnaspor; Neurox; Sefuxim; Zinacef; amounts present 8 hours after a dose. Up to 50% of Zinnat; Zocef; Zoneft; Turk. : Aksef; Cefaks; Cefatin; Cefurol; cefuroxime in the circulation is bound to plasma proteins. Enfexia; Multisef; Oraceftin; Sefaktil; Seffur; Sefuroks; Zinnat; The plasma half-life is about 70 minutes and is prolonged in UAE: Cefuzime; UK: Aprokam; Zinacef; Zinnat; Ukr. : Aksef patients with renal impairment and in neonates. (AKcerp); Biofuroksym (BHorpypoKcHM)t; Cefoctam (l(erpmcraM); Cefumax (l(erpyMaKc); Cefutil (l(erpyrHJJ); Cetil (ljenm); Enfexia Cefuroxime is widely distributed in the body including (3HrpeKCHH); Kimacef (KHMauerp); Mikrex (MmqJeKc); Spizef pleural fluid, sputum, bone, synovial fluid, and aqueous (CnH3erp); Zinacef (3nnaJ1erp) ; Zinnat (3HHHaT); USA: Ceftin; humour, but only achieves therapeutic concentrations in Zinacef; Venez. : Xorim; Zencef; Zinacef; Zinnat. the CSF when the meninges are inflamed. It crosses the placenta and has been detected in breast milk. Multi-ingredient Preparations. India: Bactocef; C -Tri EM; Cefos­ Cefuroxirne is excreted unchanged, by glomerular S; Covatil-CV; Intracef-CV; Ocef-CV. filtration and renal tubular secretion, and high concentra­ tions occur in the urine. On injection, most of a dose of Pharmacapoeial Preparafians cefuroxime is excreted within 24 hours, the majority within BP 2 0 14: Cefuroxime Axetil Oral Suspension; Cefuroxime Axetil 6 hours. Probenecid competes for renal tubular secretion Tablets; Cefuroxime Eye Drops; Cefuroxime Injection; Cefur­ with cefuroxime resulting in higher and more prolonged oxime Intracarneral Injection; plasma concentrations of cefuroxime. Small amounts of USP 36: Cefuroxime Axetil for Oral Suspension; Cefuroxime cefuroxime are excreted in bile. Axetil Tablets; Cefuroxime for Injection; Cefuroxime Injection. Plasma concentrations are reduced by dialysis. I.

Katta R, Anusuri V. Serum sickness-like reaction to cefuroxime: a case report and review of the literature.

Interactions

Antimicrobial Action

Pharmacokinetics

J Drugs Dennato/ 2007; 6: 747-8.

Cefuroxime/Chloramphenicol degrees. Chloramphenicol palntitate shows polymorphism and the thermodynantically stable form has low bioavail­ ability following oral administration. Practically insoluble in water; sparingly soluble in alcohol; freely soluble in acetone; very slightly soluble in hexane. Protect from light.

Cethromycin {USAN, riNNJ

Profile Cethromydn is a ketolide antibacterial under investigation for the treatment of susceptible respiratory-tract infections. References. 1.

Dougherty T J , Barrett JF. ABT-7 7 3 : a new ketolide antibiotic.

2.

Zhanel GG,

Expert Opin Invest Drugs 200 1 ; 10: 343-5 1 . e t al. The ketolides: a critical review. Drugs 2002; 62: 1 7 7 1 1 804.

3.

Zhanel GG,

et al. Ketolides: an emerging treatment for macrolide­ Expert Opin

resistant respiratory infections, focusing on S. pneumoniae.

Bmerg Druos 2003; 8: 297-3 2 1 . 4.

Reinert R R . Clinical efficacy o f ketolides i n the treatment o f respiratory

5.

Anonymous. Cethromycin: A- 1 9 5 7 7 3 , A- 1 9 57 7 3 -0, Abbott- 1 9 57 7 3, ABT 7 7 3 . Drugs R D 2007; 8: 95-102.

6.

Hammerschlag MR. Sharma R. Use of cethromydn, a new ketolide, for

tract infections.

7.

J Antimicrob Chemother 2004; 53: 9 1 8-2 7. A - 1 9 5 7 7 3 0,

treatment of community-acquired respiratory infections. Expert Opin Invest Drugs 2008; 17: 387-400. Rafie S, et al. Cethromycin: a promising new keto!ide antibiotic for respiratory infections. Pharmacctherapy 2 0 1 0; 30: 29D-303.

NOTE. CPL is a code approved by the BP 2014 for use on single unit doses of eye drops containing chloramphenicol where the individual container may be too small to bear all the appropriate labelling information.

Pharmacopoeias. In Chin., Bur. (see p . vii) , Int., Jpn, US, and Viet.

Ph. Eur. 8: ( Chloramphenicol) . A substance produced by the growth of certain strains of Streptomyces venezuelae, but now mainly prepared synthetically. A white, greyish-white or yellowish-white, fine crystalline powder or fine crystals, needles, or elongated plates. Slightly soluble in water; freely soluble in alcohol and in propylene glycol. Protect from light. USP 36: ( Chloramphenicol) . Fine, white to greyish-white or yellowish-white, needle-like crystals or elongated plates. Soluble 1 in 400 of water; freely soluble in alcohol, in acetone, in ethyl acetate, and in propylene glycol. pH of a 2 . 5 % suspension in water is between 4.5 and 7 . 5 . Its solutions are practically neutral to litmus. It is reasonably stable in neutral or moderately add solutions. Store in airtight containers.

Chloramphenicol Palmitate {BANM, r!NNMJ

Pharmacopoeias. In Chin., Bur. (see p . vii) , Int., Jpn, US, and Viet.

Ph. Eur. 8: ( Chloramphenicol Palntitate) . A fine, white or almost white, unctuous, powder. M.p. 87 degrees to 9 5

257

When given systemically, chloramphenicol is usually-used orally as capsules or as a suspension of chloramphenicol palntitate. When oral use is not feasible, water-soluble chloramphenicol sodium succinate may be given intrave­ nously, but oral therapy should be substituted as soon as possible; an intravenous dose should be injected over at USP 36: (Chloramphenicol Palntitate) . A fine, white, least 1 minute or given by slow intravenous infusion. unctuous, crystalline powder, having a faint odour. M.p. 87 Intramuscular injection is controversial because of doubts degrees to 9 5 degrees. Insoluble in water; sparingly soluble whether absorption is adequate. in alcohol; freely soluble in acetone and in chloroform; Doses are expressed in terms of chloramphenicol base soluble in ether; very slightly soluble in hexane. Store in and are similar whether given orally or intravenously. airtight containers. Chloramphenicol palmitate I. 7 g and chloramphenicol sodium succinate 1 .4 g are each equivalent to about 1 g of chloramphenicol base. Chloromphenicol Sodium Succinate The usual dose is 5 0 mg/kg daily in divided doses every 6 {BANM, r/NNM} or 8 hours; up to 1 00 mg/kg daily may be given in meningitis or severe infections due to moderately resistant organisms, although these higher doses should be reduced as soon as possible. It has been recommended that treatment should be continued after the patient's temperature has returned to normal for a further 4 days in rickettsial diseases, and for 8 to 10 days in typhoid fever, to minintise the risk of relapse. In the topical treatment of eye infections, chlorampheni­ col is usually applied as a 0 . 5 % solution or as a I % ointment. Generally, drops are applied up to 6 times daily. Severe infections may need more frequent dosing initially, reducing gradually once the infection is controlled. When ointment is used, it may be applied once daily at night if drops are used during the day, or 3 or 4 times daily if used alone. For bacterial infections in otitis extema, chlorampheni­ col has been given as ear drops in a strength of 5 or 1 0 % . A , dose of 2 or 3 drops to the affected ear 2 or 3 times daily has Pharmacopoeias. In Bur. (see p . vii) , Int., Jpn, US, and Viet. been used. Chin. includes Chloramphenicol Hydrogen Succinate. Chloramphenicol has also been used in the form of other Ph. Eur. 8: (Chloramphenicol Sodium Succinate) . A white derivatives including the glydnate, the pabnitoylglycolate, or yellowish-white hygroscopic powder. Very soluble in the pantothenate, the steaglate, the stearate, and the water; freely soluble in alcohol. A 2 5 % solution in water has hydrogen succinate. a pH of 6.4 to 7 .0. Store in airtight containers. Protect from light. Administration. When parenteral use of chloramphenicol USP 36: ( Chloramphenicol Sodium Succinate) . A light is necessary the intravenous route is generally preferred, yellow powder. Freely soluble in water and in alcohol. pH of although the intramuscular route has been advocated. a solution in water containing the equivalent of chloram­ Adequate serum concentrations after intramuscular injec­ phenicol 2 5 % is between 6.4 and 7 . 0 . Store in airtight tion have been reported, 1.2 although this is contrary to the widely held belief that chloramphenicol sodium succinate Incompatibility. Incompatibility or loss of activity has been is poorly absorbed by this route. Pain on injection was also claimed to be minimal.1 After a study in children with reported between chloramphenicol and many other sub­ bacterial meningitis,' treatment with intramuscular chlor­ stances. Other factors, especially drug concentration, may amphenicol for 2 or 3 days followed by oral therapy has play a part and incompatibilities are most often seen with been suggested, although a later study2 found that the concentrated solutions. intramuscular route produced therapeutic concentrations when the oral route did not. However, it has been said4 that children describe intramuscular chloramphenicol as amongst the worst treatments they ever receive, and cer­ The risk of life-threatening adverse effects, particularly tainly much worse than the insertion of intravenous can­ bone- marrow aplasia, has severely lintited the clinical nulae. usefulness of chloramphenicol, although it is still widely l. Shann F, et al. Absorption of chloramphenicol sodium succinate after used in some countries. It should never be given intramuscular administration in children. N Engl J Med 1 9 8 5; 313: 4 1 Dsystentically for ntinor infections and regular blood counts 14. are usually advisable during treatment. The third­ 2 . Weber MW, et al. Chloramphenicol pharmacokinetics in infants less generation cephalosporins replaced chloramphenicol for than three months Of age in the Philippines and The Gambia. Pediatr Infect Dis J 1 999; 18: 896-90 1 . many of its former uses, and there are consequently few 3 . Shann F , e t al. Chloramphenicol alone versus chloramphenicol plus unambiguous indications for its use. It has been used in penicillin for bacterial meningitis in children. Lancet 1 985; ii 6 8 1 - 3 . severe typhoid and other salmonella! infections, although it 4. Coulthard M G , Lamb WH. Antibiotics: intramuscular or intravenous? does not eliminate the carrier state. Chloramphenicol is an Lancet 1 98 5 ; ii: 1 0 1 5 . alternative to a third-generation cephalosporin in the treatment of bacterial meningitis, both empirically and Administration in children. Because of metabolic differ­ against sensitive organisms such as Haemophilus injluenzae. It ences, neonates and premature infants will generally may be used as part of a multidrug regimen for the require lower systemic doses than older infants and chil­ treatment of inhalation and gastrointestinal anthrax. It has dren. Where there is no alternative to the use of chloram­ been used in the treatment of severe anaerobic infections, phenicol, the doses recommended according to age and particularly in brain abscesses, and in infections below the maturity are as follows: diaphragm where Bacteroides fragilis is often implicated; • all neonates up to 2 weeks old: 25 mg/kg daily in divided however, other drugs are usually preferred. Although the doses (the BNFC suggests 2 divided doses at intervals of tetracyclines remain the treatment of choice in rickettsial 12 hours) by intravenous injection infections such as typhus and the spotted fevers, chloram­ • full-term neonates 2 weeks of age and older: 25 to 50 mg/kg phenicol is also used as an alternative where the daily given in divided doses of 1 2 . 5 mg/kg every 6 to 1 2 tetracyclines cannot be given. hours Other bacterial infections in which chloramphenicol may • premature neonates 2 weeks of age or older, and infants with be used as an alternative or adjunct to other drugs include suspected immature metabolic processes: 25 mg/kg daily actinomycosis, ehrlichiosis, cystic fibrosis, severe gastro­ intravenously in divided doses enteritis (including Salmonella enteritis, cholera, and • infants and children aged 1 month to 18 years: where Yersinia enteritis), gas gangrene, granuloma inguinale, metabolic processes are mature, as for adults (see Uses severe Haem"fJhilus injluenzae infections (for example in and Adntinistration, above) . Where immature metabolic epiglottiti s ) , severe melioidosis, pelvic inflammatory processes are suspected a reduced dose of 25 mg/kg daily disease, plague ( especially if meningitis develops), pneu­ in divided doses has again been recommended monia, psittacosis, Q fever, relapsing fever, tularaemia Blood concentration monitoring is recommended when (especially when meningitis is suspected), and Whipple's using parenteral or oral chloramphenicol in neonates, disease. For details of these infections and their treatment, children with inunature metabolic processes, and for see under Choice of Antibacterial, p. 1 72 . 2 . children receiving higher dose ranges for serious infections. Chloramphenicol is extensively u s e d in the topical It is also preferred for those under 4 years of age. For details treatment of ear and, in particular, eye infections, despite the fact that many of these are ntild and self-lintiting. It has of recommended plasma concentrations, see Precautions, p . 260.2. also been used topically in the treatment of skin infections.

Uses and Administration

The symbol t denotes a preparation no longer actively marketed

258

Antibacterials

Chloramphenicol topical eye and ear preparations are used similarly to use in adults (see Uses and Administration, p. 2 5 7 .2 ) .

Enterococcal infections. The emergence o f resistance to vancomycin among enterococcal isolates has required the development of new therapeutic options such as linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin for the treatment of vancomycinRresistant enterococcal infec­ tions (p. 1 8 1 . 1 ) . There is, however, no standard treatment and choice of antibacterial depends on local patterns of resistance and antibacterial sensitivity tests. Some reports have indicated that chloramphenicol may be effective against vancomycin-resistant Enterococcus [aecium.1-3 Although no significant effect of chloramphenicol on mor­ tality was found in one small study,4 a retrospective analy­ sis5 of the outcomes of 6 patients with bacteraemia due to vancomycin-resistant Enterococcus faecium concluded that chloramphenicol was effective and should be considered as a treatment option. However, vancomycin-resistant enterococci also resistant to chloramphenicol have been reported.6 1.

et a!. Chloramphenicol for the treatment of vancomycin1 9 9 5 ; 20: 1 1 37-44. 2 . Papanicolaou GA. et al. with vancomycinresistant Enterococcus faecium in liver transplant recipients: risk factors for acquisition and mortality.

Clin Infect Dis 1 996; 23: 760--6. et al. Vancomycin-resistant Enterococcus faecium meningitis successfully treated with chloramphenicol. Pediatr Infect Dis J 1 999; 18:

Mato SP, 483-4.

4.

Aplastic anaemia.

A review1 of the toxicity of chloram­ phenicol and related drugs, including the potential role of the p-nitro group in producing aplastic anaemia, indicated that derivatives such as thiamphenicol, which lack this grouping, are not associated with increased incidence of aplastic anaemia. For a discussion of the risk of aplastic anaemia associated with topical use of chloramphenicol eye drops, see under Ocular Use, p. 260. 3 . 1.

Lautenbach E.

et a!. The role of chloramphenicol in the treatment of Clin Infect Dis 1998; 27: 1 2 59-6 5 . 5 . Ricaurte JC, et a!. Chloramphenicol treatment f o r vancomycin-resistant Enterococcus faecium bacteremia. Clin Microbio! Infect 200 1 ; 7: 1 7-2 1 . 6 . Lautenbach E , e t al. Emergence o f resistance to chloramphenicol among vancomycin-resistant enterococcal (VRE) bloodstream isolates. lnt J Antimicrob Agents 2004; 23: 200-3. bloodstream infection due to vancomycin-resistant Enterococcus.

Adverse Effects and Treatment Chloramphenicol may cause severe and sometimes fatal adverse effects. The most serious of these is bone-marrow depression, which can take two different forms. The first is a fairly common dose-related reversible depression occurring usually when plasma- chloramphenicol concentrations exceed 25 micrograms/mL or when adult doses are greater than 4 g daily, and is characterised by morphological changes in the bone marrow, decreased iron utilisation, reticulocytopenia, anaemia, leucopenia, and thrombocyto­ penia. This effect may be due to inhibition of protein synthesis in the mitochondria of bone marrow cells. The second and apparently unrelated form of bone­ marrow toxicity is severe irreversible aplastic anaemia. This is fairly rare, with a suggested incidence of about I : I 8 000 to 1 : 5 0 000, although the incidence varies throughout the world, and is not considered to be dose-related. The aplasia usually develops after a latent period of weeks or even months and has been suggested to be the result of a nitrated benzene radical produced in vivo. It is considered that there may be some genetic or biochemical predisposition, but there is no way of identifying susceptible patients. Although most cases follow oral use, aplasia has also occurred after intravenous and topical (eye drops) use of chloramphenicol. Survival is most likely in those with early onset aplasia, but they may subsequently develop acute myeloid leukaemia. A toxic manifestation-the 'grey syndrome' or 'grey baby syndrome' -characterised by abdominal distension, vomi­ ting, ashen colour, hypothermia, progressive pallid cyanosis, irregular respiration, and circulatory collapse, followed by death in a lew hours or days, has occurred in premature and other newborn infants given large doses of chloramphenicol. The syndrome is associated with high plasma concentrations of chloramphenicol, due to reduced capacity for glucuronidation and decreased glomerular filtration in children of this age, leading to drug accumulation. Recovery is usually complete if the drug is withdrawn early enough after onset, but up to 40% of infants with the full-blown syndrome may die. The syndrome has also been reported in infants born to mothers given chloramphenicol in late pregnancy or labour. A similar syndrome has been reported in adults and older children given very high doses. Prolonged oral use of chloramphenicol may induce bleeding, either by bone-marrow depression or by reducing the intestinal flora with consequent inhibition of vitamin K synthesis. Haemolytic anaemia has occurred in some patients with the Mediterranean form of glucose 6phosphate dehydrogenase deficiency, but is rare in patients with milder forms of the deficiency. Paroxysmal nocturnal haemoglobinuria has also been reported. Peripheral as well as optic neuritis has been reported, usually in patients treated over prolonged periods. Although ocular symptoms are often reversible if treatment is withdrawn early, permanent visual impairment or blindness has occurred. Other neurological symptoms have included encephalo­ pathy with confusion and delirium, depression, and All cross-references refer to entries in Volume A

Yunis AA. Chloramphenicol: relation o f structure t o activity and toxicity.

Norris AH,

resistant enterococcal infections.

3.

headache. Ototoxicity has also occurred, especially after the use of ear drops. Hypersensitivity reactions including rashes, fever, and angioedema may occur especially after topical use; anaphylaxis has occurred but is rare. Jarisch-Herxheimer reactions may also occur. Gastrointestinal symptoms including nausea, vomiting, and diarrhoea can follow oral use. Disturbances of the oral and intestinal flora may cause stomatitis, glossitis, and rectal irritation. Patients may experience an intensely bitter taste after rapid intravenous use of chloramphenicol sodium succinate.

Ann Rev Pharmacal Toxicol 1 988; 28: 83-100.

Effects on the liver.

Isolated cases of hepatotoxicity, including hepatitis and jaundice, have been reported after systemic use of chloramphenicol. In a case report1 hepatitis also occurred in a 3 7-year-old patient after a 5 -day course of chloramphenicol 0 . 5 % eye drops; the patient presented 7 days after the end of treatment with lethargy, pruritus, dark urine, scleral icterus, and elevated liver-transaminase values. A liver biopsy 6 weeks after stopping chloramphenicol was highly sugges­ tive of drug-induced hepatitis, and transaminase values returned to normal within I 0 months of stopping the eye drops. 1.

Doshi B, Sarkar S . Topical administration of chloramphenicol can induce acute hepatitis.

BMJ 2009; 339: 574.

Overdosage. Charcoal haemoperfusion was found to be far superior to exchange transfusion in the removal of chloramphenicol from blood, although it did not prevent death in a 7-week-old infant with the 'grey syndrome' after a dosage error . 1 l.

Freundlich M ,

e t al. Management o f chloramphenicol intoxication in J Pediatr 1 9 8 3 ; 103: 485-7.

infancy by charcoal hemoperfusion.

Precautions Chloramphenicol is contra-indicated in patients with a history of hypersensitivity or toxic reaction to the drug. It should never be given systemically for minor infections, prophylaxis, or where less toxic antibacterials could be used. Repeated courses and prolonged treatment should be avoided and it should not be used in patients with pre­ existing bone-marrow depression or blood dyscrasias. Routine periodic blood examinations are advisable in all patients, but will not warn of aplastic anaemia. Use of chloramphenicol with other drugs liable to depress bone-marrow function should be avoided. Excessive blood concentrations may occur after usual doses in patients with hepatic or renal impairment, or in premature and full-term neonates who have immature metabolic processes. Licensed product information recom­ mends dose reduction in such patients, based on monitoring of serum chloramphenicol concentrations; a suggested range for peak plasma concentrations is l 0 to 2 5 micrograms/mL, and for trough concentrations, 5 to 1 5 micrograms/mL. In addition, specific dosage guidance is given for neonates (see Adrninistration in Children, p. 2 5 7 . 3 ) , although they should never be given chloram­ phenicol systemically ( unless it may be life-saving and there is no alternative treatment) because of the risk of 'grey syndrome'. Chloramphenicol readily crosses the placenta and US licensed product information recommends that use during pregnancy or at term shonld be undertaken with caution due to potential toxic effects on the fetus. Equivalent UK information lists pregnancy as a contra-indication to the systemic use of chloramphenicol. However, see also p. 2 6 0 . 3 Chloramphenicol may interfere with the development o f immunity a n d it should n o t be given during active immunisation.

Breast feeding. Chloramphenicol is distributed into breast milk 1 and the last available guidance from the American Academy of Pediatrics2 considered that its use by mothers during breast feeding might be of concern, since there have been reports of possible idiosyncratic bone-marrow suppression in the infant. I. Havelka J, et a!. Excretion of chlorampht>niml in human milk. Chemotherapy 1 968; 1 3 : 204-1 1 . 2.

American Academy o f Pediatrics. The transfer o f drugs and other chemicals into human milk. 2 0 1 0]

Correction.

Pediatrics 2 0 0 1 ; 108: 776-89. [Retired May ibid.; 1029. Also available at: http:l/aappolicy.

aappub lication s. org/ cgi/ content/full/pediatrics % 3 b I 08/ 3 !77 6 (accessed 2 5 /05 /04)

Ocular use.

Ocular chloramphenicol is widely used in the UK for the treatment of superficial eye infections. In view of the potential for serious toxicity, such as aplastic anae­ mia, after systemic absorption some, particularly in the USA, have advised that its ocular use should be restricted to situations where there is no alternative treatment. l However, apart from patients with a personal or family history of blood dyscrasias, the use, particularly of short courses, was defended by several specialists in the UK,2-4 and the arguments have been the subject of several reviews.5-7 Prospective case-control studies were consid­ ered necessary to clarify the risk.8 One such study,9 invol­ ving 145 patients with aplastic anaemia and 1 2 2 6 controls, found that only 3 of the patients had been exposed to ocu­ Jar chloramphenicol, and calculated that the absolute risk was no more than 0.5 cases per million treatment courses. Similarly, data1 0 from 2 other studies revealed that none of 426 patients with aplastic anaemia and 7 of 3 1 1 8 con­ trols had used chloramphenicol eye drops. In a survey 1 1 of patients who received prescriptions for chloramphenicol eye drops the risk of serious haematological toxicity was 3 per 442 543 patients or 3 per 674 1 48 prescriptions. 1.

Doona M, Walsh JB. Use of chloramphenicol as topical eye medication: time to cry halt?

2.

Mulla RJ,

BMJ 1 99 5 ; 3 10: 1 2 1 7- 1 8 . et a!. Is i t time t o stop using chloramphenicol o n t h e eye: fears six cases. BMJ 1 9 9 5 ; 3 l l : 4 5 0 .

are based on 3.

Buckley RJK,

4.

Hall AV,

Is it time to stop using chloramphenicol on t h e eye:

safe in patients with no history of blood dyscrasia.

5.

BMJ 1 9 9 5 ; 3 l l : 450. et a!. Is it time to stop using chloramphenicol on the eye: risk is low in short courses. BMJ 1 99 5 ; 311: 450-- l . McGhee

CNJ,

Anastas

chloramphenicol: is there aplastic anaemia?

CN.

Widespread

ocular

use

o f topical

concern regarding idiosyncratic 1 996; 80: 182-4.

6.

Rayner SA, Buckley RJ.

7.

Titcomb L. Ophthalmk chloramphenicol and blood dyscrasias: a review.

8.

Pharm J 1 997; 258: 28-3 5 . Gordon-Smith EC, e t al. Is i t time t o stop using chloramphenicol o n the

is there a link?

chloramphenicol and aplastic anaemia:

Dru.g Safety 1 996; 14: 273-6.

eye: prospective study of aplastic anaemia should give definitive answer. 9.

BMJ 1 995; 3 l l : 45 1 . Laporte J-R et a!. Possible association between ocular chloramphenicol and aplastic anaemia-the absolute risk is very low. Br J Clin Pharmacal 1 998; 46: 1 8 1-4.

1 0 . Wiholm

B-E,

et al. Relation of aplastic anaemia to use of

chloramphenicol eye drops in two international case-control studies.

BMJ 1 998; 316: 666. 1 1 . Lancaster T, et a!. Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database. BMJ 1 998; 316: 667.

Porphyria. The Drug Database for Acute Porphyria, com­ piled by the Norwegian Porphyria Centre (NAPOS) and the Porphyria Centre Sweden, classifies chloran1phenicol as porphyrinogenic; it should be prescribed only for com­ pelling reasons and precautions should be taken in all patients. 1 l.

The Drug Database for Acute Porphyria. Available at: http:l/www. drugs-porphyria.org (accessed 09/08/ 1 1 )

Pregnancy. A case-control study involving 2 2 8 6 5 women whose babies had congenital abnormalities and 38 I 5 1 controls found that 5 2 o f the former and 5 I o f the latter had taken oral chloramphenicol (usually with other drugs) during pregnancy.1 There was no evidence of a ter­ atogenic effect of chloramphenicol, and it was thought to pose little risk in early pregnancy. l.

Czeizel AE,

et al. A population-based case-control teratologic study of Eur J Epidemiol 2000;

oral chloramphenicol treatment during pregnancy. 16: 32 3-7.

Sodium content. Each g of chloramphenicol sodium succinate represents about 2.2 mmol of sodium.

Interactions The use of chloramphenicol with other drugs that can cause bone -marrow depression may increase the risk of haematological toxicity, and should be avoided. Chloramphenicol is inactivated in the liver and may, therefore, interact with drugs that are metabolised by hepatic microsomal enzymes. For example, it enhances the effects of coumarin anticoagulants, such as dicoumarol and warfarin, some hypoglycaemics such as chlorpropamide and tolbutamide, and antiepileptics such as phenytoin. Conversely, the metabolism of chloramphenicol may be increased by inducers of hepatic enzymes such as phenobarbital or rifampicin. Some other interactions affecting the activity of chloramphenicol are discussed below. Chloramphenicol may decrease the effects of iron and vitamin B in anaemic patients and has occasionally 12 impaired the action of oral contraceptives. For the effects of chloramphenicol on the activity of other antibacterials, see Antimicrobial Action, p. 26 I . I .

Analgesics.

A report o f a n increase i n chloramphenicol half-life from 3 . 2 5 to 1 5 hours when intravenous paraceta­ mol was given to 6 patients in intensive care 2 hours after intravenous chloramphenico11 was not confirmed by sub­ sequent studies in patients receiving oral paracetamol. A study in 5 children found that the half-life of intravenous

Chloram henicol 259 chloramphenicol was reduced from 3 to 1 . 2 hours, with an increase in clearance, when oral paracetamol was given 30 minutes beforehand.2 Furthermore, a study in 26 cbildren found no evidence of altered disposition when oral paracetamol was given to patients receiving intra­ venous chloramphenicol.' and no significant cbange in chloramphenicol pharmacokinetics was found in 5 patients given oral chloramphenicol and paracetamol.4 l. Buchanan N, Moodley GP. Interaction between chloramphenicol and paracetamol. BMJ 1 979; 2: 307-8. 2. Spika JS, et al. Interaction between chloramphenicol and acetamino­ phen. Arch Dis Child 1 986; 61: 1 1 2 1-4. 3 . Keams GL, et al. Absence of a pharrnacokinetic interaction between chloramphenicol and acetaminophen in children. J Pediatr 1 985; 107: 1 34-9. 4. Stein CM, et al. Lack of effect of paracetamol on the pharmacokinetics of chloramphenicol. Br J Clin Pharmacol l 989; 27: 262-4.

Antiepileptics.

Serum concentrations of chloramphenicol are usually reduced by the hepatic enzyme induction that occurs with phenobarbital, 1•2 and similar reductions have been reported in a case study during phenytoin use -' Con­ versely, elevated and potentially toxic serum-chloram­ phenicol concentrations have resulted during phenytoin use, 2 apparently due to competition for binding sites, although increased metabolism may alternatively lead to decreased serum-chloramphenicol concentrations. For reference to the effects of chloramphenicol on phenobarbital and phenytoin, see p. 537.2 and p. 542 . 3 , respectively. Bloxhaffi RA,

et al. Chloramphenicol and phenobarbitone-a drug Arch Dis Child 1 979: 54: 76-7. 2 . Krasinski K. et al. Pharmacologic interactions among chloramphenicol, phenytoin and phenobarbital. Pediatr Infect Dis 1 982; 1: 232-5. 3 . Powell DA, et al. Interactions among chloramphenicol, phenytoin, and phenobarbital in a pediatric patient. J Pediatr 1981; 98: 100 1-3. 1.

interaction.

Antineoplastics.

For the effect of chloramphenicol on cyclophosphamide, see p. 7 7 3 . 2 .

Gastroinlestinal drugs.

Fatal aplastic anaemia of rapid onset has occurred in 2 patients who received intravenous chloramphenicol and dmetidine. 1.2 As there is usually a latent period of 2 weeks to 12 months before aplastic anaemia develops after chloramphenicol therapy it is plau­ sible that an additive or synergistic effect may have occurred between the 2 drugs to cause bone-marrow toxi­ city. 1.

Farber BF, Brody JP. Rapid development of aplastic anemia after intravenous chloramphenicol and dmetidine therapy. South Med J

1981; 74: 1 2 5 7-8. 2 . West BC, et al. Aplastic anemia associated with parenteral chloram­ phenicol: review of 10 cases, including the second case of possible increased risk with dmetidine. Rev Infect Dis 1 988; 10: 1048-5 1 .

Immunosuppressants. F o r the effect of chloramphenicol on dclosporin and on tacrolimus, see p. 1 9 5 6 . 1 and p . 1 977.3, respectively. Oral contraceptives.

oral contraceptives, p . 2243 . 1 .

For the effect of chloramphenicol on see Hormonal Contraceptives,

Antimicrobial Action Chloramphenicol is a bacteriostatic antibiotic with a broad spectrum of action against both Gram-positive and Gram­ negative bacteria, as well as some other organisms. Mechanism ofaction. Chloramphenicol is thought to enter sensitive cells by an active transport process. Within the cell it binds to the 50S subunit of the bacterial ribosome at a site adjacent to the site of action of the macrolides and clindamycin, and inhibits bacterial protein synthesis by preventing attachment of aminoacyl transfer RNA to its acceptor site on the ribosome, thus preventing peptide bond formation by peptidyl transferase. The block in protein synthesis results in a mainly bacteriostatic action, although it may be bactericidal to some organisms, including Haemophilus influenzae, Neisseria meningitidis, and Streptococ­ cus pneumoniae, at higher concentrations. Spectrum ofactivity. Chloramphenicol has activity against many types of bacteria, although in most cases there are less toxic alternatives available. The following pathogens are usually susceptible (but see also Resistance, below ) : • Gram-positive cocci including streptococci sucb as Str., pneumoniae, Str. pyogenes, and the viridans streptococci. Strains of Staphylococcus aureus may be less susceptible, and meticillin-resistant staphylococci are commonly found to be resistant. Enterococcal species are often resistant, but activity against some strains of vanco­ mycin-resistant enterococci has been reported • other Gram-positive species including Badllus anthracis, Corynebacterium diphtheriae, Listeria monocytogenes, and anaerobes sucb as Actinomyces spp ., Peptococcus, and Peptostreptococcus spp . are usually susceptible. While most Clostridium spp. are susceptible, many strains of C. diffidle, particularly those of serogroup C, are resistant • Gram-negative cocci such as Neisseria meningitidis and N. gonorrhoeae are usually highly sensitive, as are HaemoThe symbol

phi/us influenzae and a variety of other Gram-negative bacteria including Bordetella pertussis, Brucella abortus, Campylobacter spp., Pasteurella, and Vibrio spp. Despite good in-vitro activity against Legionella spp .. chloram­ phenicol is not as active in-vivo as many other antibacterials (particularly macrolides and fluoroquino­ lones) against L. pneumophila The Enterobacteriaceae vary in their susceptibility, and many strains have shown acquired resistance {see below) . The susceptibility of Escherichia coli has marked geographic variability, but other Enterobacteriaceae, including Citrobacter, Enterobacter, Klebsiella, Proteus, Shigella, Salmonella, and Yersinia spp. are generally susceptible. Chloramphenicol has poor activity against Serratia spp., and Pseudomonas aeruginosa are invariably resistant. although Burkholderia (formerly Pseudomonas) spp . are often susceptible • Gram-negative anaerobes are generally susceptible including Bacteroides fragilis, Veillonella, and Fusobacterium spp . • other susceptible organisms include Leptospira spp., spirochaetes such as Treponema pallidum, Chlamydiaceae, Mycoplasma spp., and Rickettsia spp. • Nocardia spp. are resistant • Chloramphenicol is ineffective against protozoa and viruses. However, its reported activity against Batracho­ chytrium dendrobatitis, a fungus affecting frogs, has suggested the possibility of activity against other fungi Activity with other antimicrobials. As with other bacteriostatic antimicrobials, the possibility exists of an antagonistic effect if chloramphenicol is given with a bactericidal drug, and some antagonism has been shown in vitro between chloramphenicol and various beta lactams and aminoglyco­ sides. The clinical significance of most of these interactions is usually held to be doubtful, but care is advisable where patient factors or infection severity make bactericidal activity desirable. Chloramphenicol may competitively inhlbit the effects of macrolides or lincosamides sucb as clindamycin because of the adjacency of their binding sites on the ribosome. Resistance. Acquired resistance has been widely reported, although the prevalence of resistance has tended to decline where use of the drug has become less frequent. The most commonly seen form of resistance has been the production of an acetyltransferase that inactivates the drug. Sucb resistance is usually plasmid-me diated and may be associated with resistance to other drugs such as the tetracyclines. Other mecbanisms that may reduce sensitivity to chloramphenicol include reduced permeability or uptake, and ribosomal mutation. The actual incidence of resistance varies considerably in different countries and different centres. Epidemics of chloramphenicol-resistant Salmonella and Shigella spp. have occurred in many areas of the world, particularly in South and South-east Asia and Central and South America, and often reflect local usage patterns of chloramphenicol. Greater use of alternative antibacterials has more recently resulted in a decline in chloramphenicol resistance in some countries where it was formerly common. Resistance among Haemophilus and Neisseria spp. occurs, and the latter may be problematic in developing countries, although it does not yet seem to be widespread. Acquired resistance has also been reported in Staph. aureus, Str. pneumoniae, and Str. pyogenes.

Pharmacokinetics Chloramphenicol is readily absorbed when given orally. Blood concentrations of 10 micrograms/mL or more may occur about 1 or 2 hours after a single oral dose of 1 g. Chloramphenicol palmitate is hydrolysed to chlorampheni­ col in the gastrointestinal tract before absorption, and the sodium succinate, which is given parenterally, is probably hydrolysed to free drug mainly in the liver, lungs, kidneys, and plasma; such hydrolysis may be incomplete in infants and neonates, contributing to the variable pharmacoki­ netics in this age group. Chloramphenicol sodium succinate is, even in adults, only partially and variably hydrolysed, so that blood concentrations of chloramphenicol obtained after the sodium succinate is given parenterally are often lower than those obtained after oral chloramphenicol. with up to 3 0 % of a dose excreted unchanged in the urine before hydrolysis can take place (but see under Administration, p. 2 5 7 . 3 ) . Chloramphenicol i s widely distributed i n body tissues and fluids; it enters the C SF, giving concentrations of about 5 0 % of those existing in the blood even in the absence of inflamed meninges; it diffuses across the placenta into the fetal circulation, into breast milk, and into the aqueous and vitreous humours of the eye. It also enters the aqueous humour after topical application. Up to about 60% in the circulation is bound to plasma protein. The half-life of chloramphenicol has J:>een reported to range from l . 5 to 4 hours; the half-life is prolonged in patients with severe hepatic impairment and is also much longer in neonates.

t denotes a preparation no longer actively marketed

Renal impairment has relatively little effect on the half-life of the active drug, due to its extensive metabolism, but may lead to accumulation of the inactive metabolites. Chloramphenicol is excreted mainly in the urine but only 5 to 1 0 % of an oral dose appears unchanged; the remainder is inactivated in the liver, mostly by conjugation with glucuronic acid. About 3% is excreted in the bile. However, most is reabsorbed and only about 1 %, mainly in the inactive form, is excreted in the faeces. The absorption, metabolism, and excretion of chloram­ phenicol are subj ect to considerable interindividual variation, especially in infants and children, making monitoring of plasma concentrations necessary to deter­ mine pharmacokinetics in a given patient.

P.r.�P.�.��ti,".� ........................................................................... .

Proprietary Preparotions (details are given in Volume B ) Single-ingredient Preparations. Arg. : Anuar; Bioticaps;

Chloromycetin; Farmicetina; Isopto Fenicol; Klonalfenicol; Plu­ sdorant; Poenfenicol; Quemicetinat; Austral.: Chloromycetin; Chlorsig; Austria: Halomycetin; Kemicetint; Oleomycetint; Braz.: Arifenicol; Clorafenil; Neo Fenicol; Profenicolt; Quemi­ cetina; Sintomicetina; Uni Fenicolt; Visalmin; Vixmicina; Canad.: Ak-Chlor; Chloromycetin; Chloroptict; Diochloram; Pentamycetin; Chile: Chloromycetint; Clorampast; Gemitin; China: Moisten (ll'iJ!if); ShuEr (!if.iJ;); Tianli Runzhu (;IC;/Jll'il l.li1); Fin.: Chloromycetin; Oftan Akvakol; Oftan Chlora; Ger.: Posifenicol C; Gr.: Chloranic; Chlorocollyre; Chloromyk; Chlor­ optic; Kemicetine; Kemipen; Kramerin; Maltogen; Niamyce­ tine; Ursa-Fenol; Hong Kong: Aristophen; Chloroph; Chlorsig; Elisca; Europhenicol; Isopto Fenicolt; Kemicetine; Optivis; Venicolt; Xepanicol; India: Aglomycetin; Andrecin; Biopheni­ cpl; Chemocetin; Chloraxin; Chlormet; Chlorocin; Chloromycetin; Dador; Decol; Dexoren; Enclor; Enteromyce­ tin; Eptico; Fencol; Kemicetine; Labchlor; Larmycetin; Ocu­ chlor; Ocular; Optocol; Paraxin; Rector; Vanmycetin;. Vitamyce­ tin; Indon.: Chloramex; Chlorbiotict; Cloramidina; Colaint; Colme; Colsancetine; Combicetin; Empeecetin; Enkacetyn; Fenicol; Ikamicetin; Isotic Salmicol; Kahnicetine; Kemicetine; Lanacetine; Licoklor; Microtinat; Neophenicolt; Palmicol; RECO; Ribocine; Spersanicolt; Suprachlor; Xepanicol; Ir1.: Chloromycetin; Israel: Chlorphenicol; Phenicol; Synthomycine; Ital. : Chemicetina; Mycetin; Sificetina; Vitamfenicolo; Malay­ sia: Beaphenicol; Chloramex; Nicol; Xepanicolt; Mex. : Abefen; Bariclort; Brocil; Chloromycetin; Clomicint; Clorafent; Clor­ amedt; Cloramfeni; Clorampler; Cloran; Cloranmicron; Clora­ tenol; Clorazin; Clordilt; Clorfenilt; Clorofunon; Clorotan; Diarman; Dilclort; Enteromicin; Estreptopal; Exacol; Fenicol; Fenisol; Fenizzardt; Lebrocetin; Leclor At; Naxot; Oftadil; Omycett; Palcolt; Pabniclor; Palmifer; Pabnisol; Proclorilt; Pro­ nicol; Quemicetina; Solvaris; Uniclor; NZ: Chlorafast; Chloromycetin; Chlorsig; Philipp. : Alphagram Otic; Anpheclor; Aphrenil; Biomycetin; C-Phenicol; Chloro-S; Chloro-V; Chiaro­ caire; Chloromycetin; Chlorsig; CLM; Clovicol; Esnicolt; Fen­ Alcont; Forastrolt; Genphenil; Gerafen; Kemicetinet; Klorfen; Klornik; Medimycetin; Medoptic; Metrophenicol; Oliphenicol; Optomycin; Pediachlor; Penachlor; Septicyn; Typhiclor; Veni­ micetin; Vistachlor; Pol. : Detreomycyna; Port.: Clorocil; Miceti­ noftalmina; Rus.: Levomycetin (JleBOMHD;eTHH) ; Synthomydn (CHHTOMHlfi!H); S.Afr. : Chloramex; Chlorchol; Chlorcol; Chlor­ nicol; Chloromycetin; Chlorphen; Lennacolt; Spersanicol; Sin­ gapore: Beaphenicol; Enclor; Isopto Fenicol; Kemicetinet; Opti­ chlor; Xepanicol; Swed.: Chloromycetin; Switz.: Septicolt; Thai.: Antibi-Otic; Arcbifen; Chlor-Pyrad; Chloracil; Chloram­ P; Chloramnot; Chloroph; Chlorosint; Cogenatet; Cogetine; Fenicol; Genercint; Levorqycetint; Med-Chloramp; Mycochlor­ int; Pharmacetin; Pisalin; Silmycetin; Synchlolim; Unison Oint­ ment; Vanafen; Turk.: Armisetint; Kemicetine; Klorasuksinat; UK: Brochlor; Chloromycetin; Clorogen; Golden Eye; Kemicetine; Optrex Infected Eyes; Ukr. : Laevomycetin (JleuoMI!IIenm); USA: Chloromycetint; Venez. : Cloftal.

Multi-ingredient Preparations. Arg.: Acnoxin; Antiflogol; Bioftal;

Clorfibrase; Colirio Antibiotico CNH; Colirio Oftalmico; Esodar; Fluoropoen; Iruxol; Klonovan; Neocortizult; Oftal-D; Poen­ bioptal; Quemicetina con Hidrocortisona; Quemicetina Nasal Compuesta; Austria: Cortison Kemicetint; Oleomycetin-Pre­ dnisont; Belg.: De leal; Braz.: Dexafenicol; Epitezan; Fenidex; Fibrase; Fibrinase c/Cloranfenicol; Gino Fibrase; Gino Kollagen­ ase; Gyno Iruxol; Iruxol; Kollagenase com doranfenicol; Naxo­ gin Composto; Otomicina; Ouvidonal; Profenicolt; Regencel; Regenom; Sulnil; Canad.: Pentamycetin-HC; Chile: Gemitin con Prednisolona; Naxogin Compositumt; Otandrol; Sintofto­ na; China: Fukexin ( �PJJTX); Cz.: Spersadex Compositum; Denm.: Spersadex Comp; Fin.: Iruxolt; Oftan C-C; Oftan Dexa­ Chlora; Fr.: Cebedexacolt; Ger.: Aquapredt; Ichthoseptalt; Gr.: Chlorapred; Cortiphenol H; Dexachlor; Dispersadron-C; Geypirina; Neo-Otil; Nezefib; Otenor; Spersadexoline; Sulfa­ chlor; Sulfachloramphenicol; Sulfanicole; Hong Kong: Anlinat; Cortiphenol Ht; Dexanicolt; Eurodron; Neo-Dex (Improved) ; Sonexa-C; Spersadex Comp; India: A-Col; Adcort; Advin-NC; Arima; Bactisone; Beclodn-0; Belmycetin-Ct; Bestec; Biomy­ cetin; Candibiotic; CBL; Chloramsone; Chlormet-DM; Chlor­ mixint; Chloromycetin Ear Drops; CLCD; Clobiotic; Deco-AT; Deco; Decol-C; Decol-P; Denclor; Dexamon; Dexoren-S; Dexo­ syn-Ct; Eligao; Enteromycetin Otic; Eptico-D; Excan; Eyclor­ Dexa; Eyclor; Flubichlor; Fungi-BC; Infabact; Kemicetine Anti­ ozena; LB C; Mycin; Mycotic; Ocupol-D; Ocupol; Olotic; Otek­ AC Plus; Otiden; Otiderm; Otina; Otocin; Otocos; Otosym; Per­ focynt; Pyrimon; Indon. : Chloramphecort-H; Chloramphecort;

260

Antibacterials

Gynoxa; Indoson; Kemiderrn; Kloramixin D; Kloramixin; Klor� feson; Naxogin Complex; Otolin; Particolt; Ramicort; Spersadex Camp; Israel: Phenimixin; Tarocidin D; Tarocidin; Threolone; Ital. : Antibioptal; Betabioptal; Cloradex; Colbiocin; Colbiocin; Cortison Chemicetina; Cosmiciclina; Eubetal Antibiotico; Eube­ tal Antibiotico; Idracemi; Iruxol; Vasofen; Xantervit Antibiotico; Malaysia: De leal; Spersadexolinet; Mex. : Cloramfeni Otico; Cloran Oticot; Cloxona-0; Fibrase; Levodexan; Levofenil; Nis­ pil; Ofodex; Otalgan; Otifar; Otiser; Poral; Pre Clor; Soldrin; Sol­ franicol; Sulfa Cloran; Treclorant; Ulcodermat; Norw. : Spersa­ dex med kloramfenikol; Philipp.: Dexanicol; Iclodex; Ipecor; Spersadex Compound; Port.: Predniftalmina; Rus.: Candibiotic (KaH.llH6HOTHK); Colbiocin (Kon6uouuH); Colbiocin (Kon6HOUHH); Cortomycetin (KopToMHUenm) ; Iruxol (11p)'Kcon)t; Levomecol (JiesoMeKom.); Levometil (JiesoMeTHJI); Levosin (JiesocuH); Netran (HeTpaH); Olasol (Om!301Ib); Saledez (Cane�e3); S.Afr. : Covomycin�D; Covomycin; Covotopt; Spersadex Comp; Sper­ sadexolinet; Singapore: Spersadex Comp; Spersadexoline; Spain: Blefaridat; Cloram Hemidext; Cloram Zinct; Cortison Chemicet Topica; Dermisone Epitelizantet; leal; Medrivas Antib; Switz. : Spersadex Camp; Thai. : Archifen; CD�Oph; Chlorotracint; Dermasol; Levoptin; Spersadexolinet; Vagicin; UK: Actinact; Ukr.: Candibiotic (KaH,rm6uOTHK); Micogynax (MuKO)IG{HaKc); Venez. : Clorasona.

C; Nerisone C; Philipp. : Nerisona H; Gynalgin; Laticort-CHt; Port.: Rus.: Gynalgin (rnnanriiH); Spain: zol; Turk.: Colposeptine; Impetex;

Combi; Pol.: Chlorchinaldin Nerisona C; Trophoseptine; Claral Plus; Switz. : Angina­ Nerisona C; Ukr.: Colposep­ tine (KoJillocerrTHH); Gynalgin (rHHanrnH); Venez. : Binerisona.

Multi-ingredient Preparations. Austria: den; Ital. : Aureocort.

Aureocon;

Aureomix;

Aureocort; Braz. : Cord­ S.Afr. : Tritett; UK:

Pharmacopoeial Preparations

BP 2014: Chlortetracycline Eye Ointment; Chlortetracycline Ointment; USP 36: Chlortetracycline Hydrochloride Ointment; Chlortetra­ cycline Hydrochloride Ophthalmic Ointment.

Ciclacillin is an aminopenicillin with properties similar to those of ampicillin (p. 2 1 8 . 2 ) , although it is generally less active in vitro.

Pharmacopoeial Preparations

BP 20 14: Chloramphenicol Capsules; Chloramphenicol Ear Drops; Chloramphenicol Eye Drops; Chloramphenicol Eye Ointment; Chloramphenicol Sodium Succinate Injection; USP 36: Chloramphenicol and Hydrocortisone Acetate for Ophthalmic Suspension; Chloramphenicol and Polymyxin B Sulfate Ophthalmic Ointment; Chloramphenicol and Predniso­ lone Ophthalmic Ointment; Chloramphenicol Capsules; Chlor­ amphenicol Cream; Chloramphenicol for Ophthalmic Solution; Chloramphenicol Ophthalmic Ointment; Chloramphenicol Ophthalmic Solution; Chloramphenicol Otic Solution; Chlor­ amphenicol Palmitate Oral Suspension; Chloramphenicol Sod­ ium Succinate for Injection; Chloramphenicol, Polymyxin B Sulfate, and Hydrocortisone Acetate Ophthalmic Ointment.

Ph. Eur. 8: (Cilastatin Sodium ) . A white or light yellow,

Chloroxine is a halogenated hydroxyquinoline with antibacterial and antifungal properties similar to those of clioquinol (p. 2 7 5 . 1 ) . It is given orally in preparations for acute infectious diarrhoea. It has also been used topically in the treatment of dandruff and seborrhoeic dermatitis of the scalp. Chloroxine is a component of halquinol (p. 3 1 1 . 1 ) .

P.r.�pa ra li ()ns ................................ . .

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Cz.: Endiaron; Endioderm;

USA:

Capitrolt.

Multi-ingredient Preparations.

Cz. : Triadermt; Triamdnolon E;

Ital. : Beben Clorossina.

Chlorquinaldol (BAN, r/NN)

�

Chlmodrin,>ld(lt; � iorquin1lldolum; Oorquirialdol;. Kloonki­ nalooli; Kl�rklna!('f?l;•?H· 'APocrPemoi-MU11Ha Cynb(j)ar · . . C > •• : . ·• Qc2:t;.Je.c>X)''2�rnethyl3mino-a:L-gl� c;opyriJD()Syl{1 � 2k0: 5& (,!eo�y�3-C:!"1ydrown�thyi:a,�,l yxqfurano.sy.l:( 1. --:-4· ),;N',N3diaml;ilno-o:-streptamine sulphate. , (C2,to�rN.,O ,ih.31dzSP4"':1 4614 0As. · 7 . f2/3'4fi-i (dihydrosrreptorny¢in): trep,tor:ny_ cin·?Uiftlte!.

ATC ""-' $01AA Hi. •· . A"TC Vet -"-' .050 lAA 1$. U/1111.... T7D4876/U£

Pharmacopoeias. In Bur. ( see p . vii) and US, both for veterinary use only.

Ph. Eur. 8: ( Dihydrostreptomycin Sulfate for Veterinary Use; Dihydrostreptomycin Sulfate BP(Vet) 2 0 1 4 ) . The sulfate of a substance obtained by catalytic hydrogenation of streptomycin or by any other means. The semisynthetic product is derived from a fermentation product. Stabilisers may be added. A white or almost white, hygroscopic powder. It contains a maximum of 2 . 0 % streptomycin sulfate calculated with reference to the dried drug. Freely soluble in water; practically insoluble in alcohol, in acetone, and in methyl alcohol. A 2 5 % solution in water has a pH of 5 . 0 to 7 .0. Store in airtight containers. Protect from light.

287

Di bekacin USP 36: (Dihydrostreptomycin Sulfate) . A white or almost white amorphous or crystalline powder; the amorphous form is hygroscopic. Freely soluble in water; practically insoluble in acetone, in chloroform, and in methyl alcohol. pH of a solution in water containing the equivalent of dihydrostreptomycin 2 0 % is between 4.5 and 7.0, except that if it is labelled as being solely for oral use, the pH is between 3 . 0 and 7 .0. Store in airtight containers.

Profile Dihydrostreptomycin is an aminoglycoside antibacterial with actions similar to those of streptomycin (p. 36 1 . 1 ) . Since i t i s more likely than streptomycin to cause partial or complete loss of hearing it is not used parenterally in humans. It is not absorbed after oral doses, and has been given by this route for gastrointestinal infections. It is also used as the sulfate in veterinary medicine.

P. . .r.epa a ons . . . . . . . .r. . . .ti. . . . . . . . .

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Spain: Citrocil. Multi-ingredient Preparations. Arg.: Vagisan Compuesto;

Vagi­ san; Mex.: Estrefen; Spain: Cilinafosal Dihidroestreptomicinat; Salitanol Estreptomicinat; Sulfintestin Neomicina.

Dirithromycin (BAN, USAN, r/NN)

ASE 1 36BS; . oliithrom;tcine; Dirithromycinum; Qirltrdtnicin;

D!rit:orpicina; · Diritrornidnas; Diritrornisin; . Diritrornycll\ Diritrornysilni; lY-237216; /li1PWTpOM>ll\!1H. (1 R,21i,31l,61?,75,8$,9R,1 OR,l 2R,1 3S, 1 5R, 1 75): 7-(2,6cDideo,xy-3C.3-0-d irn'"thyi-a:t-ribo-hexopyrano:;yloxy):3 -eltwl- 2,1 0' d ihydroxy- 1 5-(2-rnethoxyethoxymethyl)-2,6,8, 10, r 2, 1 7-hex­ a methyl-9-(3,4,6-rrideoxy-3-di methylatnino-ih:xyio-hexo­ pyranosyloxyH. 1 6-dioxa-1 4-azabicydo[1 1 .3.1]1\eptadem}

Expert Opin Invest Drugs 2008; 17: 749-7 1 . et al. Efficacy and safety of intravenous infusion of doripenem

meropenem in adults with complicated intra-abdominal infection: a

Pharmacokinetics

Doripenem

Chastre J,

randomized study. 4.

As for Erythromycin, p. 297. 1 . Dirithromycin i s reported t o b e generally less active than erythromycin in vitro, but may show greater activity in vivo than is indicated by in-vitro studies and may exert a postantibiotic effect.

Pharmacopoeial Preparations

USP 36: (Dirithromycin) . A white or practically white powder. Very slightly soluble in water; very soluble in dichloromethane and in methyl alcohol.

treatment of infections caused by multidrug-resistant Gram-negative 3.

Antimicrobial Action

2.

Poulakou G , Giamarellou H. Doripenem: an expected arrival in the pathogens.

versus imipenem in ventilator-associated pneumonia: a multicenter,

USP 36: Dirithromycin Delayed-Release Tablets.

Ph. Eur. 8: (Dirithromycin) . A white or almost white powder. It exhibits polymorphism. Very slightly soluble in water; very soluble in dichloromethane and in methyl alcohol.

2.

1

of

complicated

lower

urinary

tract

infection

and

Antimicrob Agents Chemother 2009; 53: 3782-92.

8.

Mandell L. Doripenem: a new carbapenem in the treatment of

9.

nosocomial infection. Clin Infect Dis 2009; 49 (suppl I ) : S l-S3. Chahine EB, et al. Doripenem: a new c.:arbapenem antibiotic. Am J Health-Syst Pharm 2 0 1 0; 67: 2 0 1 5�24.

10. Overturf GD. Doripenem: an early look at a carbapcnem not yet approved for pediatrics.

Pediatr Infect Dis J 2 0 1 0; 29: 1 63-5 .

Administration in renal impairment. Doses of doripenem given by intravenous infusion should be reduced in patients with renal impairment according to creatinine clearance ( C C ) : • C C 30 t o 50 mLiminute: 2 5 0 mg every 8 hours • C C greater than 10 to less than 30 mL/minute: 250 mg every 12 hours The pharmacokinetics of doripen em have been examined in a small study1 in 1 1 dialysis-dependent patients with end­ stage renal disease who were undergoing continuous renal replacement therapy ( CRRT), either via 1 2 -hour contin­ uous venovenous haemofiltration ( CVVH) or continuous venovenous haemodiafiltration (CVVHD F ) . The study found that despite significant removal of doripenem and the active metabolite (doripenem-M l ) by CRRT, a single 500-mg doripenem dose infused over 1 hour produced significantly higher plasma concentrations of doripenem, higher systemic exposure, and longer half-life in those undergoing CRRT than in healthy subjects. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38 and 2 9 % , and clearances of doripenem were 22 and 25 mL/minute. It was recommended that dosage regimens for doripenem in patients receiving CRRT should be adjusted. The results of another small study2 in patients with end-stage renal disease (CC less than 1 0 mLiminute) who were receiving 3· times weekly haemodialysis suggested that an intravenous dose of doripenem 500 mg once every 24 hours would provide adequate serum concentrations. l.

Cirillo I,

et al. Influence of continuous venovenous hemofiltration and

continuous

venovenous hemodiafiltration

on

the

dispo�ition

of

doripcnem.

2.

Antimicrob Agents Chemother 2 0 1 1 ; 55: 1 1 87-93. et al. Validation of doripenem dosing in palients with end-stage renal disease receiving hemodialysis. Ann Pharmacother 2 0 1 1 ; 45: 1 4 5 5-

Heil EL, 6.

Pneumonia. Regulatory authorities in Europe1 and the USA2 have recently issued safety alerts after a study evalu­ ating the use of doripencm in the treatment of ventilator­ associated pneumonia was stopped early. Preliminary results had shown a lower cure rate and an excess mortal­ ity in patients receiving an unlicensed dose of doripenem (I g every 8 hours for 7 days) when compared with treat· ment with imipenem-cilastatin for 10 days. Based on the available data, it was considered that the shorter duration of treatment, augmented renal clearance, and infection with some specific types of bacteria had all contributed to the outcome. In view of these findings, the EMEAI has made the following recommendations when giving doripenem to patients with hospital-acquired pneumonia, which includes ventilator-associated pneumonia: • The dose of doripenem should be increased to I g every 8 hours and infused over 4 hours for patients with augmented renal clearance or with infections by nonMfermenting, Gram-negative pathogens such as Pseudomonas spp. and Acinetobacter spp . . • I f nonMfermenting Gram-negative pathogens are con­ firmed, concomitant treatment with an aminoglycoside should be considered. • For all patients, treatment should be for 10 to 1 4 days and is usually in the upper range for infections with non-fermenting, Gram-negative pathogens. In the USA, doripenem is not licensed for the treatment of pneumonia. l.

Elv1A. Questions and answers on the review of Doribax (doripenem) (issued 2 l st June, 2 0 1 2 ) . Available at: http:/ /www.ema.europa.eu/docs/ en_GB/document_library/Mcdidne_QA/ 2 0 1 2 / 0 6 / W C 5 0 0 1 29084.pdf (accessed 1 6/08 / 1 2 )

2.

Chang P. Doripenem dear healthcare professional letter (issued 3rd January, 2 0 1 2 ) . Available at: http:l/www.fda.gov/dnwnloads/Drugs/ DrugSafety/UCM286277.pdf (accessed 1 6/08/ 1 2 )

Adverse Effects and Precautions As for Imipenem, p. 3 1 2 . I . Doripenem i s more stable t o renal dehydropeptidase I than imipenem and use with dlastatin, which inhibits the

288

Antibacterials

enzyme, is not required. Excess mortality h a s been reported in patients with ventilator-associated pneumonia given inappropriate doses of doripenem; for further information, see under Uses and Administration, p. 287 .2.

Effects on the nervous system. Doripenem appears to carry a relatively low risk of inducing seizures. 1 l.

Zhanel GG, et al. Overview of seizure-inducing potential of doripenem. Drug Safety 2009; 32: 709- 1 6 .

Interactions Probenecid inhibits the renal excretion of doripenem thereby increasing its plasma concentrations and prolonging its elimination half-life; co-administration is not recom­ mended.

Antiepileptics.

For reports of decreased plasma-va/proate concentrations (sometimes with loss of seizure control) attributed to carbapenem antibacterials, see p . 5 5 7 . 2 .

Pharmacopoeias. In Bur. (see p. vii) and US.

Ph. Eur.

8: ( D oxycycline Monohydrate) . A yellow crystalline powder. Very slightly soluble in water and in alcohol. It dissolves in dilute solutions of mineral adds and in solutions of alkali hydroxides and carbonates. A I % suspension in water has a pH of 5 . 0 to 6 . 5 . Store in airtight containers. Protect from light.

USP 36: (Doxycycline) . A yellow crystalline powder. Very slightly soluble in water and in alcohol; practically lnsoluhle in chloroform and in ether; freely soluble in dilute acid and in alkali hydroxide solutions. pH of a 1 % suspension in water is between 5.0 and 6 . 5 . Store in airtight containers. Protect from light.

Antimicrobial Action Like other carbapenems (see Imipenem, p. 3 1 2 . 2 ) , doripenem i s active against most Gram-positive and Gram­ negative bacteria (including aerobes and anaerobes) with the exception of Stenotrophomonas maltophi/ia, Burkho/deria cepacia, Enterococcus faecium, and MRSA. It is reported to have good activity in vitro against a broader range of such organisms than other carbapenems. Doripenem is a particularly potent inhibitor of Gram­ negative bacteria that have a high potential for drug resistance, such as Pseudomonas aeruginosa, and the Enterobacteriaceae. Compared with other carbapenems, doripenem also appears to have a relatively weak ability to promote the emergence of antibacterial resistance in vitro. References. l.

Sahm D . In vitro activity of doripenem.

Clin Infed Dis 2009; 49 (suppl l ) :

S I I-$ 1 6 .

Pharmacokinetics After intravenous infusion of doripenem 500 mg over 1 hour, a mean peak plasma concentration of 23 micro­ grams/mL is attained, falling to I O micrograms/mL after 1 . 5 hours and I microgram/mL after 6 hours. Doripenem is less than 1 0 % bound to plasma proteins and is widely distributed into body tissues and fluids. It is metabolised via hydrolysis of its beta-lactam ring by dehydropeptidase I to an open-ringed metabolite (doripe­ nem-M I ) . The plasma elimination half-life is about I hour in adults; the half-life may be prolonged in patients with renal impairment. Doripenem is mainly excreted in the urine by tubular secretion and glomerular filtration. About 7 0 % and 1 5 % of a dose is recovered as unchanged drug and metabolite, respectively, in the urine within 48 hours. Less than 1 % is excreted in faeces. Doripenem is removed by haemodialysis. References. Cirillo I, et a!. Pharmacokinetics, safety, and tolerability of doripenem 0. 5-, 1-, and 4-hour infusions in healthy volunteers. J Clin Phannacol 2009; 49: 798-806. 2. Nandy P, et al. Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients. Antimicrob Agents Chemother 201 0; 54: 2 3 54-9. 3. Samtani MN, et al. Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients. Antimicrob Agents Chemother 2 0 1 0; 54: 2 360-4.

l.

after

Prepa ra tions

...... . . . . . . . . . . . . .. . .

Proprietary Preparations (details are given in Volume B ) Single-ingredient Preparations. Arg.: Doribax; Austral.: Doribax;

Austria: Doribax; Belg. : Doribax; Canad.: Doribax; Cz. : Doribax; Denm.: Doribax; Fr. : Doribax; Ger.: Doribax; Gr. : Doribax; Hong Kong: Doribax; Hung.: Doribax; Irl. : Doribax; Israel: Dor­ ibax; Jpn: Finibax; Malaysia: Doribax; Neth.: Doribax; Norw. : Doribax; NZ: Doribax; Philipp. : Doribax; Pol. : Doribax; Port. : Doribax; Rus.: Doriprex (,.U:opnnpeKc); Singapore: Doribax; Spain: Doribax; Swed.: Doribax; Thai.: Doribax; Turk. : Dori­ bax; UK: Doribax; USA: Doribax.

Doxycycline

(BAN, USAN, r!NN)

. [).oksiCft