Extemporaneous Ophthalmic Preparations [1st ed. 2020] 978-3-030-27491-7, 978-3-030-27492-4

Table of contents :
Front Matter ....Pages i-xxi
Front Matter ....Pages 1-2
Ocular Pharmacokinetics (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 3-4
Factors Affecting Bioavailability and Efficacy of Topical Ophthalmic Preparations (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 5-7
Ideal Characteristics of Ophthalmic Drug Delivery System (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 9-10
Inactive Ingredients Used in the Preparation of Ophthalmic Products (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 11-11
Preservatives Used in Ophthalmic Preparations (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 13-13
Front Matter ....Pages 15-15
Topical Ophthalmic Drug Forms (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 17-18
Extemporaneous Compounding of Ophthalmic Products (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 19-19
Guidelines of The American Society of Health-System Pharmacists (ASHP) on Pharmacy-Prepared Ophthalmic Products (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 21-23
Formulations of Extemporaneous Topical Ophthalmic Preparations (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 25-59
Front Matter ....Pages 61-61
Intravitreal Injections (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 63-65
Intracameral Injections (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 67-68
Formulations of Extemporaneous Intraocular Injections (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 69-89
Front Matter ....Pages 91-91
Equipments and Steps for Subconjuctival Injections (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 93-94
Formulations of Extemporaneous Subconjunctival Injections (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 95-99
Front Matter ....Pages 101-101
Extemporaneous Ophthalmic Preparations in Ocular Oncology (Eman Ali Saeed Alghamdi, Abdulmalik Yahya Al Qahtani, Mazen M. Sinjab, Khalid Mohammed Alyahya)....Pages 103-110
Back Matter ....Pages 111-113

Citation preview

Extemporaneous Ophthalmic Preparations Eman Ali Saeed Alghamdi Abdulmalik Yahya Al Qahtani Mazen M. Sinjab Khalid Mohammed Alyahya

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Extemporaneous Ophthalmic Preparations

Eman Ali Saeed Alghamdi Abdulmalik Yahya Al Qahtani Mazen M. Sinjab Khalid Mohammed Alyahya

Extemporaneous Ophthalmic Preparations

Eman Ali Saeed Alghamdi Senior Drug Safety Specialist Pharmacovigilance Department Saudi Food and Drug Authority Riyadh Saudi Arabia Mazen M. Sinjab Senior Consultant Ophthalmic Surgeon Dr. Mazen Sinjab Eye Clinic Medcare Hospital Dubai United Arab Emirates

Abdulmalik Yahya Al Qahtani Consultant of Cornea, Cataract and Refractive Surgery, Ophthalmology Department Prince Sultan Military Medical City Riyadh Saudi Arabia Khalid Mohammed Alyahya Consultant Clinical Pharmacist Prince Sultan Military Medical City (PSMMC) Riyadh Saudi Arabia

ISBN 978-3-030-27491-7    ISBN 978-3-030-27492-4 (eBook) https://doi.org/10.1007/978-3-030-27492-4 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my dear Father “Ali” (May God save him) Who taught me the meaning of life I will mention my name with his name all my life To my dear Mother “Mona” (May God save her) The source of love and the one whose prayers are behind my success I owe you who I am today To my dear Husband “Firas” (May God save him) Who has been a constant source of support and encouragement during the critical times Eman Ali Saeed Alghamdi

Preface

Pharmaceutical industries have greatly expanded their share of ophthalmic drugs in recent years. However, physicians and pharmacists are frequently called to prepare sterile products intended for ophthalmic use due to a lack of availability of licensed drugs in the market. The goal of this handbook is to produce a list of concise extemporaneous ophthalmic preparations and to standardize the formulation of the products by suggesting specific strength, route of administration, appropriate vehicle, and method of preparation. This handbook contains the most appropriate formulation of each medication based on published and documented stability data. It is divided into five sections. The first part  is an introduction to the principles of extemporaneous ophthalmic preparations in terms of ocular pharmacokinetics (Chap. 1), factors affecting bioavailability and efficacy of topical eye preparations (Chap. 2), ideal characteristics of ophthalmic drug delivery system (Chap. 3), inactive ingredients used in the preparation of ophthalmic products (Chap. 4), and the preservatives used in ophthalmic preparations (Chap. 5). The second part is devoted to extemporaneous topical ophthalmic formulations. It presents the topical ophthalmic drug forms (Chap. 6), the extemporaneous compounding of ophthalmic products (Chap. 7), and guidelines of the American Society of Health-System Pharmacists (ASHP) on pharmacy-­ prepared ophthalmic products (Chap. 8). In this part, 24 preparations are discussed in terms of formulation, use and indications, the procedure of preparation, packaging and storage, and special precautions. The third part presents the extemporaneous intraocular injections. It is divided into intravitreal injections (Chap. 10) and intracameral injections (Chap. 11). Fifteen formulations are discussed in Chap. 12 in terms of use and indications, the procedure of preparation, packaging and storage, and special precautions. The fourth part discusses the extemporaneous subconjunctival injections. Equipment and steps for subconjunctival injections are explained in Chap. 13. Four formulations of the extemporaneous subconjunctival injections are presented in Chap. 14. Finally, the fifth part is devoted to extemporaneous ophthalmic preparations in ocular oncology. Five formulations are discussed in Chap. 15. vii

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Preface

The editors feel this book will make a welcome companion for many physicians and pharmacy practitioners who are frequently engaged in the compounding of sterile ophthalmic preparations. Riyadh, Saudi Arabia  Eman Ali Saeed Alghamdi Riyadh, Saudi Arabia   Abdulmalik Yahya Al Qahtani Dubai, United Arab Emirates   Mazen M. Sinjab Riyadh, Saudi Arabia   Khalid Mohammed Alyahya

Abstract

In the daily practice of ophthalmologists, many diseases require special treatments for several reasons. The disease might be rare enough, so no commercially prepared ophthalmic drugs are available. Specific concentrations of medications are needed at eye tissue level to achieve the desired effect. The medications should be directly delivered to the site of pathology. In addition, there is a  shortage of ready-made medications. All the above reasons necessitate unlicensed extemporaneous ophthalmic formulation. Mostly, these preparations are off-label products, which means  an unapproved route of administration, unapproved indication, or unapproved age group. Pharmacist, based on physicians’ requests under specific regulations and guidelines, prepares these formulations extemporaneously. Moreover, these preparations are preservative-free; therefore, they have a short expiry date and require special precautions in preparations and storage. This book is to cover this important topic. It provides guidelines, concentrations, method of preparations, and storage conditions for pharmacists and provides indications and method of applications for ophthalmologists. This book is the first of its kind in the market. It covers all the unlicensed, off-­ label ophthalmic medications that ophthalmologists may need. It gathers all the scattered updated information from different sources. It delivers the information in a systemic, direct-to-the-point, and easy-to-find method.

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Acknowledgment

Firstly, I would like to acknowledge Professor Mazen M. Sinjab for his academic guidance and great efforts to produce the book in this systematic and academic design. We benefited to a great extent from his long experience in writing academic books in ophthalmology. A special gratitude I give to Dr. Abdulmalik Alqahtani for his contribution, advice, ideas, support, and patience in guiding me through this project. Thank you for your enthusiasm to complete this work; your wealth of knowledge in the field of ophthalmology medications, in particular, is inspiring. Thank you for giving me the opportunity to grow in this field of ophthalmic extemporaneous preparation. I extend my sincere gratitude to Dr. Khalid Alyahya whose contribution, support and encouragement helped me significantly to complete this book. I would also like to acknowledge the support of other Prince Sultan Military Medical City colleagues along the way including the pharmacists and ophthalmologists who assisted us in preparing such guidance for sterile ophthalmic extemporaneous preparation. Riyadh, Saudi Arabia

Eman Ali Saeed Alghamdi

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Contents

Part I Introduction to Extemporaneous Ophthalmic Preparations 1 Ocular Pharmacokinetics������������������������������������������������������������������������    3 References��������������������������������������������������������������������������������������������������    4 2 Factors Affecting Bioavailability and Efficacy of Topical Ophthalmic Preparations������������������������������������������������������    5 References��������������������������������������������������������������������������������������������������    6 3 Ideal Characteristics of Ophthalmic Drug Delivery System����������������    9 References��������������������������������������������������������������������������������������������������    9 4 Inactive Ingredients Used in the Preparation of Ophthalmic Products  11 References��������������������������������������������������������������������������������������������������   11 5 Preservatives Used in Ophthalmic Preparations����������������������������������   13 Reference ��������������������������������������������������������������������������������������������������   13 Part II Extemporaneous Topical Ophthalmic Formulations 6 Topical Ophthalmic Drug Forms������������������������������������������������������������   17 References��������������������������������������������������������������������������������������������������   18 7 Extemporaneous Compounding of Ophthalmic Products ������������������   19 Reference ��������������������������������������������������������������������������������������������������   19 8 Guidelines of The American Society of Health-System Pharmacists (ASHP) on Pharmacy-Prepared Ophthalmic Products������������������������   21 Reference ��������������������������������������������������������������������������������������������������   23 9 Formulations of Extemporaneous Topical Ophthalmic Preparations������   25 9.1 Acetylcysteine Ophthalmic Solution������������������������������������������������   25 9.2 Amikacin Ophthalmic Solution��������������������������������������������������������   28 9.3 Amphotericin B Ophthalmic Solution����������������������������������������������   28 9.4 Atropine Ophthalmic Solution����������������������������������������������������������   30 xiii

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9.5 Autologous Serum Ophthalmic Solution������������������������������������������   31 9.6 Bacitracin Ophthalmic Solution��������������������������������������������������������   32 9.7 Cefazolin Sodium Ophthalmic Solution ������������������������������������������   33 9.8 Ceftazidime Ophthalmic Solution����������������������������������������������������   35 9.9 Cefuroxime Ophthalmic Solution ����������������������������������������������������   36 9.10 Ceftriaxone Ophthalmic Solution ����������������������������������������������������   37 9.11 Clindamycin Ophthalmic Solution ��������������������������������������������������   38 9.12 Cyclosporine Ophthalmic Solution��������������������������������������������������   39 9.13 Colistimetate Ophthalmic Solution��������������������������������������������������   41 9.14 Edetate Disodium Ophthalmic Solution ������������������������������������������   42 9.15 5-Fluorouracil Ophthalmic Solution ������������������������������������������������   43 9.16 Gentamicin Ophthalmic Solution]����������������������������������������������������   44 9.17 Interferon Alfa-2b Ophthalmic Solution������������������������������������������   44 9.18 Medroxyprogesterone Ophthalmic Solution������������������������������������   46 9.19 Mitomycin-C Ophthalmic Solution��������������������������������������������������   47 9.20 Penicillin G Potassium Ophthalmic Solution ����������������������������������   48 9.21 Tacrolimus Ophthalmic Solution������������������������������������������������������   49 9.22 Tobramycin Ophthalmic Solution����������������������������������������������������   50 9.23 Vancomycin Hydrochloride Ophthalmic Solution����������������������������   51 9.24 Voriconazole Ophthalmic Solution ��������������������������������������������������   53 References��������������������������������������������������������������������������������������������������   54 Part III Extemporaneous Intraocular Injections 10 Intravitreal Injections������������������������������������������������������������������������������   63 References��������������������������������������������������������������������������������������������������   65 11 Intracameral Injections ��������������������������������������������������������������������������   67 Reference ��������������������������������������������������������������������������������������������������   68 12 Formulations of Extemporaneous Intraocular Injections��������������������   69 12.1 Amikacin Sulfate Intravitreal Injection������������������������������������������   69 12.2 Amphotericin B Intravitreal Injection��������������������������������������������   70 12.3 Bevacizumab Intravitreal Injection ������������������������������������������������   72 12.4 Cefazolin Sodium Intravitreal Injection������������������������������������������   73 12.5 Ceftazidime Intravitreal Injection ��������������������������������������������������   74 12.6 Cefuroxime Intracameral Injection ������������������������������������������������   75 12.7 Cidofovir Intravitreal Solution��������������������������������������������������������   76 12.8 Clindamycin Intravitreal Injection��������������������������������������������������   77 12.9 Dexamethasone Phosphate Intravitreal Injection����������������������������   78 12.10 Foscarnet Intravitreal Injection ������������������������������������������������������   78 12.11 Ganciclovir Intravitreal Injection����������������������������������������������������   79 12.12 Penicillin G Potassium Intravitreal Injection����������������������������������   82 12.13 Tissue Plasminogen Activator (TPA) Intracameral Injection����������   83

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12.14 Vancomycin Intravitreal Injection��������������������������������������������������   85 12.15 Voriconazole Intracameral Injection ����������������������������������������������   86 References��������������������������������������������������������������������������������������������������   87 Part IV Extemporaneous Subconjunctival Injections 13 Equipments and Steps for Subconjuctival Injections��������������������������   93 References��������������������������������������������������������������������������������������������������   94 14 Formulations of Extemporaneous Subconjunctival Injections������������   95 14.1 Amikacin Sulfate Subconjunctival Injection����������������������������������   95 14.2 Bevacizumab Subconjunctival Injection ����������������������������������������   96 14.3 Dexamethasone Phosphate Subconjunctival Injection��������������������   97 14.4 Gentamicin Subconjunctival Injection��������������������������������������������   97 References��������������������������������������������������������������������������������������������������   98 Part V Extemporaneous Ophthalmic Preparations in Ocular Oncology 15 Extemporaneous Ophthalmic Preparations in Ocular Oncology ������  103 15.1 5-Fluorouracil Ophthalmic Solution ����������������������������������������������  103 15.2 Melphalan Intravitreal Injection�����������������������������������������������������  104 15.3 Methotrexate Intravitreal Injection ������������������������������������������������  105 15.4 Mitomycin-C Ophthalmic Solution������������������������������������������������  106 15.5 Rituximab Intravitreal Injection������������������������������������������������������  108 References��������������������������������������������������������������������������������������������������  108 Index������������������������������������������������������������������������������������������������������������������  111

About the Authors

Eman Ali Saeed Alghamdi, BSc, MPharm (Hon)  has recently joined the Saudi Food & Drug Authority (SFDA), Riyadh, Saudi Arabia, as a Senior Drug Safety Specialist in the Pharmacovigilance department. Her current main task is monitoring the safety of medicinal products available in Saudi Arabia proactively and whenever there is a potential safety signal. The new appointment at SFDA is due to her previous extensive experience as a Drug and Poison Information Specialist at Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia. In PSMMC, she managed the hospital drug formulary and published multiple guide books internally for physicians and practitioners. She also implemented protocols and policies for the safe and effective use of medications.  Nonetheless, she was the chair of adverse drug reaction matters with SFDA during her aforementioned role. Dr. Alghamdi is currently a supervisor of pharmacy students and residents completing their clinical rotation. Earlier, she taught academic courses of pharmacology in the Nursing College at Prince Sultan Military College of Health Sciences, Riyadh, Saudi Arabia. She received her first Bachelor’s  degree in pharmaceutical science from King Saud University, Riyadh, in 2007, and her second Bachelor degree in pharmacy from Griffith University in Gold Coast, Australia, in 2011. After that, she completed her Master’s degree in pharmacy with honors from Griffith University in 2013. Dr. Alghamdi was awarded by the Pharmacy Guild of Australia, Queensland, for her outstanding achievement in her master’s dissertation. Abdulmalik Yahya Al Qahtani, MD  is a consultant ophthalmologist at Anterior Segment Division in Ophthalmology Department in Prince Sultan Military Medical City (PSMMC) in Riyadh, Saudi Arabia. He is also an adjunct assistant professor at King Saud University in Riyadh, Saudi Arabia. His main fields of specialty are cornea, cataract, and refractive surgery. Dr. Alqahtani graduated from the College of Medicine at King Saud University in Riyadh in 1997. In 2002, he received the Ophthalmology Specialty Certificate from the Saudi Commission for Health Specialty. That was followed by the

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About the Authors

Subspecialty Fellowship Certificate  in Anterior Segment from King Khaled Eye Specialist Hospital (KKESH) in 2003. He was appointed as director (2004–2006) of the Outpatient Department at King Saud Medical City, one of the largest hospitals in the Middle East. He was also the head of the Ophthalmology Department in the same medical city in 2005–2008. After that, he became the head of the Anterior Segment Division in the Ophthalmology Department in Prince Sultan Medical Military City in Riyadh in 2015–2016. Dr. Alqahtani is an active contributor to many  national, regional, and international ophthalmology conferences such as the American Society of Cataract and Refractive Surgery (ASCRS) and the European Society of Cataract and Refractive Surgeons. Mazen M. Sinjab, MD, MSc, ABO, PhD, FRCO, CertLRS  is currently working as a consultant ophthalmologist at Dr. Mazen Sinjab Eye Clinic, Dubai, UAE, and at Al Zahra Medical Center, Damascus, Syria. His main fields of specialty are laser and refractive surgery, cataract and clear lens surgery, and keratoconus management. He received a Certificate in Laser and Refractive Surgery from The Royal College of Ophthalmologists in London, UK. Professor Sinjab graduated with honors from the Faculty of Medicine at Aleppo University, Syria, in 1993. After that, he had his master’s degree in ophthalmology with honors from Damascus University, Syria, in 1996, followed by the Certificate of Arab Board in Ophthalmology in 1997. In 2009, he had his PhD with honors during the Professorship Program between Damascus University and Moorfields Eye Hospital in London. Professor Sinjab has a considerable contribution to ophthalmology education through his distinguished books, his outstanding Sinjab Academy channel on YouTube, and his instructional courses in ophthalmology conferences. In 2015, The Royal College of Ophthalmologists in London honored him the Honorary Fellowship Certificate (FRCOphth) because of his remarkable contribution to ophthalmology education at an international level. For the same reason, he was awarded by many regional and international institutes. Professor Sinjab is an advisory board member in several regional and international conferences and a reviewer in international ophthalmology journals. He is also a member of the examination board in The Royal College of Surgeons in Edinburgh. Khalid  Mohammed  Alyahya, BSc, MPhil-PhD in Pharmacy  is a consultant clinical pharmacist currently working at Prince Sultan Military Medical City (PSMMC) in Riyadh, Saudi Arabia. His main field of specialty is internal medicine (endocrine and diabetes). Dr. Alyahya graduated from the College of Pharmacy at King Saud University in Riyadh, Saudi Arabia, in 1994. After that, he completed his PhD in clinical pharmacy from Cardiff University, UK, in 2004. In 2005, he was certified as a specialist clinical pharmacist. Then in 2009, he was certified as a consultant clinical pharmacist. In 2016, he was appointed as the head and director of The Drug and Poisoning

About the Authors

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Information Center (DPIC) at PSMMC in Riyadh. Further to his duties, he is chairing the PSMMC Pharmacy Newsletter, Formulary Management Team. To assure the quality of service provided by the pharmacy staff at PSMMC, Dr. Alyahya is chairing the Patients’ Family Education and Counselling Team and is an active member of Preparation Team for the national and international accreditation certificate, namely, the Joint Commission International (JCI) and the Saudi Central Board for Accreditation of Healthcare Institutions (CBAHI). Dr. Alyahya has a considerable contribution to pharmacy education and training. From 2008, he has been working as a training advisor in internal medicine in Pharmacy Practice Residency Program, which belongs to the Saudi Commission for Health Specialties in Saudi Arabia. From 2013 to 2018, he was the director of the General Clinical Pharmacy Residency Program at PSMMC.  Currently, he is the director of the Clinical Pharmacy Residency Program for internal medicine at PSMMC. Furthermore, Dr. Alyahya is working as an adjunct assistant professor in several Saudi universities in the field of pharmacy, such as King Saud University, Princess Nora University, and Riyadh College of Dentistry and Pharmacy. Dr. Alyahya has participated in many local, regional, and international pharmacy conferences. Moreover, he has supervised more than 20 published and unpublished postgraduate research projects. Nevertheless, he is an advisory board member in many regional committees, like the National Committee of Bioethics (2015–2018), Medical Service Department Scientific Research Committee (2015–2016), and Medical Service Department Pharmacy Advisory Committee (2018 till now).

Abbreviations

5-FU 5-Fluorouracil AHC Acute hemorrhagic conjunctivitis AMD Age-related macular degeneration Anti-VEGF Anti-vascular endothelial growth factor ASHP American Society of Health-System Pharmacists BAK Benzalkonium chloride CNS Central nervous system CME Cystoid macular edema CMV Cytomegalovirus CNVM Choroidal neovascular membrane EDTA Ethylenediamine tetraacetic acid IL Interleukin LR Lactated Ringer LSCD Limbal stem cell deficiency MDR‑PA Multi‑drug-resistant Pseudomonas aeruginosa MMC Mitomycin-C MU Million international unit NODS New ophthalmic delivery system OSSN Ocular surface squamous neoplasia OTS Ocular therapeutic system PDR Proliferative diabetic retinopathy QS Sufficient quantity SODI Soluble ophthalmic drug inserts TASS Toxic anterior segment syndrome TPA Tissue plasminogen activator USP United States Pharmacopeia VEGF Vascular endothelial growth factor W/V Weight per volume

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Part I

Introduction to Extemporaneous Ophthalmic Preparations

Pharmacology is the science of pharmacokinetics, pharmacodynamics, and toxicology. Pharmacokinetics is the study of the mechanisms of drug absorption, distribution, metabolism, and excretion, the onset of action, duration of effect, biotransformation, and effects and routes of excretion of the metabolites of a drug in the organ. On the other hand, pharmacodynamics is the study of the biochemical and physiological effects of a drug in the organ, including mechanisms of action. Toxicology is the study of effects, including adverse effects of drugs on the organ system. Although the three terms are closely interrelated for all organ systems and drugs, the eye poses significantly more challenges than most other tissues. The eye has its unique tissue barriers to drug penetration, namely, the lipophilic corneal epithelium, the hydrophilic corneal and scleral stroma, the conjunctival lymphatics, the choroidal vasculature, and the blood-ocular barriers. The cornea is essentially a fat (epithelium), water (stroma), fat (endothelium) multilayered structure. The epithelium is the major barrier to absorption, especially for hydrophilic medications, while corneal stroma is a major barrier for lipophilic drugs. Therefore, the drug with the optimum ratio of hydrophilicity and lipophilicity provides best the corneal transfer. Moreover, tear film has its effect on drugs in terms of dilution and washout, pH modification, and interaction with preservatives. The strong, fibrous ocular scleral layer is a substantial barrier to the penetration of medication into the eye. The ability of a drug to diffuse across the sclera is directly related to the thickness of the sclera and its total surface area, and permeability of a drug across the human sclera decreases as scleral thickness increases. Delivery of therapeutics to the posterior segment of the eye, especially the vitreous body and retina, poses a significant challenge. Topical ocular medications may not reach therapeutic drug levels in the posterior segment of the eye, and traditional medical therapy methods have their disadvantages when targeting the retina. Traditionally, medication is delivered to the eye by four main routes: topical ocular administration, periocular administration, intraocular administration, and systemic administration. Each of these methods has significant disadvantages. Topical ocular solutions or ointments have minimal penetration, rapid dilution, and tear washout and rely substantially on patient compliance to administer the medica-

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Part I  Introduction to Extemporaneous Ophthalmic Preparations

tion. Moreover, the therapeutic dose delivered by a drop is quickly reduced by the action of blinking and nasolacrimal drainage. Only about 20% of the dose is retained in the pre-corneal pocket, and less than 5% of that dose reaches deeper ocular ­tissues. Periocular administration consists of subconjunctival, anterior subtenon, and posterior subtenon routes. Although these routes provide direct and concentrated access of water-soluble medications to the periocular tissue, they are invasive and have limited applications. Similarly, intraocular administration provides direct and concentrated delivery to intraocular structures. However, it is invasive and toxic in some instances. Systemically administered medications, in general, have limited ocular penetration and may require high peripheral drug levels with the potential of toxicity. Moreover, in specific diseases, e.g., bacterial or fungal corneal ulcers, a specific concentration of specific medications should be used; unfortunately, in many occasions, such medications in such concentrations are commercially unavailable. Another example is some retinal diseases, such as proliferative diabetic retinopathy, in which specific medications, namely, anti-vascular endothelial growth factor (anti-VEGF), should be injected directly into the virtuous because they cannot be used topically or systemically. This puts ophthalmologists, pharmacists, and pharmaceutical companies at a challenge, especially when specific concentrations of medications, special delivery systems, or special forms are needed to treat specific ocular diseases. In many instances, off-label preparations are requested by ophthalmologists and are formulated by pharmacists following very strict rules and guidelines. This is known as “Extemporaneous Ophthalmic Preparations.”

Chapter 1

Ocular Pharmacokinetics

In general, ocular pharmacokinetics have two routes, permeation and direct delivery [1–7]. • Permeation: There are different mechanisms of permeation including: –– Transcorneal permeation from the lacrimal fluid into the anterior chamber. –– Non-corneal drug permeation across the conjunctiva and sclera into the anterior uveal tract. –– Drug distribution from the bloodstream via the blood-aqueous barrier into the anterior chamber. –– Drug elimination from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Schlemm’s canal. –– Drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier. –– Drug distribution from the blood into the posterior eye across the blood-retina barrier. –– Drug elimination from the vitreous via the posterior route across the bloodretina barrier. –– Drug elimination from the vitreous via the anterior route to the posterior chamber. • Direct delivery: There are two routes of the direct delivery of medications into intraocular structures: –– Intravitreal drug administration. –– Intracameral drug administration.

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References 1. Baranowski P, Karolewicz B Gajda M, Pluta J.  Ophthalmic drug dosage forms: characterisation and research methods. Scientific World Journal. 2014;2014:861904. https://doi. org/10.1155/2014/861904, 14 pages. 2. Rathore S, Nema R, Sisodid S. An overview and advancement in ocular drug delivery systems. Int J Pharm Sci Res. 2010;1(10):11–23. Available from www.ijpsr.com; ISSN: 0975-8232. 3. Patel A, Cholkar K, Agrahari V, Mitra A. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. https://doi.org/10.5497/wjp.v2.i2.47. 4. McGhee PC. An overview of topical ophthalmic drugs and the therapeutics of ocular infection. In: Ocular therapeutics; 2008. Available from Semantic Scholar. 5. Tangri P, Khurana S.  Basics of ocular drug delivery systems. Int J Res Pharm Biomed Sci. 2011;2(4):1541. ISSN: 2229-3701. 6. Patel PB, Shastri DH, Shelat PK, Shukla AK. Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm. 2010;1(2):113. 7. Kumar S, Bhowmik D, Paswan S, Srivastava S. Recent challenges and advances in ophthalmic drug delivery system. Pharm Innov J. 2012;1(4):1. Available from www.thepharmajournal. com. ISSN 2277-7695.

Chapter 2

Factors Affecting Bioavailability and Efficacy of Topical Ophthalmic Preparations

Several factors affect the efficacy of topical ophthalmic preparations. Some factors are related to the preparation technique while other factors are related to the structural and biochemical properties of the human eye [1–15]. • Factors related to preparation technique: Important factors to be considered in preparing an ophthalmic medication include the following: –– Sterility. –– Tonicity. Topical products require adjustment of tonicity close to that of natural tears. In general, a range of 0.5–2% saline tonicity is well-tolerated. Hypertonic solutions can induce tearing, which increases tear outflow and reduces the concentration and efficacy of the medication in the tears, while hypotonic solutions are often used effectively in tear substitutes to compensate for the high tonicity in the tears in dry eye diseases. –– pH and buffering. Control of pH through the addition of buffers is necessary not only for comfort but also for drug solubility and stability. Since tear fluid has a very low buffering capacity, ophthalmic formulations contain excipients that maintain a pH range of 4.75–7.40. –– Solubility. Many medications are poorly soluble in water, and substances must be added to increase solubility, and, therefore, therapeutic concentration, and improve bioavailability. Micro-emulsions are used for this purpose. They are oil and water mixtures that are homogenized to maintain uniformity. One example is Durezol (difluprednate). It is used to enhance the dispersion of the hydrophobic active ingredient from the oil phase into the aqueous mixture, creating a uniform product when shaken. Other examples that improve solubility include certain surfactants, caffeine, nicotinamide derivatives and cyclodextrins. –– Stability in an appropriate vehicle. Surfactants and co-surfactants are usually added to the medications to increase stability. Micro-emulsions possess low © Springer Nature Switzerland AG 2020 E. A. S. Alghamdi et al., Extemporaneous Ophthalmic Preparations, https://doi.org/10.1007/978-3-030-27492-4_2

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surface tension that assists in corneal spreading and mixing with the pre-­ corneal tear film. In spite of the advantage of extended-release and residence time, potential toxicity associated with high concentrations of surfactants may restrict their use. –– Viscosity. The higher the viscosity the longer the resident time of medications over ocular surface, and the less the frequency of dose. Synthetic and natural polymers can be added to create a gel-like formulation; these improve the viscous and mucoadhesive properties of the drop, increase its residence time on the ocular surface, and slow its rapid dilution and drainage caused by tear-­ film turnover. –– Packaging and storage. • Factors related to the human eye: Important factors affecting penetration, efficacy and lifetime of an ophthalmic medication include the following: –– –– –– –– –– –– –– ––

Small absorptive surface. Low transparency of the scarred cornea. Lipophilicity of corneal epithelium. Hydrophilicity of corneal stroma. Metabolism. Enzymolysis. Bonding of the drug with proteins contained in tear fluid. Defense mechanisms such as tear reflex and blinking, causing decreased drug concentration, and flow of the substance through the nasolacrimal duct, leading to a shorter time of contact with the ocular surface. –– Low capacity of conjunctival sac.

References 1. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacy-preparedophthalmic-products.ashx. 2. Baranowski P, Karolewicz B, Gajda M, Pluta J.  Ophthalmic drug dosage forms: characterisation and research methods. Scientific World Journal. 2014;2014:861904. https://doi. org/10.1155/2014/861904, 14 pages. 3. Rathore S, Nema R, Sisodid S. An overview and advancement in ocular drug delivery systems. Int J Pharm Sci Res. 2010;1(10):11–23. Available from www.ijpsr.com. ISSN: 0975-8232 4. Patel A, Cholkar K, Agrahari V, Mitra A. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. https://doi.org/10.5497/wjp.v2.i2.47. 5. McGhee PC. An overview of topical ophthalmic drugs and the therapeutics of ocular infection Professor. In: Ocular therapeutics; 2008. Available from Semantic Scholar. 6. Tangri P, Khurana S. Basics of ocular drug delivery systems. Int J Res Pharmaceut Biomed Sci. 2011;2(4):1541. ISSN: 2229-3701. 7. Patel PB, Shastri DH, Shelat PK, Shukla AK. Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm. 2010;1(2):113.

References

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8. Kumar S, Bhowmik D, Paswan S, Srivastava S. Recent challenges and advances in ophthalmic drug delivery system. Pharm Innov J. 2012;1(4):1. Available from www.thepharmajournal. com. ISSN 2277-7695. 9. Morrison PW, Khutoryanskiy VV.  Advances in ophthalmic drug delivery. Ther Deliv. 2014;5(12):1297–315. 10. Liang H, Brignole F, Rabinovich-Guilatt L, et al. Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions. Invest Ophthalmol Vis Sci. 2008;49(13):2357. 11. Evstigneev M, Evstigneev V, Santiago AH, Davies DB.  Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B 2) in aqueous solution. Eur J Pharm Sci. 2006;28(1):59–66. 12. Morrison PW, Connon CJ, Khutoryanskiy VV. Cyclodextrin-mediated enhancement of riboflavin solubility and corneal permeability. Mol Pharm. 2013;10(2):756–62. 13. Coffman RE, Kildsig DO.  Hydrotropic solubilization—mechanistic studies. Pharm Res. 1996;13(10):1460. 14. Ali Y, Lehmussaari K.  Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev. 2006;58(11):1258–68. 15. Rajasekaran A, Kumaran K, Preetha JP, Karthika K. A comparative review on conventional and advanced ocular drug delivery formulations. Int J PharmTech Res. 2010;2(1):668–74.

Chapter 3

Ideal Characteristics of Ophthalmic Drug Delivery System

An ideal ophthalmic drug delivery system does not exist. Great efforts are being exerted to approximate the ideal system that is characterized by the following [1–7]: 1. Free of micro-organisms. 2. Good corneal penetration. 3. Maximum ocular drug absorption through prolonging contact time with corneal tissue. 4. Simplicity of instillation for the patient. 5. Reduced frequency of administration. 6. Patient compliance. 7. Low toxicity and side effects. 8. Minimal precorneal drug loss. 9. Non-irritative and comfortable form (e.g. viscous solution should not provoke lacrimal secretion and reflex blinking). 10. Should not blur vision. 11. Relatively non-greasy. 12. Appropriate rheological properties and concentrations of the viscous system.

References 1. Baranowski P, Karolewicz B, Gajda M, Pluta J.  Ophthalmic drug dosage forms: characterisation and research methods. Scientific World Journal. 2014;2014:861904. https://doi. org/10.1155/2014/861904, 14 pages. 2. Rathore S, Nema R, Sisodid S. An overview and advancement in ocular drug delivery systems. Int J Pharm Sci Res. 2010;1(10):11–23. Available from www.ijpsr.com. ISSN: 0975-8232. 3. Patel A, Cholkar K, Agrahari V, Mitra A. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. https://doi.org/10.5497/wjp.v2.i2.47. 4. McGhee PC. An overview of topical ophthalmic drugs and the therapeutics of ocular infection Professor. In: Ocular Therapeutics; 2008. Available from Semantic Scholar.

© Springer Nature Switzerland AG 2020 E. A. S. Alghamdi et al., Extemporaneous Ophthalmic Preparations, https://doi.org/10.1007/978-3-030-27492-4_3

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5. Tangri P, Khurana S. Basics of ocular drug delivery systems. Int J Res Pharmaceut Biomed Sci. 2011;2(4):1541. ISSN: 2229-3701. 6. Patel PB, Shastri DH, Shelat PK, Shukla AK. Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm. 2010;1(2):113. 7. Kumar S, Bhowmik D, Paswan S, Srivastava S. Recent challenges and advances in ophthalmic drug delivery system. Pharm Innov J. 2012;1(4):1. Available from www.thepharmajournal. com. ISSN 2277-7695.

Chapter 4

Inactive Ingredients Used in the Preparation of Ophthalmic Products

Some inactive ingredients are used in the preparation of ophthalmic solutions. These ingredients act as diluent or vehicle and are called “excipients.” The excipients play an essential role in therapeutic effectiveness by performing one or more of the following functions [1–3]: 1 . Adjust concentration and tonicity. 2. Buffer and adjust pH. 3. Stabilize the active ingredients against decomposition. 4. Increase solubility. 5. Impart viscosity. 6. Increase drug permeability and residence time in ocular tissues by enhancing corneal permeability, either by modifying the continuity of the epithelium, altering the lipid/protein components of cell membranes, or changing cell-to-cell junctions. Often these effects are mediated by the same compounds that act as preservatives or buffers: chelating agents (EDTA); preservatives (e.g. benzalkonium chloride); surfactants (e.g. polyoxol 40); tonicity agents (e.g. NaCl and propylene glycol); and bile acid salts.

References 1. Divya N, Muthukumaran M, Krishnamoorthy B. A review on recent studies and advances in ocular drug delivery system. Res J Pharm Biol Chem Sci. 2013;3(4):529. 2. Chung S-H, Lee SK, Cristol SM, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Mol Vis. 2006;12:415–21. 3. Morrison PW, Khutoryanskiy VV.  Enhancement in corneal permeability of riboflavin using calcium sequestering compounds. Int J Pharm. 2014;472(1):56–64.

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Chapter 5

Preservatives Used in Ophthalmic Preparations

As mentioned in the previous chapter, preservatives are excipients that are commonly used in preparing ophthalmic products. The following preservatives are the most commonly used [1]: 1 . Benzalkonium chloride (BAK). 2. Thimerosal. 3. Methylparaben and Propylparaben. 4. Phenyl Ethanol. 5. Chlorhexidine. 6. Polyaminopropyl biguanide. It is important to know that Extemporaneous ophthalmic preparations are preservative-­free products, and therefore have a short expiry date.

Reference 1. Robinson JC.  Ophthalmic drug delivery systems. New  York, NY: Marcel Dekker; 1993. p. 29–57.

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Part II

Extemporaneous Topical Ophthalmic Formulations

In this section, 24 medications will be presented in terms of description, indications, dose, and procedure of preparation, in addition to the expiration date, storage conditions, packaging, and special instructions. Before going into details, it is important to have an idea about topical ophthalmic drug forms, extemporaneous compounding of ophthalmic products, and the American Society of Health-System Pharmacists (ASHP) guidelines on pharmacy-prepared ophthalmic products.

Chapter 6

Topical Ophthalmic Drug Forms

There are several forms of topical ophthalmic drugs, including liquid, semisolid, solid, multi-compartment, and others [1–7]. • Liquid Ophthalmic Drug Forms: They are eight forms: –– –– –– –– –– –– –– ––

Eye drops. Ophthalmic solutions. Microemulsions. Modifications of liquid ophthalmic dosage forms. Addition of substances increasing viscosity/adhesion. Addition of penetration-increasing substances. Prodrugs. Cyclodextrins.

• Semisolid Ophthalmic Drug Forms: they consist of two forms: –– In-situ gels (or Sol-to-Gel Systems). –– Eye ointments. • Solid Ophthalmic Drug Forms: They include eight forms: –– –– –– –– –– –– –– ––

Contact lenses coated with drugs. Ocular inserts. Soluble Ophthalmic Drug Inserts (SODI). Ocular Therapeutic System (OTS) or. Artificial tear inserts. Collagen shield. New Ophthalmic Delivery System (NODS). Minitablets.

• Multi-compartment Drug Delivery Systems: They are four forms: –– Nanoparticles and Microparticles. –– Liposomes. © Springer Nature Switzerland AG 2020 E. A. S. Alghamdi et al., Extemporaneous Ophthalmic Preparations, https://doi.org/10.1007/978-3-030-27492-4_6

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–– Niosomes and Discosomes. –– Dendrimers. • Other Ophthalmic Drug Forms and Methods of Application: –– Filter paper strips. –– Sprays. –– Ocular iontophoresis.

References 1. Baranowski P, Karolewicz B, Gajda M, Pluta J.  Ophthalmic drug dosage forms: characterisation and research methods. Scientific World Journal. 2014;2014:861904. https://doi. org/10.1155/2014/861904, 14 pages. 2. Rathore S, Nema R, Sisodid S. An overview and advancement in ocular drug delivery systems. Int J Pharm Sci Res. 2010;1(10):11–23. Available from on www.ijpsr.com. ISSN: 0975-8232. 3. Patel A, Cholkar K, Agrahari V, Mitra A. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. https://doi.org/10.5497/wjp.v2.i2.47. 4. McGhee PC. An overview of topical ophthalmic drugs and the therapeutics of ocular infection Professor. In: Ocular Therapeutics; 2008. Available from Semantic Scholar. 5. Tangri P, Khurana S. Basics of ocular drug delivery systems. Int J Res Pharmaceut Biomed Sci. 2011;2(4):1541. ISSN: 2229-3701 6. Patel PB, Shastri DH, Shelat PK, Shukla AK. Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm. 2010;1(2):113. 7. Kumar S, Bhowmik D, Paswan S, Srivastava S. Recent challenges and advances in ophthalmic drug delivery system. Pharm Innov J. 2012;1(4):1. Available from www.thepharmajournal. com. ISSN 2277-7695.

Chapter 7

Extemporaneous Compounding of Ophthalmic Products

Pharmacists are frequently requested to prepare sterile products intended for ophthalmic administration when a suitable sterile ophthalmic product is not available from a licensed manufacturer or when there is a shortage of commercially available products. These products may be administered topically, in the form of solutions, suspensions, or ointments, or by subconjunctival or intraocular (e.g., intravitreal and intracameral) injections. These prepared products are called “extemporaneous ophthalmic products” and are mostly given off-label. Although these products are off-label, they are supported by evidence-based medicine and are well controlled and regulated by many of authorities. The American Society of Hospital Pharmacists (ASHP) established guidelines for the preparation of such products [1]. In the following chapter, the ASHP guidelines are fully discussed. N.B.: Off-Label means “unapproved indication, age group, dose, or form of administration.”

Reference 1. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacy-preparedophthalmic-products.ashx.

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Chapter 8

Guidelines of The American Society of Health-System Pharmacists (ASHP) on Pharmacy-Prepared Ophthalmic Products

Guidelines on extemporaneous compounding of ophthalmic products have been produced by the concern authorities. One of these is the ASHP guidelines for the extemporaneous preparation of ophthalmic products. The ASHP has designed this guideline to assess the pharmacist in producing efficient, safe, and effective, ophthalmic preparations [1]. • Before preparing any ophthalmic preparation, the pharmacist should evaluate available documents that support the use of compounded products for ophthalmic use, particularly for its safety and efficacy. For ophthalmic preparation that is not supported by any documents, the pharmacist should seek a professional person to judge the request. • There are elements that need to be considered when preparing extemporaneous ophthalmic preparation: –– –– –– –– –– –– –– –– ––

Sterility. Tonicity. PH, buffering. Inherent toxicity of the drug. Need for a preservative. Solubility. Stability in an appropriate vehicle. Viscosity. Packaging and storage of the final product.

• A clear written procedure for each compounding product should be kept in a file that can be used for future preparation. The procedure should also specify the aseptic technique used. • Before carrying out the preparation of ophthalmic products, a second person or an alternative method of mathematical calculation should be performed to minimize the incidence of error and maximize the accuracy of the compounded product.

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• Using a large volume is an important factor that has a positive impact on increasing the accuracy of the produced extemporaneous ophthalmic preparations. Furthermore, special attention is paid to mixing procedures because they have an impact on the quality of the prepared product. • The adherence to aseptic techniques and sterilization procedures is very important when preparing any ophthalmic preparations. • The followings should be considered when preparing an extemporaneous ophthalmic preparation: –– The compounding should be performed in a certified laminar airflow hood or a biological safety cabinet for a cytotoxic or hazardous product. –– Quality-assurance law and guidelines should be implemented while compounding a sterile product for ophthalmic use. –– Methods should be established to validate all procedures and processes related to sterile product preparation. –– Ingredients should be mixed in sterile empty containers. –– For better measurement accuracy, the use of the smallest syringe for measuring the required volume is preferred. –– To prevent contamination and minimize error, disposable material (e.g. needle and syringe) should be used. –– When using more than one container for compounding sterile preparation, each container should be labeled. –– When preparing an ophthalmic product either from a sterile powder that has been reconstituted or a liquid from a glass ampule, the ingredients should be filtered by using a 5-μm filter to remove any particulate matter. • For sterilized extemporaneous ophthalmic preparations, an appropriate and validated method of sterilization should be determined on the basis of the characteristics of the particular product and container. • Preservative-free ingredients should be used in the preparation of intraocular injections since some preservatives are known to be harmful to the intraocular structures. • When preparing ophthalmic products by using cytotoxic or other hazardous agents, the pharmacist should adhere to the established guidelines for handling such agents. • When preparing the extemporaneous ophthalmic product, the final packaging material should be appropriate for ophthalmic use and should not interfere with the stability and efficacy of the preparation. • There should be agreed expiration dates for all extemporaneous ophthalmic products based on documented stability data as well as the potential of microbial contamination. In addition, chemical stability of the active ingredient, preservative, and packaging material should be considered in determining the overall stability of the final ophthalmic product. • Extemporaneous ophthalmic products dispensed for outpatient use should be labeled according to the hospital’s or pharmacy’s wide policies of prescription-­ labeling. For inpatients use, the extemporaneous ophthalmic products should be

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clearly and accurately labeled. However, in some cases, it may be appropriate to label the products with weight, the concentration of active ingredients, preservatives, storage, handling requirements, and expiration dates. • Storage instructions should be clear and labeled. The pharmacist should clarify that Room Temperature means 15–30  °C, Refrigerator means 2–8  °C, and Freezer means below 0 °C. Moreover, the pharmacist should specify the degree if needed, e.g. −70 °C.

Reference 1. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/pharmacy-preparedophthalmic-products.ashx.

Chapter 9

Formulations of Extemporaneous Topical Ophthalmic Preparations

In the following, the most common 24 formulations are presented and discussed following a systematic methodology starting with the composition and drug family, followed by use, dose, and preparation. The preparation is discussed in detail in terms of concentration(s), procedure, expiration date, storage, packaging, and special precautions. Some formulations are hazardous; therefore, special caution is highlighted so that the medication must be prepared in compliance with the United States Pharmacopeia (USP) . N.B.: Off-Label means “unapproved indication, age group, dose, or form of administration.”

9.1  Acetylcysteine Ophthalmic Solution [1–4] • Description: –– N-acetyl-l-cysteine is an amino acid derived from l-cysteine. It is widely used as a mucolytic in a variety of broncho-pulmonary disorders to reduce the viscosity of mucus. This reduction in viscosity is achieved by the action of the free sulphydryl group in the molecule on the disulphide bonds of the mucoproteins present in mucus. Due to this property, topical form of it has been successfully used in dry eye disease. Absolon and Brown demonstrated that topical administration of 20% Acetylcysteine produce better results in objective signs than artificial tears in keratoconjunctivitis sicca. Williamson et al., reported that patients, suffering from Sjogren’s syndrome and keratoconjunctivitis sicca, who had not responded to tear substitute therapy or nasolacrimal obliteration responded to 5% acetylcysteine therapy. It is used in keratoconjunctivitis sicca which follows the reduction of secretion of lacrimal glands and characterized by thick stringy mucous strands in the lower fornices, and corneal filaments. © Springer Nature Switzerland AG 2020 E. A. S. Alghamdi et al., Extemporaneous Ophthalmic Preparations, https://doi.org/10.1007/978-3-030-27492-4_9

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• Use: Off Label –– Alkali burns and corneal melting. –– Keratoconjunctivitis sicca and dry eye syndrome. • Dose: It can be applied hourly in acute conditions and four times daily in maintenance therapy. • Preparation: –– First Formulation: Acetylcysteine 10% in 15 ml Ingredients Acetylcysteine 20% ampule Benzalkonium chloride 0.16% Hypromellose 0.5%

Quantity 7.5 ml 0.5 ml 7 ml

Procedure: • Under a laminar flow hood, aseptically withdraw 7.5 ml of Acetylcysteine 20% and 0.5 ml of Benzalkonium chloride 0.16%. • Dilute with 7 ml of Hypromellose 0.5%. • The solution must be drawn into a plastic syringe and filtered through a 0.22-μm filter. • Transfer the solution to a sterile dropper bottle. • Label the bottle. Expiration Date: 90 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light. –– Second Formulation: Acetylcysteine 10% in 15 ml Ingredients Quantity Acetylcysteine 20% ampule 7.5 ml Sodium chloride 0.9% 7.5 ml (preservative free)

Procedure: • Under a laminar flow hood, aseptically withdraw 7.5 ml of Acetylcysteine 20% (Injectable form) and add it to 7.5 ml of Sodium chloride 0.9%. • The solution must be drawn into a plastic syringe and filtered through a 0.22-μm filter. • Transfer the solution to a sterile dropper bottle. • Label the bottle.

9.1  Acetylcysteine Ophthalmic Solution

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Expiration Date: 4 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light. –– Third Formulation: Acetylcysteine 200 mg/ml 20% in 10 ml Ingredients Acetylcysteine 20% oral inhalation solution

Quantity 10 ml

Procedure: • Under a laminar flow hood, aseptically withdraw solution from the vial using a sterile 0.22-μm filter needle affixed to a sterile syringe. • Remove the filter needle and add the solution to a sterile ophthalmic dropper bottle. • Replace the tip, and cap on the ophthalmic dropper bottle and seal it. • Label the bottle. Expiration Date: 4 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light. –– Fourth Formulation: Acetylcysteine 200 mg/ml 20% in 10 ml Ingredients Quantity Acetylcysteine 20% solution 10 ml

Procedure: • Under a laminar flow hood, aseptically withdraw solution from the vial using a sterile 0.22-μm filter needle affixed to a sterile syringe. • Replace the filter needle with a fresh regular needle. • Transfer the solution to a sterile ophthalmic dropper bottle. • Cap on the ophthalmic dropper bottle and seal it. • Label the bottle. Expiration Date: 4 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light.

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9  Formulations of Extemporaneous Topical Ophthalmic Preparations

9.2  Amikacin Ophthalmic Solution [5, 6] • Description: Amikacin is an aminoglycoside antibiotic obtained from kanamycin, showing a broad-spectrum action and strong resistance against the enzymes inactivating the other aminoglycoside antibiotics. It is commercially available as sulfate salt in injection dosage form. The pharmacological action is inhibiting protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to gram-negative bacteria resistant to gentamicin and tobramycin. • Dose: Frequency and duration depends on type and severity of the disease. • Preparation: –– Amikacin 25 mg/ml 2.5% in 10 ml Ingredients Quantity Amikacin 250 mg/2 ml 2 ml Artificial tears 8 ml

Procedure: • Under a laminar flow hood,  aseptically withdraw 2  ml of Amikacin 250 mg/2 ml. • Add it to 8 ml of the commercial artificial tears. • Transfer the composition to an empty amber glass dropper bottle by a 0.22-­ μm filter needle. • Close the bottle, shake to mix, and label. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.3  Amphotericin B Ophthalmic Solution [7–12] • Description: • Amphotericin B injection is typically a complex of amphotericin B and deoxycholate with suitable buffers which form a colloidal dispersion when reconstituted. It is an anti-fungal drug and is indicated to treat systemic and local fungal infections, such as Aspergillus, Candida, Cryptococcus, Fusarium, and

9.3  Amphotericin B Ophthalmic Solution

29

Curvularia, which can lead to serious ulceration to the cornea and must be treated immediately. The ophthalmic drop is prepared in a concentration of 0.1%, 0.15%, 0.2%, and 0.5% (w/v). Ocular administration of amphotericin drop may cause pain and irritation due to the Deoxycholate components, which leads to poor adherence and aggravate patient’s symptoms. This toxicity is minimized when lipid formulation such as AmBisome® is used in the preparation instead of the conventional Amphotericin. Moreover, Kaur et  al. has shown that ocular bioavailability of some liposomal drugs were equal to or better than that of non-­ liposomal ones. • N.B.: –– Amphotericin B is incompatible with solutions containing sodium chloride. –– Amphotericin B is a colloidal dispersion and should not be filtered. –– Amphotericin B liposomal should not be filtered through a filter with a porosity of less than 1 μm. • Use: Off Label Treatment of ocular fungal infections with Candida, Fusarium, Curvularia, and Aspergillus. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– First Formulation: Amphotericin B 0.1%, 0.15%, 0.2%, 0.5% in 10 ml Desired final amphotericin B concentration mg/ml 1 (0.1%) 1.5 (1.5%) 2 (0.2%) 5 (0.5%)

Required amphotericin B volume (ml) 2 3 4 10

Required distilled water volume (ml) 8 7 6 0

Procedure: • Under a laminar flow hood, aseptically add 10 ml of distilled water used for injection (preservative-free) to Amphotericin B 50 mg vial. Shake the vial completely and allow it  to stand for complete dissolution before proceeding. • Select the desired final concentration as per the table above. • From the Amphotericin B vial, withdraw the appropriate volume according to the desired final product concentration. Transfer to a sterile ophthalmic dropper bottle. • Add to the dropper bottle the corresponding amount of distilled water used for injection (preservative-free). • Cap dropper bottle and shake to mix before use. • Label the bottle. • Expiration Date: 7 days.

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9  Formulations of Extemporaneous Topical Ophthalmic Preparations

• Storage Conditions: Refrigerator. Protect from Light. • Packaging: Sterile amber dropper bottle (plastic or glass). • Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light. –– Second Formulation: Liposomal Amphotericin B 0.5% in 10 ml Ingredients Quantity Liposomal Amphotericin B 50 mg vial 1 vial Distilled water used for injection 10 ml (preservative-free)

Procedure: • Under a laminar flow hood, aseptically add 10 ml of distilled water used for injection (preservative-free) to Liposomal Amphotericin B 50 mg vial. Shake the vial completely and allow it to stand for complete dissolution before proceeding. • The solution must be drawn into a plastic syringe and filtered through a 5-μm filter. • Transfer the solution to a sterile dropper bottle. • Cap dropper bottle and shake to mix before use. • Label the bottle. Expiration Date: 180 days. Storage Conditions: Refrigerator or room temperature. Protect from Light. Packaging: Sterile amber dropper bottle (glass) with PVC Dropper. Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator or room temperature. Shake well before use.

9.4  Atropine Ophthalmic Solution [13–15] • Description: Atropine is a tertiary amine antimuscarinic alkaloid with both central and peripheral actions. It is usually given as sulfate. It first stimulates and then depresses the central nervous system (CNS). It has antispasmodic actions on smooth muscle. It reduces secretions, especially salivary and bronchial secretions, and also reduces perspiration, but has little effect on biliary or pancreatic secretion. Atropine depresses the vagus and thereby increases the heart rate. Atropine ophthalmic drops can slow the progression of myopia in children. However, their use has been limited by adverse effects, including light sensitivity and blurred near vision. Atropine sulfate eye drops have been shown to provide the most effective myopia control at a dose of 0.05% once daily with less visual adverse effects and myopic rebound. • Use: Off Label Slowing down progression of myopia in children.

9.5  Autologous Serum Ophthalmic Solution

31

• Dose: One drop in each eye at night. • Preparation: –– Atropine 0.05% (10 ml) Ingredients Isopto® Atropine, 10 mg/mL (1%); Alcon, Fort Worth, TX, USA Sodium chloride 0.9%

Quantity 5 ml QS 10 ml

Procedure: • Under a laminar airflow hood, aseptically dilute 5  ml (10  mg/ml) of Isopto®Atropine with 5  ml of Sodium chloride 0.9%, and shake to mix. This is Atropine vial A of 5 mg/ml (0.5%). • Withdraw 1 ml from vial A and transfer to 10 ml sterile empty vial. This is vial B. • Add 9 ml of preservative-free 0.9% Sodium chloride to Vial B and shake to mix. The concentration in vial B becomes 0.5 mg/ml (0.05%). • The solution must be drawn into a plastic syringe and filtered through a 0.22-μm filter. • Cap dropper bottle and shake it to mix before use. • Label the bottle. Expiration Date: 28 days. Storage Conditions: Refrigerator. Packaging: Sterile in a low-density polyethylene plastic dropper bottle with a low-density polyethylene tip. Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator or room temperature. Shake well before use.

9.5  Autologous Serum Ophthalmic Solution [16–22] • Description: Human serum constitutes of a number of epitheliotropic factors that are available in tears. These factors are mainly responsible for the therapeutics benefits when treating severe dry eyes. The mechanism of action appears in the reduction of friction and shear forces caused by blink-induced biomechanical trauma. Additionally, autologous serum eye drops provide a variety of nutritional molecules such as vitamins, glucose, growth factors, and immunoglobulins. These help to restore an environment that promotes re-epithelialization and supports ocular surface health. • Use: Off Label –– Severe ocular surface disease such as Sjogren’s syndrome (primary or secondary), and immunobullous disorders (Stevens-Johnson syndrome, graft versus host disease).

32

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

–– Persistent and recurrent corneal epithelial defect. –– Neurotropic keratopathy. –– Supportive therapy in patients undergoing ocular surface reconstruction after chemical or thermal ocular surface injury. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– Autologous Serum 20% in 20 ml Sodium Chloride Ingredients Autologous Serum Sodium chloride 0.9% (preservative free) Total ophthalmic serum volume

Quantity 4 ml 16 ml 20 ml

Procedure: • Blood should be drawn from the subject at hospitals by using a serum separator tube and centrifuged for 20 min. • The  serum must be tested for hemolysis (H-index value from HIL test, normal ≤1) and delivered on ice to the pharmacy. • Eye drop should be compounded within 2 days of receipt (upon arrival, the serum should be labeled and stored in the refrigirator). • Under a laminar airflow workbench, aseptically withdraw 4 ml of the sterile autologous serum and place it in an appropriate container. • Aseptically, withdraw 16 ml of 0.9% sodium chloride used for injection, add it to the sterile autologous serum, and mix well. • Optionally, filter the mixture through a sterile 0.22-μm low-protein binding filter. • Package the mixture into sterile containers and label them. Expiration Date: 31 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile single-use dropper containers. Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light.

9.6  Bacitracin Ophthalmic Solution [15, 23] • Description: Bacitracin is a mixture of antimicrobial polypeptides produced by the growth of an organism of the Licheniformis group of Bacillus Subtilis (Bacillaceae). The

9.7  Cefazolin Sodium Ophthalmic Solution

33

antimicrobial pharmacological effect is obtained from interfering with bacterial cell wall synthesis by inhibiting the lipid-carrier molecule that transfers cell wall subunits across the cell membrane. • Use: Off Label Treatment of ocular bacterial infection by many Gram-positive species including Staphylococci, Streptococci (particularly group A Streptococci), Corynebacterium, and Clostridia. It is also active against Actinomyces, Treponema pallidum, and some Gram-negative species such as Neisseria and Haemophilus Influenza, although most Gram-negative organisms are resistant. Acquired bacterial resistance to bacitracin rarely occurs, but resistant strains of Staphylococci have been detected. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– Bacitracin 10,000 U/ml in 5 ml Ingredients Quantity Bacitracin 50,000 Unit (dry powder) 1 vial Distilled water used for injection 5 ml (preservative free)

Procedure • Under a laminar airflow workbench, aseptically reconstitute 50,000 Unit (dry powder) of Bacitracin with 5 ml of distilled water used for injection (preservative-free) to produce a concentration of 10,000 unit/ml. • Transfer to a sterile ophthalmic dropper bottle. • Cap dropper bottle and shake to mix before use. • Label the bottle. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile syringe with sterile tamper-evident cap. Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Shake well before use.

9.7  Cefazolin Sodium Ophthalmic Solution [15, 24–29] • Description: Cefazolin as sodium salt is a bactericidal broad-spectrum antibacterial. It is classified as a first-generation cephalosporin. It acts by inhibiting the synthesis of the bacterial cell wall.

34

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

• N.B.: The use of artificial tears as vehicles provide a variety of advantages: –– It increases the viscosity of Cefazolin eye drop, consequently, it prolongs the contact time between antibiotics and corneal tissues. –– It prolongs the expiry date of the multi-dose formulations by inhibiting microbial contamination and biodegradation by the action of preservatives. • Use: Off Label Treatment of bacterial ocular infection caused by Staphylococcus Aureus, which is a common ocular pathogen causing a variety of infections, such as conjunctivitis, blepharitis, and keratitis. The drug is often prescribed for topical application when Staphylococcus Aureus is identified as an etiologic agent. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: There are two different methods of preparation for the same concentration. The first one is to use distilled water and artificial tears, while only distilled water is used in the second one. Consequently, the expiration date differs. –– First Formulation: Cefazolin Sodium 50 mg/ml 5% in 10 ml Ingredients Cefazolin Sodium injection powder Distilled water used for injection (preservative-free) Artificial tears—Tears Naturale II (Alcon) or Natear (Silom Medical)

Quantity 1 g 4.5 ml 3 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 1  g vial of Cefazolin Sodium with 4.5 ml of distilled water used for injection (preservative-free) then shake to mix. Label it as vial A. • From vial A, withdraw 1 ml and further dilute it in 3 ml of artificial tears vehicle. Label it as vial B. • Withdraw the entire content of vial B into a syringe by a 0.22-μm filter needle, and then remove the filter needle and transfer the solution to a sterile ophthalmic dropper bottle. • Cap the dropper and label it. Expiration Date: 28 days Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.8  Ceftazidime Ophthalmic Solution

35

–– Second Formulation: Cefazolin Sodium 50 mg/ml 5% in 10 ml Ingredients Cefazolin Sodium injection powder Distilled water used for injection, (preservative-free)

Quantity 500 mg QS 10 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 500 mg vial of Cefazolin Sodium with the proper amount of distilled water used for injection (preservative-free) to form 10 ml, and then shake to mix. • From the reconstituted Cefazolin solution vial, withdraw the entire content into a syringe by a 0.22-μm filter needle, and then remove the filter needle and transfer the solution to a sterile ophthalmic dropper bottle. • Cap the dropper and label it. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.8  Ceftazidime Ophthalmic Solution [15, 24, 30–33] • Description: Ceftazidime has a bactericidal action and broad-spectrum of activity. It is a semisynthetic, third-generation cephalosporin antibiotic, which is highly resistant to beta-lactamase and possesses a broad spectrum of anti-microbial activity, including gram-negative bacteria, particularly Pseudomonas Aeruginosa. The bactericidal effect results from inhibiting mucopeptide synthesis in the bacterial cell wall like other cephalosporin. • Use: Off Label Currently used for the treatment of severe Pseudomonas ocular infections. • Dose: One drop every 1 min for the first 5 min, as a loading dose, and thereafter two drops hourly for the first 72 h. Medication can be tapered accordingly based on response.

36

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

• Preparation: –– Ceftazidime 50 mg/ml 5% in 10 ml Ingredients Ceftazidime injection powder Distilled water used for injection (preservative-free) Or Ceftazidime 1 g/10 ml Distilled water used for injection (preservative-free)

Quantity 500 mg 9.5 ml 5 ml 5 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 1 g Ceftazidime vial with 9.5 ml of distilled water used for injection (preservative-free) to constitute 1 g/10 ml. • Withdraw 5 ml (500 mg) and transfer to an empty dropper bottle by a 0.22-­ μm filter needle. • Add 5 ml of distilled water used for injection (preservative-free) to constitute Ceftazidime 500 mg/10 ml = 50 mg/ml. • Close bottle, shake well and label. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Tight-light resistant sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.9  Cefuroxime Ophthalmic Solution [15, 34, 35] • Description: Cefuroxime as sodium salt is bactericidal, second generation cephalosporin antimicrobial. The antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall. • Use: Off Label –– Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. –– Prophylaxis of postoperative endophthalmitis after cataract surgery. • Dose: Frequency and duration depend on the type and severity of the disease.

9.10  Ceftriaxone Ophthalmic Solution

37

• Preparation: –– Cefuroxime sodium 50 mg/ml 5% in 15 ml Ingredients Cefuroxime sodium Distilled water used for injection (preservative-free)

Quantity 750 mg 15 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 750  mg of Cefuroxime Sodium injection with 15 ml of distilled water used for injection (preservative-free) to constitute 50 mg/ml. • Transfer to an empty dropper bottle by a 0.22-μm filter needle. • Close bottle, shake well and label. Expiration Date: 14 days. Storage Conditions: Refrigerator. Packaging: Tight-light resistant sterile dropper bottle (glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.10  Ceftriaxone Ophthalmic Solution [36, 37] • Description: Ceftriaxone is a semisynthetic, third-generation cephalosporin antibiotics. It contains an Aminothiazolyl-acetyl side chain, which is responsible for antibacterial activity and results in enhanced stability against Beta-lactamase. The mechanism of action of ceftriaxone is like other cephalosporin by inhibition of cell wall synthesis. Ceftriaxone has a wide spectrum of activity against a variety of gram-­ negative and gram-positive  bacteria, but has less activity against gram-­ negative than the first and the second generations of cephalosporin. Therefore, it should not be used in the treatment of infection caused by those bacteria. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– First Formulation: Ceftriaxone 50 mg/ml 5% in 10 ml Ingredients Ceftriaxone 1 g vial for injection 0.9% Sodium chloride (preservative-free)

Quantity 500 mg 9.6 ml

38

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

See procedure below. –– Second Formulation: Ceftriaxone 100 mg/ml 10% in 10 ml Ingredients Ceftriaxone 1 g vial for injection 0.9% Sodium chloride (preservative-free)

Quantity 1000 mg 9.6 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 1 g Ceftriaxone vial with 9.6 ml of 0.9% sodium chloride (used for injection) to prepare the desired Ceftriaxone concentration 100 mg/ml. • To prepare 50 mg/ml of Ceftriaxone, withdraw 5 ml (500 mg) and transfer to an empty dropper bottle by a 0.22-μm filter needle. Add 5 ml sodium chloride 0.9% to constitute Ceftriaxone 500 mg/10 ml = 50 mg/ml • Transfer to an empty sterile dropper bottle by a 0.22-μm filter needle. • Replace the tip and cap on the ophthalmic dropper bottle. • Seal and label the bottle. Expiration Date: 10 days if in refrigerator, and 2 days if in room temperature. Storage Conditions: Refrigerator or room temperature. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator or in room temperature.

9.11  Clindamycin Ophthalmic Solution [38] • Description: Clindamycin is a semisynthetic bactericidal antibiotic agent. The mechanism of action is by inhibiting protein synthesis in susceptible bacteria. It has been noted that the ophthalmic route of administration has favorable outcomes and tolerance in preventing acute bacterial endophthalmitis. It is more likely used in patients who are allergic to penicillin or in whom the use of cephalosporin is unwise. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– Clindamycin 50 mg/ml (10 ml) Ingredients Clindamycin injection 900 mg/6 ml Distilled water used for injection (preservative free)

Quantity 6 ml 10 ml

9.12  Cyclosporine Ophthalmic Solution

39

Procedure: • Under laminar airflow hood, aseptically withdraw 5  ml (750  ml) of clindamycin injection into a syringe using a 0.22-μm filter needle. • Remove the filter needle and transfer the clindamycin solution into a sterile ophthalmic drop bottle. • Add 10 ml of distilled water used for injection (preservative-free) into the dropper bottle. • Replace the tip, cap the ophthalmic dropper bottle, and gently shake to mix. • Seal and label the bottle. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instruction: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.12  Cyclosporine Ophthalmic Solution [39–49] • Description: Cyclosporine is a cyclic polypeptide consisting of 11 amino acids, it acts as an immunomodulatory that inhibits proliferation and differentiation of the T cells and decreases the production of cytokines, such as interleukin (IL)-2, IL-4, IL-5, and interferon-gamma by inhibiting calcineurin activation in the  cytoplasm. Cyclosporine is lipophilic, therefore oily-based solutions, such as olive oil and castor oil, should be used to prepare the topical drops. However, oily-based eye drops have poor tolerability since they may cause discomfort because of burning sensation, blurring of vision, or contact blepharitis. Recent studies have shown that cyclosporine in artificial tears is effective and has better tolerability. • Use: Off Label –– Adjunctive maintenance of corneal transplant. –– Adjunctive treatment of conjunctivitis, keratoconjunctivitis and corneal inflammatory disease associated with systemic autoimmune disease. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: Caution: Hazardous Medication. Must be prepared in compliance with USP . –– First Formulation: Cyclosporine 10 mg/ml 1% in 15 ml

Ingredients Cyclosporine 50 mg/ml Injection (5 ml) Sandimmune® Liquifilm tears (polyvinyl alcohol and povidone 1.4%, 0.6%)

Quantity 10 mg/ml 3 ml 12 ml

40

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

–– Second Formulation: Cyclosporine 20 mg/ml 2% in 15 ml

Ingredients Cyclosporine 50 mg/ml Injection (5 ml) Sandimmune® Liquifilm tears (polyvinyl alcohol and povidone 1.4%, 0.6%)

Quantity20 mg/ml 6 ml 12 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the Cyclosporine and the vehicle to prevent contamination of the laminar flow hood. • Reconstitute 3  ml (for the 1%) or 6  ml (for the 2%) of 50  mg/ml Cyclosporine solution with 12 ml of Liquifilm tears. • Transfer the composition to an empty dropper bottle by a 0.22-μm filter needle. • Close bottle, shake well, and label. Expiration Date: 30 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. –– Third Formulation: Cyclosporine 20 mg/ml 2% in 15 ml Ingredients Oral solution of Cyclosporine 10% (Sandimmune®) Sterile castor oil

Quantity 50 ml 200 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the Cyclosporine and castor oil to prevent contamination of the laminar flow hood. • One volume of Cyclosporine (50 ml) is added to 4 volume of castor oil (200 ml). • Transfer to an empty dropper bottle by a 5-μm filter needle. • Close bottle, shake well and label. Expiration Date: 12 months. Storage Conditions: Room temperature. Special Instructions: Caution reproductive hazards. Keep out of reach of children. For ophthalmic use only.

9.13  Colistimetate Ophthalmic Solution

41

9.13  Colistimetate Ophthalmic Solution [50–54] • Description: Colistimetate sodium is the sulfamethyl derivative (methanesulfonate) of colistin. It is a prodrug that is hydrolyzed in vivo and in vitro to colistin. It is polymyxin antibiotics obtained from cultures of bacillus polymyxa var. The structure and pharmacology of colistin is related to polymyxin B (also known as polymyxin E). The antibacterial activity of colistin is obtained from binding and damaging the cytoplasmic membrane of susceptible bacteria, alter the osmotic barrier of the membrane and causing leakage of essential intracellular metabolites and nucleosides. Literature has shown that topical Colistimetate is an effective antibiotic to treat Multi-Drug Resistant Pseudomonas Aeruginosa (MDR-PA) bacterial keratitis. • Use: Off Label Bacterial eye infection and corneal ulceration due to many gram-negative species. The drug is inactive against gram-positive bacteria, fungi, and viruses. • Dose: One drop to be instilled half-hourly for 48–72 h, and then 1 hourly during daytime and 3 hourly during the night. Thereafter, the frequency is reduced according to the clinical response. • Preparation: –– Colistimetate 16 mg/ml 1.6% in 15 ml Ingredients Colistimethate sodium injection Distilled water used for injection (preservative-free)

Quantity 1 million IU/80 mg 5 ml

Procedure: • Under laminar airflow hood, aseptically reconstitute 80  mg vial of Colistimetate with 5  ml distilled water used for injection (preservativefree) to prepare 16 mg/ml concentration. • Shake well to dissolve the powder. • Withdraw Colistimetate solution into a sterile syringe, and add to a sterile, plastic, ophthalmic dropper bottle. • Replace the tip and cap on the ophthalmic dropper bottle, and gently shake to mix. • Seal and label the bottle. Expiration Date: 1 day. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

42

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

9.14  Edetate Disodium Ophthalmic Solution [15, 55–58] • Description: Edetate Disodium (EDTA) is a heavy metal chelator that has high affinity to calcium. It has been administered topically to the eyes as a collagenase inhibitor or to chelate calcium deposit in corneal band keratopathy and lime injury. In most cases, vision improves; however, in the eyes with poor visual potential, EDTA is applied mainly to improve ocular discomfort. • N.B.: Disodium Edetate should not be confused with Calcium Edetate, which is stocked in the pharmacy as an antidote for heavy metal intoxication. • Use: Off Label Treatment of corneal calcific band keratopathy and calcium deposits in the cornea. • Preparation: –– Disodium Edetate 3.7–20 mg/ml 2% in 10 ml Desired final edetate concentration mg/ml 3.7 mg/ml 7.4 mg/ml 10 mg/ml 11.1 mg/ml 18.5 mg/ml 20 mg/ml

Required edetate volume (ml) 0.25 0.5 0.68 0.75 1.25 1.35

Required distilled water volume (ml) 9.75 9.5 9.32 9.25 8.75 8.65

Procedure • Select the desired final concentration from the table above. • Under a laminar airflow workbench, aseptically withdraw the required amount of EDTA ampoule by a filter needle to avoid glass fragments. • Replace the filter needle of the EDTA-solution syringe by a fresh regular needle, and then transfer to a sterile ophthalmic dropper bottle • To the dropper bottle containing the correct amount of EDTA, add the corresponding amount of distilled water used for injection (preservative-free). • Cap dropper bottle, shake to mix before use and label. Expiration Date: 1 day. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.15  5-Fluorouracil Ophthalmic Solution

43

9.15  5-Fluorouracil Ophthalmic Solution [59–65] • Description: 5-Fluorouracil (5-FU) is a structural analog of thymine, which is a fluorinated pyrimidine antagonist. The pharmacological effect comes from impairing of DNA and RNA synthesis in tumor cells and normal cells as well. However, it is relatively more selective in cancerous cells due to higher DNA and RNA synthesis. It is applied topically at a concentration of 1%. • Use: Off Label Treatment of Ocular Surface Squamous Neoplasia (OSSN), including a broad spectrum of conjunctival malignancies, ranging from mild epithelial dysplasia to invasive squamous carcinoma. 5-FU has shown efficacy of 85–100%, with a tumor recurrence rate ranging from 1.1% to 43%. • Dose: There are two methods to apply the drops depending on the study: –– One drop four times a day for 4 weeks. –– One drop four times a day for 1 week followed by a drug holiday of 3 weeks. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– 5-Fluorouracil 10 mg/ml 1% in 5 ml Ingredients 5-Fluorouracil 50 mg/ml vial (10 ml) Sodium chloride 0.9% (preservative-free)

Quantity 50 mg 4 ml

Procedure: • Aseptically withdraw 1 ml of 5-FU (50 mg) into a syringe by a 0.22-μm filter needle. • Replace the filter needle of the 5-FU-solution syringe by a fresh regular needle, and then transfer to a sterile ophthalmic dropper bottle. • Add 4 ml of sodium chloride 0.9% for injection (preservative free). • Cap dropper bottle and shake to mix before use. • Label with chemotherapy handling and disposal precautions. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Cytotoxic precaution (special handling and disposal required). Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

44

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

9.16  Gentamicin Ophthalmic Solution [38, 66, 67] • Description: Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora Purpura. It is available as a mixture of the  sulfate salts of Gentamicin C1, C2, and C1A. Mechanism of action is inhibiting microbial protein synthesis in susceptible pathogens. Gentamicin is physically incompatible with semisynthetic Penicillin such as Ampicillin. For this reason, they should never be mixed together in the same syringe or bottle for ophthalmic use. It is recommended that concomitant use is separated by 15 min. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible gram-negative anaerobic organisms. • Dose: Frequency and duration depend on type and severity of the disease. • Preparation: –– Gentamicin 14 mg/ml 1.4% in 20 ml Ingredients Gentamicin sulfate 80 mg/2 ml Commercial Gentamicin ophthalmic solution 0.3% (15 mg/5 ml).

Quantity 2 ml 5 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 2  ml of Gentamicin sulfate 80 mg/2 ml. • Add it to 5 ml of the commercially available Gentamicin ophthalmic solution 0.3% (15 mg/5 ml). • Transfer the composition to an empty amber glass dropper bottle by a 0.22-­ µm filter needle. • Close the bottle, shake to mix, and label. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.17  Interferon Alfa-2b Ophthalmic Solution [68–80] • Description: Interferon alfa-2b is a natural glycoprotein. It has antimicrobial, antiviral and antineoplastic properties. Its role as an antineoplastic agent is due to its anti-­

9.17  Interferon Alfa-2b Ophthalmic Solution

45

proliferative, anti-angiogenic and cytotoxic effects. In addition, it has potential-­ inducer properties of the host anti-tumor immunosurveillance. The first evidence of the efficacy of the product in treating limbal epithelial dysplasia was in 1994. Thereafter, it has become the main treatment agent of corneal and conjunctival tumors. It is used topically as ophthalmic drops and locally as subconjunctival injection. Generally, it is more tolerable than chemotherapy. However, the subconjuctival injection administration is associated with transient flu-like symptoms, while the administration of the  ophthalmic drops may cause irritation, conjunctival hyperemia, reactive lymphoid hyperplasia, and follicular conjunctivitis. These side effects usually resolve after discontinuation of treatment. Additional limitation for interferon alfa-2b treatment when compared to surgery is the cost burden. • Use: –– Off-Label topical application to treat ocular surface squamous neoplasia with less ocular toxicity than chemotherapeutic agents. –– Off-Label topical application to treat Acute Hemorrhagic Conjunctivitis (AHC), which is a rapidly progressive contagious viral infection. • Dose: One drop four times daily. The total length of treatment varies amongst different studies, ranging from 1 to 4 months. • Preparation: –– Interferon Alfa-2b One Million International Unit 1 MU/ml in 10 ml Ingredients Quantity Interferon Alfa-2b 10 MU/ml vial 1 ml Distilled water used for injection 9 ml (preservative-free)

Procedure: • Under Laminar airflow hood, transfer 1 ml from a 10 MU (10 MU/ml) vial of INTRON-A® Ready-To-Use solution to a sterile 15  ml eye dropper bottle. • Add 9 ml of distilled water used for injection (preservative-free) to constitute a concentration of 1 MU/ml. • The final product is stable for 14 days refrigerated. • Cap the dropper bottle, shake to mix and label. Expiration Date: 14 days. Storage Conditions: Refrigerator. Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

46

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

9.18  Medroxyprogesterone Ophthalmic Solution [81–83] • Description: Medroxyprogesterone acetate is a synthetic progestin. It is a derivative of 17 α-hydroxyprogesterone that differs structurally by the addition of a 6 α-methyl group and a 17 α-acetate group. It is available in the market in injection form. For ophthalmic administration, it is constituted in a concentration of 10  mg/ml. This off-label use has been shown in animals’ study to exhibit anti-inflammatory activity and collagenase inhibiting. • Use: Off Label Treatment of corneal alkali and chemical burn. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: • Caution: Hazardous Medication. Must be prepared in compliance with USP . –– Medroxyprogesterone acetate 10 mg/ml 1% in 10 ml Ingredients Medroxyprogesterone acetate injection 100 mg (Depo-Provera®) Distilled water used for injection (preservative-free)

Quantity 1 vial 9 ml

Procedure: • Under Laminar airflow  hood, shake the medroxyprogesterone injection vial vigorously. • Withdraw 1 ml from the vial and transfer it to a sterile ophthalmic dropper bottle. Do not use any filter during this transfer. • Add 9  ml of distilled water used for injection (preservative-free) to the ophthalmic dropper. • Cap the dropper bottle, shake to mix, and label. Expiration Date: 1 day. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Caution reproductive Hazardous drug. Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.19  Mitomycin-C Ophthalmic Solution

47

9.19  Mitomycin-C Ophthalmic Solution [84–100] • Description: Mitomycin-C (MMC) is an antineoplastic antibiotic agent, produced by Streptomyces Caespitosus. It is a potent alkylating agent. The treatment is usually limited by the side effect related to Mitomycin-C including photophobia, dry eye, punctal stenosis, persistent epithelial defects, Limbal Stem Cell Deficiency (LSCD), and allergic reactions, all of which are very common. Mitomycin-C has been administered topically in two different concentrations 0.02% and 0.04% based on the indication. • Use: Off Label –– Treatment of Ocular Surface Squamous Neoplasia. It is used as topical ophthalmic drops as a primary treatment or adjunctive to surgical resection either before the surgery as a chemoreduction measure, during the surgery (intraoperatively), or after the surgery as a chemopreventive measure to reduce the risk of recurrence. –– During glaucoma filtration surgery to reduce the incidence of postoperative adhesions. –– At the end of surface laser ablation as a preventive measure of corneal haze. • Dose: –– Treatment of Ocular Surface Squamous Neoplasia. Based on one study, MMC 0.02% was used as one drop three times daily for at least two 1-week courses and based on another study 0.04% was used as one drop four times daily for at least two 1-week courses. In both studies, that was in both primary and adjunctive treatments. –– During glaucoma filtration surgery, MMC 0.02% can be applied intraoperatively for 1–5 min (differs between studies). –– At the end of surface laser ablation, MMC 0.02% is applied on the cornea. There is no consensus on the period of application. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– First Formulation: Mitomycin-C 0.02% (0.2 mg/ml)

Ingredients Mitomycin injection 5 mg/vial (Powder) Distilled water used for injection (preservative-free)

Quantity 0.2 mg/ml (0.02%) 5 mg 25 ml

48

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

–– Second Formulation: Mitomycin-C 0.04% (0.4 mg/ml) Ingredients Mitomycin injection 5 mg/vial (Powder) Distilled water for used injection (preservative-free)

Quantity0.4 mg/ml (0.04%) 5 mg 12.5 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the MMC vial and the distilled water used for injection (preservative-free) to prevent contamination of the laminar flow hood. • Aseptically reconstitute (5  mg) of MMC vial with (25  ml) of distilled water to obtain a concentration of 0.2 mg/ml (0.02%), or (12.5 ml) of distilled water to obtain a concentration of 0.4 mg/ml (0.04%). • From the MMC solution vial, withdraw the whole contents into a syringe by a 0.22-μm filter needle and transfer the solution to the sterile ophthalmic dropper bottle. • Cap the dropper bottle and label with chemotherapy handling and disposal precaution. Expiration Date: 14 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Cytotoxic precaution (special handling and disposal required). Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light.

9.20  Penicillin G Potassium Ophthalmic Solution [84, 85, 101] • Description: Penicillin G is a Beta-Lactam antibacterial and has a bactericidal action against Gram-positive bacteria, Gram-negative cocci, some other Gram-negative bacteria, Spirochetes, and Actinomyces. It is natural penicillin produced by fermentation of Penicillium Chrysogenum in a medium containing Phenylacetic acid. Penicillin G potassium is frequently referred to as aqueous, crystalline forms of penicillin G. The potency of Penicillin G potassium is expressed in terms of USP Penicillin G units rather than weight. Each mg of Penicillin G potassium equals 1440–1680 USP Penicillin G units and contains 80.8–94.3% Penicillin G. The bactericidal activity on growing and dividing bacteria is related to inhibiting bacterial cell-wall synthesis. However, the action is inhibited by penicillinase

9.21  Tacrolimus Ophthalmic Solution

49

and other Beta-lactamases that are produced during the growth of certain micro-organisms. • Use: Off Label Bacterial eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– Penicillin G Potassium 100,000 units/ml in 10 ml Ingredients Penicillin 1 Million unit (MU) vial for injection Magnesium sulfate 50% Distilled water used for injection (preservative-free)

Quantity 1 vial 1.6 ml 10 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 1.6  ml of Magnesium sulfate  50% into a sterile syringe, and add to the vial of Penicillin G potassium 1 MU that will be diluted. • Add sufficient quantity of distilled water used for injection (preservativefree) to make up a solution of 10 ml of 100,000 units/ml concentration. • Shake the vial gently to mix. The vial may need to sit a few minutes to allow the dissolution of the penicillin powder. • Withdraw all the content from the Penicillin G vial by a 0.22-μm filter needle. • Transfer the solution into a sterile ophthalmic dropper bottle. • Cap the dropper bottle and label. Expiration Date: 10 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.21  Tacrolimus Ophthalmic Solution [102, 103] • Description: Tacrolimus is a weak macrolide antibiotic and a potent non-steroidal immunosuppressant agent, derived from Streptomyces tsukubaensis. The immunosuppressive action results from inhibition of T-cell activation by: (1) binding to an intracellular protein, FKBP-12; (2) Calcineurin Phosphatase activity which may result in inhibition of dephosphorylation and translocation of nuclear factor of

50

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

activated T-cells. Tacrolimus is approximately 100 times more potent than cyclosporine. • Use: Off Label Tacrolimus may be administered topically into the eye in a concentration of 0.1% to treat: –– Giant Papillary Conjunctivitis. –– Atopic Keratoconjunctivitis (AKC). –– Vernal Keratoconjunctivitis (VKC). • Dose: One drop twice a day for a duration that differs according to the severity and response of the case. • Preparation: –– Tacrolimus 100 μg/ml 0.01% in 10 ml Ingredients Tacrolimus capsule (Prograf; Astellas Pharma Inc., Tokyo, Japan) 1000 μg Balanced salt solution

Quantity 1 Capsule 10 ml

Procedure: • Under a laminar airflow workbench, aseptically add 10 ml of balanced salt solution to 1000 μg tacrolimus capsule (Prograf; Astellas Pharma Inc.) to achieve a concentration of 10 μg/ml. • Withdraw all the content of the above solution by a 0.22-μm filter needle. • Transfer the solution into a sterile ophthalmic dropper bottle. • Cap the dropper bottle and label. Expiration Date: 30 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.22  Tobramycin Ophthalmic Solution [84, 85, 104] • Description: Tobramycin is an aminoglycoside antibiotic obtained from cultures of Streptomyces Tenebrarius. The antimicrobial activity is exerted in the same way of Gentamicin by inhibiting microbial protein synthesis in susceptible pathogens. Tobramycin is physically incompatible with semisynthetic penicillin such

9.23  Vancomycin Hydrochloride Ophthalmic Solution

51

as ampicillin. For this reason, the combination should never be mixed together in the same syringe or bottle for ophthalmic use. It is recommended that concomitant use is separated by 15 min. • Use: Off Label Bacterial eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on type and severity of the disease. • Preparation: –– Tobramycin 15 mg/ml 1.5% in 10 ml Ingredients Quantity 3.75 ml Tobramycin sulfate injection 40 mg/ml (30 ml) Artificial tear solution QS to 10 ml

Procedure: • Under a laminar flow hood, aseptically withdraw 3.75 ml of Tobramycin Sulfate vial (40 mg/ml) using a 5-ml syringe. • Transfer the solution to a sterile, plastic, ophthalmic dropper bottle. • Uncap and remove the tip of the artificial tear solution bottle, withdraw the solution into a sterile syringe and needle and add it to a sterile plastic ophthalmic dropper bottle. • Replace the tip and cap of the ophthalmic dropper bottle, and gently shake to mix. • Seal and label the bottle. Expiration: 28 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

9.23  V  ancomycin Hydrochloride Ophthalmic Solution [38, 105–107] • Description: Vancomycin is a semisynthetic member of beta-lactamase resistant penicillins, a tricyclic glycopeptide antibiotic obtained from cultures of Amycolatopsis Orientalis (formerly Nocardia Orientalis). It is bactericidal inhibiting cell wall synthesis by binding to carboxyl units on peptide subunits containing free d-Ala-

52

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

nyl-d-alanine. Vancomycin is not active against Gram-negative bacteria, fungi, or yeast. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: –– First Formulation: Vancomycin Hydrochloride 50 mg/ml 5% in 10 ml Ingredients Quantity Vancomycin injection (dry powder) 500 mg Distilled water used for injection, USP 10 ml

Procedure: • Under laminar airflow workbench, aseptically reconstitute 500  mg of Vancomycin with 10 ml of distilled water used for injection (preservativefree) to obtain 10 ml of 50 mg/ml of Vancomycin. • Transfer the solution to an empty dropper bottle by a 0.22-μm filter needle. • Close bottle, shake to mix and label. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. –– Second Formulation: Vancomycin Hydrochloride 31 mg/ml 3.1% in 15 ml Ingredients Vancomycin injection (dry powder) Distilled water used for injection, USP Artificial tears

Quantity 500 mg 5 ml 10.4 ml

Procedure: • In a laminar airflow hood, reconstitute vancomycin 500 mg vial with 5 ml of distilled water used for injection (preservative-free) to yield a 100 mg/ ml solution. • Remove dropper from artificial tears bottle (15 ml bottle). Discard 4.6 ml of solution leaving 10.4 ml remaining. • Withdraw 4.6 ml from the reconstituted vancomycin vial into a syringe. • Attach a 0.22-μm filter to the syringe and transfer the vancomycin solution into the artificial tears bottle. • Replace dropper, shake well to mix, and label.

9.24  Voriconazole Ophthalmic Solution

53

Expiration Date: 7  days if in room temperature and 21  days if in refrigerator. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out reach of children. For ophthalmic use only. Keep in the refrigerator.

9.24  Voriconazole Ophthalmic Solution [108–118] • Description: Voriconazole is a second-generation Triazole anti-fungal agent and a synthetic derivative of Fluconazole with extended-spectrum antifungal activity. It presumably exerts its anti-fungal activity by inhibiting fungal cytochrome P450-­ dependent ergosterol synthesis (mediated via 14-alpha-sterol demethylation), resulting in a loss of ergosterol in the fungal cell wall. It is highly effective against Candida, Aspergillus, Fusarium, Paecilomyces, and Scedosporium species with a minimum inhibitory concentration required to inhibit the growth of 90% of strains of 0.015 mg/ml, 1 mg/ml, 2 mg/ml, 0.5 mg/ml, and 0.25 mg/ml, respectively. It is currently available only in oral and parenteral formulations. Oral Voriconazole can penetrate ocular tissue and demonstrate good efficacy in treating eye keratitis; however, it has been found that the treatment is often limited with the adverse drug reaction that is associated with oral Voriconazole plus the high cost, which leads to treatment discontinuation. Recent studies demonstrate the efficacy and safety of the off-label direct application of 1% and 2% Voriconazole on ocular tissue. • Use: Off Label Treatment of fungal eye infection and corneal ulceration due to susceptible organisms. • Dose: Frequency and duration depend on the type and severity of the disease. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– First Formulation: Voriconazole 10 mg/ml 1% in 10 ml

Ingredients Voriconazole injection (dry powder) Distilled water used for injection (preservative free)

Quantity 10 mg/ml (1%) 200 mg 18 ml

54

9  Formulations of Extemporaneous Topical Ophthalmic Preparations

–– Second Formulation: Voriconazole 2 mg/ml 2% in 10 ml Ingredients Voriconazole injection (dry powder) Distilled water used for injection (preservative free)

Quantity2 mg/ml (2%) 200 mg 9 ml

Procedure: • Under laminar airflow hood, aseptically reconstitute 200 mg of Voriconazole with 18 or 9 ml of water for injection (containing 0.01% of benzalkonium chloride solution) to obtain 20 ml of 1% (10 mg/ml) or 2% (20 mg/ml), respectively, of Voriconazole solution. • Transfer the solution to an empty dropper bottle by a 0.22-μm filter needle. • Close the bottle, shake to mix and label. Expiration Date: 30 days. Storage Conditions: Refrigerator or room temperature. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator or room temperature.

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33. McEvoy GK, editor. AHFS drug information 93. Bethesda, MD: American Society of Health-­ System Pharmacists; 1993. p. 126–34. 34. Hebron B, Scott H. Shelf life of cefuroxime eye‐drops when dispensed in artificial tear preparations. Int J Pharm Pract. 1993;2(3):163–7. 35. Barnes AR, Nash S. Preservative efficacy in cefuroxime and ceftazidime eye drop formulations. J Clin Pharm Ther. 1994;19(5):327–32. 36. Trissel L. Handbook on injectable drugs. 7th ed. Bethesda, MD: American Society of Hospital Pharmacists; 1992. p. 181–2. 37. McEvoy GK, editor. AHFS drug information 93. Bethesda, MD: American Society of Health-­ System Pharmacists; 1993. p. 139–48. 38. Reynolds LA, Closson RG.  Extemporaneous ophthalmic preparations. Am J Ophthalmol. 1994;117(2):277. 39. Fiscella RG, Le H, Lam TT, et  al. Stability of cyclosporine 1% in artificial tears. J Ocul Pharmacol Ther. 1996;12:1–4. 40. Elliott JF, Lin Y, Mizel SB. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984;226:1439–41. 41. Liu J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP–FK506 complexes. Cell. 1991;66:807–15. 42. Shii D, Fukushima A.  Therapeutic effects and mechanisms of action of cyclosporine A ophthalmic solution in the treatment of vernal keratoconjunctivitis. Curr Pharm Anal. 2007;3:213–20. 43. BenEzra D, Pe’er J, Brodsky M, et  al. Cyclosporine eyedrops for the treatment of severe vernal keratoconjunctivitis. Am J Ophthalmol. 1986;101:278–82. 44. Gupta V, Sahu PK. Topical cyclosporin A in the management of vernal keratoconjunctivitis. Eye. 2001;15:39–41. 45. Pucci N, Novembre E, Cianferoni A, et al. Efficacy and safety of cyclosporine eyedrops in vernal keratoconjunctivitis. Ann Allergy Asthma Immunol. 2002;89:293–303. 46. Cetinkaya A, Akova YA, Dursun D, et al. Topical cyclosporine in the management of shield ulcers. Cornea. 2004;23:194–200. 47. Spadavecchia L, Fanelli P, Tesse R, et al. Efficacy of 1.25% and 1% topical cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood. Pediatr Allergy Immunol. 2006;17:527–32. 48. Kilic A, Gurler B. Topical 2% cyclosporine A in preservative-free artificial tears for the treatment of vernal keratoconjunctivitis. Can J Ophthalmol. 2006;41:693–8. 49. Chast F, Lemare F, Legeais JM, Batista R, Bardin C, Renard G. Préparation d’un collyre de Cyclosporine à 2 %. J Fr Ophtalmol. 2004;27:567–76. 50. Baum JL.  Initial therapy of suspected microbial corneal ulcers. Board antibiotics therapy based on prevalence of organism. Surv Ophthalmol. 1979;24:97–105. 51. Trissel L. Handbook on injectable drugs. 7th ed. Bethesda, MD: American Society of Hospital Pharmacists; 1992. p. 253–4. 52. McEvoy GK, editor. AHFS drug information 93. Bethesda, MD: American Society of Health-­ System Pharmacists; 1993. p. 331–3. 53. Lim LM, Ly N, Anderson D, et  al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy: J Human Pharm and Drug Ther. 2010;30(12):1279–91. 54. Chatterjee S, Agrawal D.  Multi-drug resistant Pseudomonas aeruginosa keratitis and its effective treatment with topical colistimethate. Indian J Ophthalmol. 2016;64(2):153. 55. Ellis P. Ocular theraputics and pharmacology, vol. 153. 7th ed. St. Louis, MO: CV Mosby; 1985. p. 302–3. 56. Havener WH. Ocular pharmacology. 5th ed. St. Louis, MO: CV Mosby; 1983. p. 431. 57. Trissel L. Handbook on injectable drugs. 7th ed. Bethesda, MD: American Society of Hospital Pharmacists; 1992. p. 38–9. 58. Najjar DM, Cohen EJ, Rapuano CJ, Laibson PR. Edeta chelation for calcific band keratopathy: results and long-term follow up. Am J Ophthalmol. 2004;137(6):1056–64.

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59. Fuhrman LC, Godwin DA, Davis RA.  Stability of 5-fluorouracil in an extemporaneously compounded ophthalmic solution. Int J Pharm Compd. 2000;4:320–3. 60. Midena E, Angeli CD, Valenti M, de Belvis V, Boccato P. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84(3):268–72. 61. Gichuhi S, Macharia E, Kabiru J, et al. Topical fluorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial. Lancet Glob Health. 2016;4(6):e378–85. 62. Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-­fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol. 2011;95(3):355–9. 63. Joag MG, Sise A, Murillo JC, et al. Topical 5-fluorouracil 1% as primary treatment for ocular surface squamous neoplasia. Ophthalmology. 2016;123(7):1442–8. 64. Parrozzani R, Frizziero L, Trainiti S, et al. Topical 1% 5-fluorouracil as a sole treatment of corneoconjunctival ocular surface squamous neoplasia: long-term study. Br J Ophthalmol. 2017;101(8):1094–9. 65. Bahrami B, Greenwell T, Muecke JS.  Long-term outcomes after adjunctive topical 5-­flurouracil or mitomycin C for the treatment of surgically excised, localized ocular surface squamous neoplasia. Clin Experiment Ophthalmol. 2014;42(4):317–22. 66. Trissel LA, Allwood MC, Haas DP, Hale KN, American Society of Hospital Pharmacists. Handbook on injectable drugs, vol. 14. Bethesda, MD: American Society of Health-System Pharmacists; 2007. 67. Prabhasawat P, Chotikavanich S, Leelaporn A. Sterility of non-preservative eye drops. J Med Assoc Thai. 2005;88(Suppl 9):S6–10. 68. Schechter BA, Koreishi AF, Karp CL, et al. Long-term follow-up of conjunctival and corneal intraepithelial neoplasia treated with topical interferon alfa-2b. Ophthalmology. 2008;115(8):1291–6. 69. Ruiz L, Rodriguez I, Baez R, et al. Stability of an extemporaneously prepared recombinant human interferon alfa-2b eye drop formulation. Am J Health Syst Pharm. 2007;64(16):1716–9. 70. Department of Pharmacy. Extemporaneous compounding records: interferon alfa-2b (Intron-A) 1 million units/mL. Miami, FL: Bascom Palmer Eye Institute. Undated. Interferon alfa-2b BC Cancer Agency Cancer Drug Manual© Page 12 of 12 Interferon alfa-2b Developed: 1994. Revised: 1 June 2015. 71. The United States Pharmacopeia (USP). General chapter 797: pharmaceutical compounding - sterile preparations. USP 27-NF 22. Rockville, MD: The United States Pharmacopeia Convention, Inc.; 2004. 72. Parmar S, Platanias LC.  Interferons: mechanisms of action and clinical applications. Curr Opin Oncol. 2003;15(6):431–9. 73. Gonzalez-Navajas JM, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012;12(2):125–35. 74. Bracarda S, Eggermont AM, Samuelsson J. Redefining the role of interferon in the treatment of malignant diseases. Eur J Cancer. 2010;46(2):284–97. 75. Maskin SL.  Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol. 1994;112(9):1145–6. 76. Karp CL, Galor A, Chhabra S, Barnes SD, Alfonso EC.  Subconjunctival/perilesional recombinant interferon alpha2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology. 2010;117(12):2241–6. 77. Galor A, Karp CL, Chhabra S, Barnes S, Alfonso EC.  Topical interferon alpha 2b eye-­ drops for treatment of ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol. 2010;94(5):551–4. 78. Kaliki S, Singh S, Iram S, Tripuraneni D. Recombinant interferon alpha 2b for ocular surface squamous neoplasia: an efficient and cost-effective treatment modality in Asian Indian patients. Indian J Ophthalmol. 2016;64(10):702–9. 79. Lee GA, Hess L, Glasson WJ, Whitehead K. Topical interferon alpha-2b induced reactive lymphoid hyperplasia masquerading as orbital extension of ocular surface squamous neoplasia. Cornea. 2018;37(6):796–8.

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80. Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea. 2013;32(3):248–56. 81. Reynolds LA.  Extemporaneous ophthalmic preparations. New  York, NY: Applied Therapeutics, Inc.; 1993. 82. Phillips K, Arffa R, Cintron C, Rose J, Miller D, Kublin CL, Kenyon KR. Effects of prednisolone and medroxyprogesterone on corneal wound healing, ulceration, and neovascularization. Arch Ophthalmol. 1983;101(4):640–3. 83. Newsome NA, Gross J.  Prevention by medroxyprogesterone of perforation in the alkali-­ burned rabbit cornea: inhibition of collagenolytic activity. Invest Ophthalmol Vis Sci. 1977;16(1):21–31. 84. Trissel L. Handbook on injectable drugs. 7th ed. Bethesda, MD: American Society of Hospital Pharmacists; 1992. p. 625–6. 85. McEvoy GK, editor. AHFS drug information 93. Bethesda, MD: American Society of Health-­ System Pharmacists; 1992. p. 628–30. 86. Singh P, Singh A. Mitomycin-C use in ophthalmology. IOSR J Pharm. 2013;3:12–4. 87. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology. 2007;114(5):976–82. 88. Chen C, Louis D, Dodd T, Muecke J. Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2004;88(1):17–8. 89. Rahimi F, Ali PF, Ghazizadeh HH, Saleh SB, Hashemian M, Mehrdad R. Topical mitomycin-­C for treatment of partially-excised ocular surface squamous neoplasia. Arch Iran Med. 2009;12(1):55. 90. Gupta A, Muecke J. Treatment of ocular surface squamous neoplasia with Mitomycin C. Br J Ophthalmol. 2010;94(5):555–8. 91. Russell HC, Chadha V, Lockington D, Kemp EG. Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications. Br J Ophthalmol. 2010;94(10):1316–21. 92. Birkholz ES, Goins KM, Sutphin JE, Kitzmann AS, Wagoner MD.  Treatment of ocular surface squamous cell intraepithelial neoplasia with and without mitomycin C.  Cornea. 2011;30(1):37–41. 93. Besley J, Pappalardo J, Lee GA, Hirst LW, Vincent SJ. Risk factors for ocular surface squamous neoplasia recurrence after treatment with topical mitomycin C and interferon alpha-2b. Am J Ophthalmol. 2014;157(2):287–93. 94. Kalamkar C, Radke N, Mukherjee A, Radke S. Topical mitomycin-C chemotherapy in ocular surface squamous neoplasia. J Clin Diagn Res. 2016;10(9):NJ01. 95. Singh S, Mittal R, Rath S.  Multifocal ocular surface squamous neoplasia. Ophthal Plast Reconstr Surg. 2017;33(6):e156–7. 96. Wilson MW, Hungerford JL, George SM, Madreperla SA.  Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol. 1997;124(3):303–11. 97. Frucht-Pery J, Sugar J, Baum J, Sutphin JE, Pe’er J, Savir H, et al. Mitomycin C treatment for conjunctival—corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology. 1997;104(12):2085–93. 98. Al Habash A, Al Jasim LA, Owaidhah O, Edward DP. A review of the efficacy of mitomycin C in glaucoma filtration surgery. Clin Ophthalmol. 2015;9:1945–51. 99. Gambato C, Ghirlando A, Moretto E, Busato F, Midena E. Mitomycin C modulation of corneal wound healing after photorefractive keratectomy in highly myopic eyes. Ophthalmology. 2005;112(2):208–18. 100. Hashemi H, Taheri SMR, Fotouhi A, Kheiltash A.  Evaluation of the prophylactic use of mitomycin-C to inhibit haze formation after photorefractive keratectomy in high myopia: a prospective clinical study. BMC Ophthalmol. 2004;4:12.

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101. Valiev АH, Zdoryk OА, Khokhlova KO, Georgiyants VA.  Chemical stability study of the benzylpenicillin eye drops compounding preparation by thin layer chromatography. IJAPBC. 2014;3(4):827. 102. Shoughy SS, Jaroudi MO, Tabbara KF. Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Clin Ophthalmol. 2016;10:643. 103. Al-Amri AM, Mirza AG, Al-Hakami AM. Tacrolimus ointment for treatment of vernal keratoconjunctivitis. Mid E Afr J Ophthalmol. 2016;23(1):135. 104. Charlton JF, Dalla KP, Kniska A. Storage of extemporaneously prepared ophthalmic antimicrobial solutions. Am J Health Syst Pharm. 1998;55(5):463–6. 105. Fleischer AB, Hoover DL, Khan JA, et al. Topical vancomycin formulation for methicillin-­ resistant Staphylococcus epidermidis blepharoconjunctivitis. Am J Ophthalmol. 1986;101:283–7. 106. Fuhrman LC, Stroman RT.  Stability of vancomycin in an extemporaneously compounded ophthalmic solution. Am J Health Syst Pharm. 1998;55(Jul):1386–8. 107. Osborn E, Baum JL, Ernst C, et al. Stability of ten antibiotics in artificial tear solutions. Am J Ophthalmol. 1976;82:775–80. 108. Dupuis A, Tournier N, Le Moal G, Venisse N. Preparation and stability of voriconazole eye drop solution. Antimicrob Agents Chemother. 2009;53(2):798–9. 109. Lau D, Fedinands M, Leung L, Fullinfaw R, Kong D, Davies G, Daniell M. Penetration of voriconazole, 1%, eyedrops into human aque-ous humor: a prospective open-label study. Arch Ophthalmol. 2008;126:343–346.9. 110. Mehta H, Mehta HB, Garg P, Kodial H.  Voriconazole for the treatment of refractory Aspergillus fumigatus keratitis. Indian J Ophthalmol. 2008;56(3):243. 111. FDA. Product Information: VFEND(R) oral tablets, oral suspension, intravenous injection, voriconazole oral tablets, oral suspension, intravenous injection. New York, NY: Roerig (per FDA); 2017. 112. Espinel-Ingroff A. In vitro activity of the new triazole voriconazole (UK-109,496) against opportunistic filamentous and dimorphic fungi and common and emerging yeast pathogens. J Clin Microbiol. 1998;36(1):198–202. 113. Fischbarg J. Mechanism of fluid transport across corneal endothelium and other epithelial layers: a possible explanation based on cyclic cell volume regulatory changes. Br J Ophthalmol. 1997;81(1):85–9. 114. Clancy CJ, Nguyen MH. In vitro efficacy and fungicidal activity of voriconazole againstAspergillus andFusarium species. Eur J Clin Microbiol Infect Dis. 1998;17(8):573–5. 115. Al-Badriyeh D, Li J, Stewart K, Kong DC, Leung L, Davies GE, Fullinfaw R. Stability of extemporaneously prepared voriconazole ophthalmic solution. Am J Health Syst Pharm. 2009;66(16):1478–83. 116. Hariprasad SM, Mieler WF, Holz ER, Gao H, Kim JE, Chi J, Prince RA. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol. 2004;122(1):42–7. 117. Ullmann AJ. Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole. Curr Med Res Opin. 2003;19(4):263–71. 118. Sponsel W, Chen N, Dang D, Paris G, Graybill J, Najvar LK, et al. Topical voriconazole as a novel treatment for fungal keratitis. Antimicrob Agents Chemother. 2006;50(1):262–8.

Part III

Extemporaneous Intraocular Injections

Intraocular injections include intravitreal injections into the vitreous cavity and intracameral injections into the anterior chamber of the eye.

Chapter 10

Intravitreal Injections

Intravitreal injections are currently considered as one of the most important procedures to treat various posterior segment diseases [1–7]. • Common diseases treated by intravitreal injections –– –– –– –– –– –– ––

Neovascular age-related macular degeneration (AMD). Proliferative diabetic retinopathy (PDR). Retinal vein occlusions. Endophthalmitis. Uveitis. Cystoid macular edema (CME). Choroidal neovascular membrane (CNV) secondary to some retinal diseases.

• Contraindications Active external eye infection, such as conjunctivitis and blepharitis. Blepharitis has been reported as a significant predisposing risk factor for endophthalmitis after intravitreal injection. • Equipment Equipment for intravitreal injection is as follows: –– –– –– –– –– –– –– –– ––

Povidone-iodine 5%. Speculum. Scleral marker (calibers). Tuberculin syringe. 30- or 32-gauge needle (27-gauge for triamcinolone). Cotton swab. Sterile powder-free gloves. Sterile drape. Mask.

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• Anesthesia Commonly used methods for local anesthesia include the following: –– Topical anesthetic drops. –– Application of cotton swabs soaked in Tetracaine or Lidocaine. –– Lidocaine 2% gel. • Steps for intravitreal injections The procedure should be carried out in a cleanroom: –– –– –– –– –– –– –– –– –– –– –– –– –– –– –– –– –– ––

The patient should be lying supine on a comfortable bed. Make sure the headrest of the chair is stable. Review the informed consent and confirm the correct eye. Proceed with the surgical time out. Instill anesthetic (e.g. Proparacaine) eye drops and then wait for 15 s. Apply Povidone-iodine 5% to the conjunctival sac, eyelids, and lashes, and ask the patient to blink several times. Wait for 30–120  s. This is the most important step in reducing the risk of endophthalmitis. Wear the sterile powder-free gloves. Apply eyelid speculum. Instill another drop of Povidone-iodine 5% on the site of injection. Mark the inferotemporal area using the caliber at 3.5 mm from the limbus in pseudophakic eyes and 4.0 mm from the limbus in phakic eyes. The patient should be asked to look opposite to the site of injection and instructed not to talk or move to avoid injury to the retina. Insert the short 30-g needle about 1/2 the length into- and towards the center of the globe to be sure that you reached the vitreous cavity rather than the sub-­ retinal space. Gently inject the recommended amount of medication inside the vitreous cavity. Apply a sterile cotton-tip applicator on the injection site for a few seconds after removal of the needle. Remove the eye speculum and irrigate the eye from the remaining Povidone-­ iodine solution to reduce irritation. Check the vision to be sure that the patient has at least light perception to exclude central retinal artery occlusion. Postoperatively, a topical antibiotic is optional. Instruct the patient that floaters are normal while severe ocular pain or Loss of vision requires immediate assessment by an ophthalmologist.

• Prophylactic topical antibiotic There is no strong evidence indicating that preoperative topical antibiotics will lower the risk of endophthalmitis. • Surgical face mask Using a surgical face mask and avoiding talking during intravitreal injection are recommended for the physician, nurses, and the patient.

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• Side effects Transient elevation of intraocular pressure. • Endophthalmitis The rate of endophthalmitis after intravitreal injection is very low (0.06%).

References 1. Lyall DAM, Tey A, Foot B, Roxburgh STD, Virdi M, Robertson C, MacEwen CJ.  Post-­ intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye. 2012;26(12):1517. 2. http://eyewiki.aao.org/Intravitreal_Injections. 3. Yin VT, Weisbrod DJ, Eng KT, Schwartz C, Kohly R, Mandelcorn E, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthal. 2013;131(4):456–61. 4. d’Azy CB, Pereira B, Naughton G, Chiambaretta F, Dutheil F. Antibioprophylaxis in prevention of endophthalmitis in intravitreal injection: a systematic review and meta-analysis. PLoS One. 2016;11(6):e0156431. 5. Mccannel CA.  Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654–61. 6. Gismondi M, Salati C, Salvetat ML, Zeppieri M, Brusini P. Short-term effect of intravitreal injection of Ranibizumab (Lucentis) on intraocular pressure. J Glaucoma. 2009;18(9):658–61. 7. Meredith TA, McCannel CA, Barr C, Doft BH, Peskin E, Maguire MG, et  al. Post injection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2015;122(4):817–21.

Chapter 11

Intracameral Injections

Intracameral injections have very limited indications. They are mainly used at the end of cataract surgery as a prophylactic measure of postoperative endophthalmitis [1]. • Equipments Equipments used for intracameral injection are as follows: –– –– –– –– ––

Povidone-iodine 5%. Speculum. 30- or 32-gauge cannula. Cotton swab. Super sharp blade.

• Steps for intracameral injections The following steps describe the procedure of intracameral injection when indicated apart from cataract surgery: –– –– –– –– –– –– –– –– –– –– –– ––

The procedure should be carried out in a cleanroom. The patient should be lying supine on a comfortable bed. Make sure the headrest of the bed is stable. Review the informed consent and confirm the correct eye. Proceed with the surgical time out. Instill anesthetic (e.g. Proparacaine) eye drops and then wait for 15 s. Apply Povidone-iodine 5% to the conjunctival sac, eyelids, and lashes, and ask the patient to blink several times. Wait for 30–120  s. This is the most important step in reducing the risk of endophthalmitis. Wear the sterile powder-free gloves. Apply eyelid speculum. Instill another drop of Povidone-iodine 5% on the site of injection. The patient should be instructed not to talk or move during the procedure. Using a super sharp blade, make a beveled paracentesis close to the Limbus in any convenient location in the upper part of the cornea.

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–– Using a 30-g cannula, aspirate 0.1–0.2 ml of aqueous humor. –– Inject the recommended amount of the desired intracameral medication using another 30-g cannula. –– Apply patch on the closed lid for 1 h. • Complications Potential concerns following intracameral injection of any drug: –– Corneal endothelial toxicity. –– Toxic anterior segment syndrome (TASS). –– Dilution errors which can lead to both anterior and posterior segment inflammation.

Reference 1. Braga-Mele R, Chang DF, Henderson BA, Mamalis N, Talley-Rostov A, Vasavada A, ASCRS Clinical Cataract Committee. Intracameral antibiotics: safety, efficacy, and preparation. J Cataract Refract Surg. 2014;40(12):2134–42.

Chapter 12

Formulations of Extemporaneous Intraocular Injections

In the following, the most common 15 formulations are presented and discussed following a systematic methodology starting with the composition and drug family, followed by use, dose, and preparation. The preparation is discussed in detail in terms of concentration(s), procedure, expiration date, storage, packaging, and special precautions. Some formulations are hazardous; therefore, special caution is highlighted so that the medication must be prepared in compliance with the United States Pharmacopeia (USP) . N.B.: Off-Label means “unapproved indication, age group, dose, or form of administration.”

12.1  Amikacin Sulfate Intravitreal Injection [1] • Description: Amikacin is an aminoglycoside antibiotic obtained from kanamycin, showing broad action spectrum and strong resistance against the enzymes inactivating the other aminoglycoside antibiotics. It is commercially available as sulfate salt in an injection dosage form. Its mechanism of action is by inhibiting protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to gram-­negative bacteria resistant to Gentamicin and Tobramycin. • Preparation: –– Amikacin 400 mcg/0.1 ml (0.3 ml) Ingredients Amikacin 100 mg/2 ml vial Sodium chloride 0.9% (preservative-free)

Quantity 1 ml 11.5 ml

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Procedure: • Under a laminar airflow workbench, aseptically withdraw 1 ml (50 mg) of Amikacin sulfate vial and inject it into a 30-ml sterile empty vial. • Withdraw 11.5 ml of sodium chloride 0.9% and add it to the sterile vial to constitute a concentration of 400 mcg/0.1 ml (final volume 12.5 ml). • Withdraw 0.3 ml into a sterile Luer-Lock® tuberculin syringe. • Cap with a tamper-resistant sterile. • Label the syringe. Expiration Date: 60 days. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe. Special Instructions: For intravitreal injection use only. Keep in the refrigerator.

12.2  Amphotericin B Intravitreal Injection [2–6] • Description: Amphotericin B injection is typically a complex of amphotericin B and deoxycholate with suitable buffers that form a colloidal dispersion when reconstituted. It is an anti-fungal drug and is indicated to treat systemic and local fungal infections, such as Aspergillus, Candida, Cryptococcus, Fusarium, and Curvularia, which can lead to serious ulceration to the cornea and must be treated immediately. The intravitreal injection is prepared at a concentration of 5 mcg/0.1 ml. Ocular administration of the conventional Amphotericin B intravitreal injection may cause pain and irritation due to the Deoxycholate components. This side effect is minimized when lipid formulation such as AmBisome® is used in the preparation. • N.B.: –– Amphotericin B is incompatible with sodium chloride-containing solutions. –– Amphotericin is a colloidal dispersion and should not be filtered. –– Amphotericin B liposomal should not be filtered through a filter with a porosity of less than 1 μm. • Use: Off Label Treatment of ocular fungal infections caused by susceptible organisms. • Preparation: –– First Formulation: Amphotericin B 5 mcg/0.1ml (0.3 ml) Ingredients Amphotericin B (colloidal) 50 mg for injection Distilled water used for injection (preservative-free)

Quantity 1 vial 19.9 ml

12.2 Amphotericin B Intravitreal Injection

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Procedure: • Under a laminar airflow workbench, aseptically withdraw 10  ml of distilled water used for injection (preservative-free) into a sterile syringe. • Add the contents of the syringe to Amphotericin B vial, and shake gently to mix. The vial may need to sit for a few minutes to allow the dissolution of lyophilized amphotericin B. This is vial A and contains amphotericin B 5 mg/ml. • From vial A, withdraw 0.1 ml (500 μg) and transfer to another empty sterile vial labeled vial B. • Add 9.9 ml of distilled water used for injection (preservative-free) to vial B and shake gently to mix. This contains amphotericin B 50 μg/ml. • Add a dispensing pin to vial B. • Withdraw 0.3 ml (5 mcg/0.1 ml dose plus 0.2 overfill) into a sterile Luer-­ Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap. • Label each syringe and place it in an amber bag. Expiration Date: 24 h. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap, placed in an amber bag. Special Instructions: For intravitreal injection only. Keep in the refrigerator. Protect from light. –– Second Formulation: Liposomal Amphotericin B 10 mcg/0.1 ml (0.3 ml) N.B.: This preparation can be given Intravitreal and Intracameral. Ingredients Quantity Liposomal Amphotericin B 50 mg for injection 1 vial Balanced salt solution (BSS; Alcon, Fort Worth, TX) 15 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 5 ml of balanced salt solution (BSS; Alcon, Fort Worth, TX) into a sterile syringe. • Add contents of syringe to Amphotericin B vial, and shake gently to mix. The vial may need to sit for a few minutes to allow dissolution of lyophilized Amphotericin B. This is vial A and contains amphotericin B 10 mg/ml. • From vial A, withdraw 0.1  ml (1000 μg) and transfer to another empty sterile vial labeled vial B. • Add 9.9 ml of BSS to vial B and shake gently to mix. This contains amphotericin B 100 μg/ml. • Withdraw 0.3 ml into a sterile Luer-Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap. • Label each syringe and place it in an amber bag.

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Expiration Date: 24 h. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap, placed in an amber bag. Special Instructions: For intravitreal or Intracameral injection only. Keep in the refrigerator. Protect from light.

12.3  Bevacizumab Intravitreal Injection [7–12] • Description: Bevacizumab is a full length humanized monoclonal antibody that binds to human vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors on the surface of endothelial cells. It is approved for intravenous treatment of metastatic colorectal cancer, non-small cell lung cancer, metastatic renal cell cancer, and glioblastoma. However, it is very common to be used in the form of an intravitreal injection to treat conditions associated with retinal neovascularization or with macular edema. When used for ophthalmic injection, it is repackaged from large glass vial to multiple small plastic (singleuse) prefilled-syringes. Several studies have suggested that it is notably less costly than the FDA approved intravitreal Ranibizumab injection with a similar safety and efficacy profile. • Use: Off Label Treatment of proliferative (neovascular) eye diseases including several types of choroidal neovascularization, retinal neovascularization, macular edema, neovascular glaucoma, and radiation-induced eye diseases. • Preparation: –– Bevacizumab 0.3  ml containing 1.25 mg/0.05  ml = 2 mg/0.08  ml = 2.5 mg/0.1 ml Preparation including batch of 40 syringes Ingredients Quantity Bevacizumab for injection 100 mg/4 ml 1.25 mg/0.05 ml 2.5 mg/0.1 ml 2 mg/0.08 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 0.3  ml (1.25 mg/0.05ml = 2 mg/0.08 ml = 2.5 mg/0.1 ml dose plus over fill) from the Bevacizumab vial 100 mg/4 ml. • Withdraw a solution into a sterile Luer-Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap. • Label each syringe and place it in an amber bag.

12.4 Cefazolin Sodium Intravitreal Injection

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Expiration Date: 14 days. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal injection only. Keep in the refrigerator.

12.4  Cefazolin Sodium Intravitreal Injection [3, 13] • Description: Cefazolin as sodium salt is a bactericidal broad-spectrum antibacterial. It is classified as a first-generation cephalosporin. It acts by inhibiting the synthesis of the bacterial cell wall. • Use: Off Label Bacterial eye infection and corneal ulceration due to susceptible organisms. –– Cefazolin Sodium 2.25 mg/0.1 ml (0.3 ml) Ingredients Cefazolin Sodium injection powder 500 mg Distilled water used for injection (preservative-free)

Quantity 500 mg 12 ml

Procedure: • Under a laminar airflow workbench, aseptically add 2 ml of distilled water used for injection (preservative-free) to Cefazolin 500 mg vial, and shake to mix. This is Cefazolin vial A. • Withdraw 1 ml from vial A, and transfer to a 10-ml sterile empty vial. This is vial B. • Add 9 ml of distilled water used for injection (preservative-free) to vial B, shake to mix. • From vial B, withdraw 0.3 ml (2.25 mg/0.1 ml, dose plus 0.2 ml overfill) into Luer-Lock® tuberculin syringe by a 0.22-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal and label the vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal injection only. Keep in the refrigerator.

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12.5  Ceftazidime Intravitreal Injection [3, 13, 14] • Description: Ceftazidime has a bactericidal action and a broad spectrum of activity. It is a semisynthetic, third-generation cephalosporin antibiotic, which is highly resistant to beta-lactamase and possesses a broad spectrum of anti-microbial activity, including gram-negative bacteria, particularly Pseudomonas Aeruginosa. The bactericidal effect results from inhibiting mucopeptide synthesis in the bacterial cell wall like other cephalosporin. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organism. • Preparation: –– Ceftazidime 2 mg/0.1 ml (0.3 ml) Ingredients Ceftazidime injection powder Water for injection(preservative free) 0.9% Sodium chloride(preservative free)

Quantity 1000 mg 9.4 ml 8 ml

Procedure: • Under a laminar airflow workbench, aseptically add 9.4 ml of water for injection to 1 g Ceftazidime preservative-free vial, and shake to mix. This is Ceftazidime Vial A of 100 mg/ml concentration. • Withdraw 2 ml from Vial A, and transfer to a 10-ml sterile empty vial. This is Vial B. • Add 8 ml of sodium chloride 0.9 % to Vial B, and shake to mix. The concentration in Vial B becomes 20 mg/ml. • From Vial B, withdraw 0.3 ml (2 mg/0.1 ml dose plus 0.2 ml overfill) into a syringe by a 0.22-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal and label the vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal injection only. Keep in the refrigerator.

12.6 Cefuroxime Intracameral Injection

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12.6  Cefuroxime Intracameral Injection [15] Use only if commercially unavailable • Description: Cefuroxime as sodium salt is bactericidal, second-generation cephalosporin antimicrobial. The antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall. • Use: Off Label –– Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. –– Prophylaxis of postoperative endophthalmitis after cataract surgery. • Preparation: –– Cefuroxime 1 mg/0.1 ml (0.3ml) Ingredients Cefuroxime injection powder 250 mg 0.9% Sodium chloride(preservative free)

Quantity 1 vial 13.5 ml

Procedure: • Under a laminar airflow workbench, aseptically dissolve the 250-mg vial of Cefuroxime with 12.5 ml of normal saline (preservative-free), and shake to mix. This is Cefuroxime vial A with 20 mg/ml concentration. • Withdraw 1 ml (20 mg) from vial A, and transfer to a 10-ml sterile empty vial. This is vial B. • Add 1 ml of normal saline to vial B to constitute a concentration of 10 mg/ ml and shake to mix. • From vial B, withdraw 0.3 ml (1 mg/0.1 ml dose plus 0.2 ml overfill) into a syringe by a 0.22-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a syringe with a sterile tamper-evident cap. • Seal and label the syringe. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intracameral injection only. Keep in the refrigerator.

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12  Formulations of Extemporaneous Intraocular Injections

12.7  Cidofovir Intravitreal Solution [16] • Description: Cidofovir is the first nucleotide analogue clinically approved as an antiviral agent. It is a synthetic acyclic purine nucleotide (phosphorylated nucleoside) analogue of cytosine. The mechanism of action is likely by inhibiting the replication of the virus by competitive inhibition of viral DNA polymerase. The intravenous route of administration is approved for use in the treatment of CMV retinitis, given in a dose of 5 mg/kg by intravenous infusion over 1 h once a week for 2 consecutive weeks, and then once every 2 weeks for maintenance. • Use: Off Label Maintenance treatment of cytomegalovirus Retinitis. • Preparation: Caution: Hazardous medication. Must be prepared in compliance with USP . –– First Formulation: Cidofovir 0.2 mg/ml (50 ml) Ingredients Cidofovir 75 mg/ml injection (5 ml) Sodium chloride 0.9% (preservative free)

Quantity 0.13 ml QS: 50 ml

–– Second Formulation: Cidofovir 8.1 mg/ml (50 ml) Ingredients Cidofovir 75 mg/ml injection (5ml) Sodium chloride 0.9% (preservative free)

Quantity 5.4 ml QS: 50 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw the required volume from a Cidofovir vial (as mentioned in the table) using a suitable syringe. • Withdraw the required volume of sodium chloride to make up 50 ml using a 60-ml syringe. • Add the Cidofovir solution to the syringe containing sodium chloride. • Cap the 60-ml syringe and mix well. • Transfer the solution to an empty Viaflex container by a 0.22-μm filter needle. • Seal and label. Expiration Date: 5 days. Storage Conditions: Refrigerator. Packaging: Polyvinyl chloride or ethylene and propylene bags.

12.8 Clindamycin Intravitreal Injection

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Special Instructions: For intravitreal use only. Keep in the refrigerator.

12.8  Clindamycin Intravitreal Injection [17–20] • Description: Clindamycin is a semisynthetic bactericidal antibiotic agent. The mechanism of action is by inhibiting protein synthesis in susceptible bacteria. It has been noted that the ophthalmic route of administration has favorable outcomes and tolerance in preventing acute bacterial endophthalmitis. It is more likely used in patients who are allergic to penicillin or in whom the use of cephalosporin is unwise. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organism. –– Clindamycin 1 mg/0.1 ml (0.3 ml) Ingredients Clindamycin injection 600 mg/2 ml Distilled water used for injection(preservative free)

Quantity 0.5 ml 14 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 0.5 ml from a Clindamycin vial and transfer it to a larger sterile empty vial. This is Clindamycin vial A. • Add 14.5  ml of distilled water used for injection (preservative-free) to Clindamycin vial A. Vial A now contains a concentration of 10 mg/ml of Clindamycin. • From vial A, withdraw 0.3 ml (1 mg/0.1 ml plus 0.2 overfill) into a sterile syringe by a 0.22-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal and label. Expiration Date: 24 h. Storage Conditions: Room temperature. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal Injection only. Keep in room temperature.

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12.9  Dexamethasone Phosphate Intravitreal Injection [21] • Description: Dexamethasone is a corticosteroid with mainly glucocorticoid activity. It is available in many forms of strength and dosage. Apart from the commercially available topical eye drops, reported ophthalmic routes of administration are intravitreal and subconjunctival injections in the treatment of the ocular inflammatory conditions. • Use: Off Label Treatment of ocular inflammatory conditions. • Preparation: –– Dexamethasone phosphate 400 mcg/0.1 ml (0.3 ml) Ingredients Dexamethasone phosphate 4 mg/1 ml

Quantity 0.3 ml

Procedure: • Under laminar airflow, aseptically withdraw 0.3ml (400 mcg/0.1 ml dose plus 0.2 ml overfill) from a dexamethasone phosphate vial, into a syringe by a 0.22-μm filter needle. • Replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal the 2-ml vial and label. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal injection only. Keep in the refrigerator.

12.10  Foscarnet Intravitreal Injection [22–24] • Description: Foscarnet is a pyrophosphate analogue, antiviral (Virostatic) agent. It acts as a non-competitive inhibitor of many viral RNA and DNA polymerase as well as HIV reverse transcriptase, and does not require activation by thymidine kinase. Foscarnet is commercially available as an intravenous injection bottle (250– 500 ml) with pH = 7.4. However, it can be administered directly into the eye for patients who can not tolerate the systemic administration of Ganciclovir, to treat Cytomegalovirus retinitis in AIDS or immunocompromised patients.

12.11 Ganciclovir Intravitreal Injection

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• Use: Off Label Treatment of cytomegalovirus (CMV) retinitis resistant to ganciclovir. It can be administered systemically to treat CMV retinitis as well as CMV infections at other sites. • Dose: –– Induction: 2.4 mg twice weekly for 3 weeks. –– Maintenance: 2.4 mg once weekly. • Preparation: –– Foscarnet 2.4 mg/0.1 ml (0.3 ml) Ingredients Foscarnet 24 mg/ml (250 ml) vial. (Foscavir®)

Quantity 2.4 mg/0.1 ml

Procedure: • Under laminar airflow, aseptically withdraw 0.3ml (2.4 mg/0.1  ml dose plus 0.2 ml overfill) from the Foscarnet 24 mg/ml vial into a syringe by a filtered 0.22 -μm filter needle. • Replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal the 2-ml vial and label. Expiration Date: 24 h. Storage Conditions: Refrigerator or room temperature. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Cytotoxic precaution (special handling and disposal required). For intravitreal injection only. Keep in the refrigerator or room temperature.

12.11  Ganciclovir Intravitreal Injection [22, 25, 26] • Description: Ganciclovir is an antiviral agent, a synthetic purine nucleoside analogue of guanine. Ganciclovir differs from Acyclovir only by the addition of a second-­ terminal hydroxymethyl group at C2 of the acyclic side chain on the ribose ring. This structural difference increases the antiviral activity against cytomegalovirus (CMV) and reduces the selectivity for viral DNA. Ganciclovir is available for oral and parenteral use (oral as a base and parenteral as a monosodium salt). However, it is well reported to be used intravitreal

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12  Formulations of Extemporaneous Intraocular Injections

in different concentrations 1 mg/0.1 ml, 2 mg/0.1 ml, and 5 mg/0.1 ml based on the level of infection severity and viral resistant. • Use: Off Label Maintenance regimen in the treatment of CMV retinitis. It can be administered systemically to treat CMV retinitis as well as CMV infections at other sites. • Dose: –– Induction: 2 mg twice weekly for 3 weeks. –– Maintenance: 2 mg weekly. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– First Formulation: Ganciclovir 1 mg/0.02 ml (0.02 ml) Ingredients Ganciclovir Injection 500 mg Powder vial Distilled water used for injection (preservative-free)

Quantity 500 mg 10 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the Ganciclovir vial and the distilled water used for injection (preservative-free) to prevent contamination of the laminar flow hood. • Aseptically reconstitute 500  mg of Ganciclovir with 10  ml of distilled water used for injection (preservative-free) to obtain 50 mg/ml Ganciclovir solution. • From the Ganciclovir vial, withdraw 0.1  ml (1 mg/0.02  ml dose plus 0.08 ml overfill) into a tuberculin syringe by a 0.22-μm filter needle. • Cap the tuberculin syringe and label with chemotherapy handling and disposal precautions. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Cytotoxic precaution (special handling and disposal required). For intravitreal use only. Keep in the refrigerator. –– Second Formulation: Ganciclovir 2 mg/0.1 ml (0.3 ml) Ingredients Ganciclovir Injection 500 mg Powder vial Sodium chloride 0.9%(preservative free)

Quantity 500 mg 12.4 ml

12.11 Ganciclovir Intravitreal Injection

81

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the Ganciclovir vial and sodium chloride 0.9% for injection to prevent contamination of the laminar flow hood. • Aseptically reconstitute 500  mg of Ganciclovir with 2.5  ml of sodium chloride 0.9% used for injection to obtain 200 mg/ml Ganciclovir solution. This is Vial A. • From Vial A, withdraw 0.1  ml solution and transfer to a 10-ml sterile empty vial. This new vial is Ganciclovir Vial B. • To Vial B, add 9.9 ml of sodium chloride 0.9 % used for injection USP (preservative-free), and shake to mix. The resulting concentration in Ganciclovir Vial B is 2 mg/ml. • From Ganciclovir Vial B, withdraw 0.3  ml (200 mcg/0.1  ml dose plus 0.2 ml overfill) to a tuberculin syringe by a 0.22-μm filter needle • Cap the tuberculin syringe and label with chemotherapy handling and disposal precautions. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Cytotoxic precaution (special handling and disposal required). For intravitreal use only. Keep in the refrigerator. –– Third Formulation: Ganciclovir 5 mg/0.1 ml (0.3 ml) Ingredients Quantity Ganciclovir Injection 500 mg vial 500 mg Balanced Salt Solution (BSS) 10 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the Ganciclovir vial and sodium chloride 0.9% used for injection to prevent contamination of the laminar flow hood. • Aseptically reconstitute 500  mg of Ganciclovir with 10  ml of Balanced Salt Solution (BSS) to obtain 50 mg/ml Ganciclovir solution. • From Ganciclovir vial, withdraw 0.1  ml (5 mg/0.1  ml dose plus 0.2  ml overfill) into a tuberculin syringe by a 0.22-μm filter needle. • Cap the tuberculin syringe and label with chemotherapy handling and disposal precautions. Expiration Date: 3 weeks.

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12  Formulations of Extemporaneous Intraocular Injections

Storage Conditions: Store in freezer at −8 °C. Special Instructions: Cytotoxic precaution (special handling and disposal required). For intravitreal use only. Keep in the freezer at −8 °C.

12.12  Penicillin G Potassium Intravitreal Injection [27–29] • Description: Penicillin G is a Beta-Lactam antibacterial that has a bactericidal action against Gram-positive bacteria, Gram-negative cocci, some other Gram-negative bacteria, Spirochetes, and Actinomyces. It is produced naturally by fermentation of Penicillium chrysogenum in a medium containing Phenylacetic acid. Penicillin G potassium is frequently referred to as an aqueous, crystalline form of penicillin G. The potency of Penicillin G potassium is expressed in terms of USP Penicillin G units rather than weight. Each 1 mg of Penicillin G potassium equals 1440– 1680 USP Penicillin G units and contains 80.8–94.3% Penicillin G. The bactericidal activity on growing and dividing bacteria is related to inhibiting bacterial cell-wall synthesis. However, the action is inhibited by penicillinase and other beta-lactamases that are produced during the growth of certain micro-organisms. • Use: Off Labe Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Preparation: –– Penicillin G Potassium 300 units/0.1 ml (0.3 ml) Ingredients Penicillin 1 Million unit (MU) vial for injection Distilled water used for injection(preservative free)

Quantity 1 vial 19.3 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 9.6 ml of distilled water used for injection (preservative-free) into a sterile syringe, and add to a vial of Penicillin G potassium 1 MU to prepare 100,000 units/ml concentration. • Shake the vial gently to mix. The vial may need to sit a few minutes to allow the dissolution of the penicillin powder. • Withdraw 0.3 ml (30,000 U) from the reconstituted Penicillin G potassium to a sterile syringe, and add to an empty sterile vial. • Withdraw 9.7  ml of distilled water used for injection (preservative-free) into a sterile syringe, add to the same vial, and shake well to mix.

12.13 Tissue Plasminogen Activator (TPA) Intracameral Injection

83

• Add a sterile dispensing pin to the same vial, withdraw 0.5 ml to a sterile Luer-Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap. • Label each syringe. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intravitreal use only. Keep in the refrigerator.

12.13  T  issue Plasminogen Activator (TPA) Intracameral Injection [30–35] • Description: Tissue Plasminogen Activator (TPA) has an important role in the regulation of fibrinolysis due to its chemical structure. The fibrinolytic activity is based on the conversion of plasminogen into plasmin, which promotes fibrin degradation. It is composed of serine protease that cleaves plasminogen to plasmin. TPA is secreted by the vascular endothelial cells as well as corneal epithelium and endothelium and the trabecular meshwork. To prevent fibrinous effusion, TPA has been used in the form of intraocular injection with different concentrations including 10 mcg/0.1 ml and 20 mcg/0.1 ml. In cataract surgery and IOL implantation, a dramatic drop in TPA activity is found during the first postoperative days. In addition, TPA concentration in the aqueous humor fluctuates after cataract surgery. If this is associated with additional risk factors that aggravate breakdown of the blood-aqueous barrier, there will be an increased risk of severe fibrinous membrane formation. • Use: Off Label –– Prevention of fibrinous effusion at least in the first 2 weeks after cataract extraction in both paediatric and adult age groups. –– Decreasing the incidence of pigmented IOL precipitates. • Dose: –– One intracameral injection at the end of the cataract surgery. • Preparation: –– First Formulation: Plasminogen Activator 10 mcg/0.1 ml (0.3 ml) Ingredients Tissue Plasminogen Activator 50 mg Distilled water used for injection (preservative-free) Subsequent dilution

Quantity 50 mg 50 ml

84

12  Formulations of Extemporaneous Intraocular Injections Ingredients Tissue plasminogen activator (1 mg/1ml) Sodium chloride 0.9%

Quantity 1 ml 9 ml

Procedure: • Under a laminar flow hood, aseptically reconstitute 50 mg of lyophilized TPA in 50 ml of the manufacturer’s diluent to get 1 mg/1 ml (100 mcg/0.1 ml). • Divide the reconstituted TPA by 1 ml syringes. • The syringes are then stored at −30  °C in an ultra-low freezing device. Before using, the syringes must be thawed to room temperature. • Subsequently dilute 1  ml of reconstituted TPA (1 mg/ml) with 9  ml of sodium chloride 0.9% to result in a final concentration of 10 mcg/0.1ml. • After preparation, divide it further into multiple aliquots of 0.3  ml (the dose is 0.1 m plus 0.2 ml overfill) of r-TPA in a tuberculin syringe. Each syringe is for one patient. Use within 24 h. Expiration Date: 24 h. Storage Conditions: Freezer at −30 °C. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For Intracameral Injection use only. Keep in the freezer at −30 °C. –– Second Formulation: Tissue Plasminogen Activator 20 mcg/0.1 ml (0.3 ml) Ingredients Lyophilized tissue plasminogen activator powder Distilled water used for injection (preservative-free) Balanced salt solution

Quantity 20 mg 10 ml 100 ml

Procedure: • Under a laminar flow hood, aseptically reconstitute 20 mg of lyophilized TPA in 10 ml of distilled water used for injection (preservative-free) to get 2 mg/1 ml (200 mcg/0.1 ml). • Dilute the reconstituted r-TPA 1:10  in sterile balanced salt solution to result in a final concentration of 20 mcg/ml. • After preparation, divide it further into multiple aliquots of 0.3  ml (the dose is 20 mcg/0.1 ml plus 0.2 ml overfill) of r-TPA in a tuberculin syringe. Each syringe is for one patient. Use within 24 h. • The syringes are then stored at −70  °C in an ultra-low freezing device. Before using, the syringes must be thawed to room temperature. Expiration Date: 1 year.

12.14 Vancomycin Intravitreal Injection

85

Storage Conditions: Freezer at −70 °C. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For intracameral injection use only. Keep in the freezer at −70 °C.

12.14  Vancomycin Intravitreal Injection [36, 37] • Description: Vancomycin is a semisynthetic member of beta-lactamase resistant penicillins, a tricyclic glycopeptide antibiotic obtained from cultures of Amycolatopsis orientalis (formerly Nocardia orientalis). It is a bactericidal antibiotic that inhibits cell wall synthesis by binding to carboxyl units on peptide subunits containing free d-Alanyl-d-alanine. Vancomycin is not active against the Gram-negative bacteria, fungi, or yeasts. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organism. • Preparation: –– Vancomycin 1 mg/0.1 ml (0.3 ml) Ingredients Vancomycin hydrochloride injection Distilled water used for injection (preservative-free) or Sodium chloride 0.9%

Quantity 500 mg 10 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 500  mg of Vancomycin hydrochloride with 10 ml of distilled water used for injection (preservative-free) or sodium chloride 0.9% to prepare a 50 mg/ml concentration. This is vial A. • Shake vial A gently to mix. Withdraw 0.2 ml (10 mg) from the vial A into a tuberculin syringe. Add the 0.2 ml to an empty sterile vial B. • To vial B, add 0.8 ml of sterile saline to constitute a concentration of 10 mg in 1.0 ml and hence 1000 μg (equals 1 mg/0.1 ml). • From vial B, withdraw 0.1 ml (1 mg/0.1 ml) dose plus 0.2 ml overfill into a tuberculin syringe by a 0.22-μm filter needle. • Label each syringe. Expiration Date: 24 h.

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12  Formulations of Extemporaneous Intraocular Injections

Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Keep out of reach of children. For intravitreal use only. Keep in the refrigerator.

12.15  Voriconazole Intracameral Injection [38, 39] • Description: Voriconazole is a second-generation Triazole antifungal agent and a synthetic derivative of Fluconazole with extended-spectrum antifungal activity. It presumably exerts its antifungal activity by inhibiting fungal cytochrome P450-­ dependent ergosterol synthesis (mediated via 14-alpha-sterol demethylation), resulting in a loss of ergosterol in the fungal cell wall. It is highly effective against Candida, Aspergillus, Fusarium, Paecilomyces, and Scedosporium species with a minimum inhibitory concentration required to inhibit the growth of 90% of strains of 0.015, 1, 2, 0.5, and 0.25 mg/ml, respectively. It is currently available only in oral and parenteral formulations. Oral Voriconazole can penetrate ocular tissue and demonstrate good efficacy in treating eye keratitis; however, the treatment is often limited by the adverse drug reaction that is associated with oral Voriconazole plus the high cost, which leads to treatment discontinuation. Recent studies demonstrate the efficacy and safety of the Off-Label direct application of 1% and 2% Voriconazole on ocular tissue. • Use: Off Label • Bacterial eye infection and corneal ulceration due to susceptible organisms. • Preparation: • Caution: Hazardous medication must be prepared in compliance with USP . –– Voriconazole 50 mcg/0.1 ml (0.3 ml) Ingredients Quantity Voriconazole injection 200 mg Lactated Ringer solution (LR) 19 ml

Procedure: • Under a laminar airflow workbench, aseptically reconstitute 200  mg of Voriconazole with 19 ml of Lactated Ringer solution (LR) to obtain 20 ml of 10 mg/ml (1%) Voriconazole solution. This is Voriconazole vial A with 10 mg/ml concentration. • Withdraw 1 ml from vial A and transfer to a sterile empty vial that has a volume of 20 ml. This is vial B

References

87

• Add 20 ml of LR solution to vial B and shake to mix. The concentration in vial B is 0.5 mg/ml. • From vial B, withdraw 0.3 ml (50 mcg/0.07 ml dose plus 0.23 ml overfill) into a syringe through a 0.22-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal and label the vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile syringe with sterile tamper-evident cap. Special Instructions: For Intracameral or Intrastromal use only, keep in the Refrigerator. Caution Reproductive Hazards.

References 1. Trissel LA. Trissel’s stability of compounded formulations. 4th ed. Washington DC: American Pharmacists Association; 2009. p. 26–7. 2. Cappelletty D, Eiselstein-McKitrick K.  The echinocandins. Pharmacotherapy. 2007;27(3):369–88. 3. Trissel LA, Trissel LA. Handbook on injectable drugs. Bethesda: American Society of Health-­ System Pharmacists; 2011. p. 613. 4. Bae JH, Lee SC. Intravitreal liposomal amphotericin B for treatment of endogenous candida endophthalmitis. Japan J Ophthalmol. 2015;59(5):346–52. 5. Brod RD, Flynn HW, Clarkson JG, Pflugfelder SC, Culbertson WW, Miller D. Endogenous Candida endophthalmitis: management without intravenous amphotericin B. Ophthalmology. 1990;97(5):666–74. 6. Shao Y, Yu Y, Pei CG, Tan YH, Zhou Q, Yi JL, Gao GP. Therapeutic efficacy of intracameral amphotericin B injection for 60 patients with keratomycosis. Int J Ophthalmol. 2010;3(3):257. 7. Gunther JB, Altaweel MM. Bevacizumab (Avastin) for the treatment of ocular disease. Survey Ophthalmol. 2009;54(3):372–400. 8. Genentech. Avastin. Summary of product characteristics. Available at http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/ WC500029271.pdf (2010). Accessed Jul 2012. 9. Novartis. Lucentis summary of product characteristics. Available at https://www.medicines.org.uk/emc/history/19409/SPC/Lucentis+10+mg+ml+solution+for+injection (2012). Accessed Jul 2012. 10. Rich RM, Rosenfeld PJ, Puliafito CA, Dubovy SR, Davis JL, Flynn HW Jr, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina. 2006;26(5):495–511. 11. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908. 12. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, et  al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-­ year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399–411. 13. Gerstenblith AT, Rabinowitz MP. The wills eye manual: office and emergency room diagnosis and treatment of eye disease. Philadelphia: Lippincott Williams & Wilkins; 2012. 14. McEvoy GK.  AHFS drug information (2006). Bethesda, MD: American Society of Health System Pharmacists; 2006.

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15. Montan PG, Wejde G, Setterquist H, Rylander M, Zetterström C.  Prophylactic intracameral cefuroxime: evaluation of safety and kinetics in cataract surgery. J Catar Refract Surg. 2002;28(6):982–7. 16. Ennis RD, Dahl TC. Stability of cidofovir in 0.9% sodium chloride injection for five days. Am J Health-Syst Pharm. 1997;54(19):2204–6. 17. Huq SM, Vazeen M.  Cataract surgery and phacoemulsification for the beginning surgeons. Bloomington, IN: Author House; 2014. 18. Baum U, Peyman GA, Barza M. Intravitreal administration of antibiotic in the treatment of bacterial endophthalmitis. III. Consensus. Surv Ophthalmol. 1982;26(4):204–6. 19. Sobrin L, Kump LI, Foster CS.  Intravitreal clindamycin for toxoplasmic retinochoroiditis. Retina. 2007;27(7):952–7. 20. Soheilian M, Rafati N, Mohebbi MR, Yazdani S, Habibabadi HF, Feghhi M, et al. Prophylaxis of acute post traumatic bacterial endophthalmitis: a multicenter, randomized clinical trial of intraocular antibiotic injection, report 2. Archiv Ophthalmol. 2007;125(4):460–5. 21. Graham RO, Peyman GA. Intravitreal injection of dexamethasone: treatment of experimentally induced endophthalmitis. Archiv Ophthalmol. 1974;92(2):149–54. 22. Panel on opportunistic infections in HIV-infected adults and adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centres for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov.proxy.hsl.ucdenver.edu/contentfiles/lvguidelines/adult_ oi.pdf. Accessed 27 Jan 2017. 23. Diaz-Llopis M, España E, Muñoz G, Navea A, Chipont E, Cano J, et al. High dose intravitreal foscarnet in the treatment of cytomegalovirus retinitis in AIDS.  British J Ophthalmol. 1994;78(2):120–4. 24. Lieberman RM, Orellana J, Melton RC.  Efficacy of intravitreal foscarnet in a patient with AIDS. N Engl J Med. 1994;330(12):868–9. 25. Arevalo JF, Garcia RA, Mendoza AJ. High-dose (5000-μg) intravitreal ganciclovir combined with highly active antiretroviral therapy for cytomegalovirus retinitis in HIV-infected patients in Venezuela. Eur J Ophthalmol. 2005;15(5):610–8. 26. Teoh SC, Ou X, Lim TH.  Intravitreal ganciclovir maintenance injection for cytomega lovirus retinitis: efficacy of a low-volume, intermediate-dose regimen. Ophthalmology. 2012;119(3):588–95. 27. Trissel LA, Trissel LA. Handbook on injectable drugs. Bethesda: American Society of Health-­ System Pharmacists; 2007. p. 701–7. 28. McEvoy GK, editor. AHFS Drug Information 93. Bethesda: American Society of Health-­ System Pharmacists; 1993. p. 230–4. 29. McElhiney LF. Compounding guide for ophthalmic preparations. Washington, DC: American Pharmacists Association; 2013. 30. Lundy DC, Sidoti P, Winarko T, Minckler D, Heuer DK. Intracameral tissue plasmmogen activator after glaucoma surgery: indications, effectiveness, and complications. Ophthalmology. 1996;103(2):274–82. 31. Siatiri H, Beheshtnezhad AH, Asghari H, Siatirit N, Moghimi S, Piri N. Intracameral tissue plasminogen activator to prevent severe fibrinous effusion after congenital cataract surgery. British J Ophthalmol. 2005;89(11):1458–61. 32. Tripathi RC, Park JK, Tripathi BJ, Millard CB. Tissue plasminogen activator in human aqueous humor and its possible therapeutic significance. Am J Ophthalmol. 1988;106(6):719–22. 33. Yoshitomi F, Utsumi E, Hayashi M, Futenma M, Yamada R, Yamada S. Postoperative fluctuations of tissue plasminogen activator (t-PA) in aqueous humor of pseudophakes. J Catar Refract Surg. 1991;17(5):543–6. 34. Wedrich A, Menapace R, Ries E, Polzer I. Intracameral tissue plasminogen activator to treat severe fibrinous effusion after cataract surgery. J Catar Refract Surg. 1997;23(6):873–7.

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35. Zalta AH, Sweeney CP, Zalta AK, Kaufman AH. Intracameral tissue plasminogen activator use in a large series of eyes with valved glaucoma drainage implants. Archiv Ophthalmol. 2002;120(11):1487–93. 36. Bhadange Y, Shah B, Takkar B, Sinha R. Review of doses of important drugs in ophthalmology. Delhi J Ophthalmol. 2011;21(3):23–7. 37. John B. Intravitreal injections. Kerala J Ophthalmol. 2007;46. 38. Prakash G, Sharma N, Goel M, Titiyal JS, Vajpayee RB. Evaluation of intrastromal injection of voriconazole as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J Ophthalmol. 2008;146(1):56–9. 39. Haddad RS, El-Mollayess GM.  Combination of intracameral and intrastromal voriconazole in the treatment of recalcitrant Acremonium fungal keratitis. Middle East Afr J Ophthalmol. 2012;19(2):265.

Part IV

Extemporaneous Subconjunctival Injections

Subconjunctival injections are occasionally used in severe ocular inflammations and rarely in severe ocular infections or after ocular surgeries.

Chapter 13

Equipments and Steps for Subconjuctival Injections

Equipments for the subconjunctival injections include [1, 2]: • • • • •

Povidone-iodine 5%. Speculum. Serrated conjunctival forceps. 25-g needle. Gloves. The procedure should be carried out in a cleanroom in the following steps:

• • • • • • • • • • • • • • • • •

The patient should be lying supine on a comfortable bed. Make sure the headrest of the chair is stable. Review the informed consent and confirm the correct eye. Proceed with the surgical time out. Instill anesthetic (e.g. Proparacaine) eye drops and wait for 15 seconds. Apply Povidone-iodine 5% to the conjunctival sac, eyelids, and lashes, and ask the patient to blink several times. Wait for 30–120  seconds. This is the most important step in reducing the risk of endophthalmitis. Wear powder-free gloves. Apply eyelid speculum. Instill another drop of Povidone-iodine 5% on the site of injection. The patient should be asked to look opposite to the site of injection and instructed not to talk or move to avoid injury to the retina. Use a conjunctival forceps to tent the inferior conjunctiva. Using a 25-gauge needle, insert the needle, with bevel up, under the subconjunctival space. Ensure that the needle bevel remains under the conjunctiva during the injection. Inject the required amount of the desired medication slowly. Withdraw the needle slowly and carefully. Remove the eyelid speculum. Eye bad maybe applied after closing the lid for a few hours.

© Springer Nature Switzerland AG 2020 E. A. S. Alghamdi et al., Extemporaneous Ophthalmic Preparations, https://doi.org/10.1007/978-3-030-27492-4_13

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References 1. Stevens S. Administering a subconjunctival injection. Commun Eye Health. 2009;22(69):15. 2. Doctor PP, Bhat PV, Foster CS. Subconjunctival bevacizumab for corneal neovascularization. Cornea. 2008;27(9):992–5.

Chapter 14

Formulations of Extemporaneous Subconjunctival Injections

In this chapter, the most common four formulations are presented and discussed following a systematic methodology starting with the composition and drug family, followed by use, dose, and preparation. The preparation is discussed in detail in terms of the concentration(s), procedure, expiration date, storage, packaging, and special precautions. N.B.: Off-Label means “unapproved indication, age group, dose, or form of administration.”

14.1  Amikacin Sulfate Subconjunctival Injection [1, 2] • Description: Amikacin is an aminoglycoside antibiotic obtained from kanamycin, showing broad action spectrum and strong resistance against the enzymes inactivating the other aminoglycoside antibiotics. It is commercially available as sulfate salt in an injection dosage form. Its mechanism of action is by inhibiting protein synthesis in susceptible bacteria by binding to 30S ribosomal subunits. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Preparation: –– Amikacin Sulfate 100 mg/0.4 ml (0.4 ml) Ingredients Quantity Amikacin 500 mg/2 ml 0.6 ml

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Procedure: • Under laminar airflow workbench, aseptically withdraw 0.6  ml (100 mg/0.4  ml plus 0.2  ml overfill) from the Amikacin sulfate vial into a syringe through a 0.22-μm filter needle. • Replace the filter needle with a fresh regular needle and transfer the solution sterile to a 2-ml empty vial. • Seal and label the vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Keep out of reach of children. Keep in the refrigerator. For subconjunctival use only.

14.2  Bevacizumab Subconjunctival Injection [3–5] • Description: Bevacizumab is a full length humanised monoclonal antibody that binds to human vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors on the surface of the endothelial cells. It is approved for intravenous treatment of the metastatic colorectal cancer, non-small cell lung cancer, metastatic renal cell cancer, and glioblastoma. However, there are many promising reports on the subconjunctival usage for ocular surface neovascularization. It is repackaged from large glass vial to multiple small plastic (singleuse) prefilled-syringes. • Use: Off Label Treatment of corneal neovascularization. • Dose: Depends on the followed protocol. • Preparation: –– Bevacizumab (0.3 ml) 2.5 mg/0.1 ml Preparation including batch of 40 syringes Ingredients Quantity Bevacizumab for injection 100 mg/4 ml 2.5 mg/0.1 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 0.3  ml (2.5 mg/0.1 ml dose plus overfill) from the Bevacizumab vial 100 mg/4 ml. • Withdraw a solution into a sterile Luer-Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap.

14.4  Gentamicin Subconjunctival Injection

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• Label each syringe and place it in an amber bag. Expiration Date: 14 days. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: For Subconjunctival only. Keep in the refrigerator.

14.3  Dexamethasone Phosphate Subconjunctival Injection [1, 2] • Description: Dexamethasone is a corticosteroid with main glucocorticoid activity. It is available in a wide range of concentrations and dosage forms. The Reported ophthalmic route of administration is intravitreal and subconjunctival injections in the treatment of some ocular inflammatory conditions. • Use: Off Label Ocular inflammatory conditions. • Preparation: –– Dexamethasone phosphate 1mg/0.25 ml (0.45 ml) Ingredients Quantity Dexamethasone 4 mg/1 ml 0.45 ml

Procedure: • From the Dexamethasone phosphate vial, withdraw 0.45 ml (1 mg/0.25 ml dose plus 0.2 ml overfill) into a syringe through a 5-μm filter needle. • Replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instructions: Keep out of reach of children. Keep in the refrigerator. For subconjunctival use only.

14.4  Gentamicin Subconjunctival Injection [1, 6, 7] • Description: Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora purpura. It is available as a mixture of the sulfate salts of Gentamicin C1, C2, and C1A. Mechanism of action is by inhibiting microbial

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protein synthesis in susceptible pathogens. Gentamicin is physically incompatible with semisynthetic Penicillin such as Ampicillin. For this reason, they should never be mixed in the same syringe or bottle for ophthalmic use. It is recommended that concomitant use is separated by 15 min. Subconjunctival injection of gentamicin would be a poor choice due to its toxicity. It may lead to pain, hyperemia, and conjunctival edema, while severe retinal ischemia has followed intraocular injections. • Use: Off Label Treatment of bacterial eye infection and corneal ulceration due to susceptible organisms. • Preparation: –– Gentamicin 20 mg/0.5 ml (0.5 ml) Ingredients Gentamicin 80 mg/2 ml

Quantity 0.5 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 0.7  ml (50 mg/0.5  ml plus 0.2ml overfill) from the Gentamicin vial into a syringe through a 0.22-μm filter needle. • Replace the filter needle with a fresh regular needle. • Transfer the solution to a sterile 2 ml vial. • Seal and label the vial. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instruction: Keep out of reach of children. Keep in the refrigerator. For subconjunctival use only.

References 1. Reynolds LA, Closson RG.  Extemporaneous ophthalmic preparations. Am J Ophthalmol. 1994;117(2):277. 2. Trissel LA. Trissel’s stability of compounded formulations. 4th ed. Washington DC: American Pharmacists Association; 2009. p. 26–7. 3. Doctor PP, Bhat PV, Foster CS. Subconjunctival bevacizumab for corneal neovascularization. Cornea. 2008;27(9):992–5. 4. Genentech. Avastin. Summary of product characteristics. (2010). Available at http://www. ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/ WC500029271.pdf. Accessed Jul 2012.

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5. Novartis. Lucentis summary of product characteristics. (2012). Available at https://www.medicines.org.uk/emc/history/19409/SPC/Lucentis+10+mg+ml+solution+for+injection. Accessed Jul 2012. 6. Jenkins CD, McDonnell PJ, Spalton DJ.  Randomised single blind trial to compare the toxicity of subconjunctival gentamicin and cefuroxime in cataract surgery. Br J Ophthalmol. 1990;74(12):734–8. 7. Trissel LA, Allwood MC, Haas DP, Hale KN, American Society of Hospital Pharmacists. Handbook on injectable drugs, vol. 14. Bethesda: American Society of Health-System Pharmacists; 2007.

Part V

Extemporaneous Ophthalmic Preparations in Ocular Oncology

In the medical literature, there are few medications that are used as extemporaneous ophthalmic preparation in ocular oncology. In this section, only evidence-based preparations will be mentioned.

Chapter 15

Extemporaneous Ophthalmic Preparations in Ocular Oncology

15.1  5-Fluorouracil Ophthalmic Solution [1–7] • Description: 5-Fluorouracil (5-FU) is a structural analog of thymine, which is a fluorinated pyrimidine antagonist. The pharmacological effect comes from impairing of DNA and RNA synthesis in tumor cells and normal cells as well. However, it is relatively more selective in cancerous cells due to higher DNA and RNA synthesis. It is applied topically at a concentration of 1%. • Use: Off Label Treatment of Ocular Surface Squamous Neoplasia (OSSN), including a broad spectrum of conjunctival malignancies, ranging from mild epithelial dysplasia to invasive squamous carcinoma. 5-FU has shown an efficacy of 85–100%, with a tumor recurrence rate ranging from 1.1% to 43%. • Dose: There are two methods to apply the drops depending on the study: –– One drop four times a day for 4 weeks. –– One drop four times a day for 1 week followed by a drug holiday of 3 weeks. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– 5-Fluorouracil 10 mg/ml 1 % in 5 ml Ingredients 5-Fluorouracil 50 mg/ml vial (10 ml) Sodium chloride 0.9%(preservative free)

Quantity 50 mg 4 ml

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Procedure: • Aseptically withdraw 1 ml of 5-FU (50 mg) into a syringe by a 0.22-μm filter needle. • Replace the filter needle of the 5-FU-solution syringe by a fresh regular needle, and then transfer to a sterile ophthalmic dropper bottle. • Add 4 ml of sodium chloride 0.9 % for injection (preservative free). • Cap dropper bottle and shake to mix before use. • Label with chemotherapy handling and disposal precautions. Expiration Date: 7 days. Storage Conditions: Refrigerator. Packaging: Sterile dropper bottle (plastic or glass). Special Instructions: Cytotoxic precaution (special handling and disposal required). Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator.

15.2  Melphalan Intravitreal Injection [8–12] • Description: Melphalan is a cell cycle nonspecific chemotherapeutic agent. It is capable of killing tumor cells in any phase of the cell cycle. As a bischloroethylamine alkylating agent, melphalan forms covalent cross-links with DNA or DNA protein complexes, thereby, resulting in cytotoxic, mutagenic, and carcinogenic effects. The result of the alkylation process is misreading of the DNA code and the inhibition of DNA, RNA, and protein synthesis in rapidly proliferating tumor cells. Melphalan is approved for intravenous treatment for Hematopoietic stem cell transplant and Multiple myeloma. Moreover, it is used in the form of an intravitreal injection to treat conditions of vitreous disease in retinoblastoma. Intravitreal injection is prepared in a concentration of 0.2 mg/ml, and the injected dose is 20 mcg, which can be cumulatively increased by 2–4 mcg up to 30 mcg depending on the patient’s situation. • Use: Off Label Treatment of vitreous disease in retinoblastoma. • Preparation: –– Melphalan 20 mcg/0.1 ml (0.3 ml) Ingredients Melphalan hydrochloride powder The Supplied diluent Sodium chloride 0.9% (preservative free)

Quantity 50 mg 10 ml QS: 25 ml

15.3  Methotrexate Intravitreal Injection

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Procedure: • Under a laminar airflow workbench, aseptically reconstitute the 50 mg of Melphalan hydrochloride powder with the 10 ml of supplied diluent, and shake to mix. This is a Melphalan Vial A of 5 mg/ml concentration. • Withdraw 1 ml from vial A and transfer to 30 ml sterile empty vial. This is vial B. • Add 24 ml of preservative-free 0.9% Sodium chloride to Vial B and shake to mix. The concentration in vial B becomes 0.2 mg/ml. • From Vial B, withdraw 0.3 ml (20 mcg/0.1 ml dose plus 0.2 ml overfill) into a syringe by a 5-μm filter needle, and then replace the filter needle with a fresh regular needle. • Transfer the solution to a 2-ml sterile empty vial. • Seal and label the vial Expiration Date: 3 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instruction: For intravitreal injection only. Keep in the refrigerator. Protect from light.

15.3  Methotrexate Intravitreal Injection [13–16] • Description: Methotrexate is a chemotherapeutic agent that acts by inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolates are utilized in the synthesis of nucleotides and thymidylate. This inhibition interferes with DNA synthesis and repair, and cellular reproduction. Generally, actively proliferating tissues are more sensitive to the effect of methotrexate. Methotrexate is used intravitreally as the first-line treatment of ocular involvement in primary vitreoretinal lymphoma (PVRL) without central nervous system (CNS) involvement with sustainable morbidity. Intravitreal methotrexate injections is prepared at a concentration of 0.4 mg/0.1 ml. It is administered two times per week for 4 weeks, once per week for 8 weeks, and once monthly for the next 9 months. The most commonly reported complications are a transient elevation of intraocular pressure and corneal epitheliopathy that subsided by increasing the intervals between consecutive injections. • Use: Off Lable CD20-positive PVRL without CNS involvement. • Preparation:

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–– Methotrexate 0.4 mg/0.1 ml (0.3 ml) Ingredients Methotrexate “Ebewe”, Liba Lab. A.S Water for injection(preservative free)

Quantity 50 mg/2ml 10.5 ml

Procedure: • Under a laminar airflow workbench, aseptically dilute 50 mg/2  ml of Methotrexate with 10.5  ml of preservative-free water for injection and shake to mix. This is a methotrexate vial of 4 mg/ml. • Withdraw 0.3 ml (0.4 mg/0.1 ml dose plus overfill) from the Methotrexate vial 4 mg/1 ml into a sterile Luer-Lock® tuberculin syringe. • Cap the syringe with a tamper-resistant sterile cap. • Label each syringe and place it in an amber bag. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instruction: For intravitreal injection only. Keep in the refrigerator. Protect from light

15.4  Mitomycin-C Ophthalmic Solution [17–30] • Description: Mitomycin-C (MMC) is an antineoplastic antibiotic agent, produced by Streptomyces caespitosus. It is a potent alkylating agent. The treatment is usually limited by the side effect related to Mitomycin-C including photophobia, dry eye, punctal stenosis, persistent epithelial defects, Limbal Stem Cell Deficiency (LSCD), and allergic reactions, all of which are very common. Mitomycin-C has been administered topically in two different concentrations of 0.02% and 0.04% based on the indication. • Use: Off Label Treatment of Ocular Surface Squamous Neoplasia. It is used as topical ophthalmic drops as a primary treatment or adjunctive to surgical resection either before the surgery as a chemoreduction measure, during the surgery (intraoperatively), or after the surgery as a chemopreventive measure to reduce the risk of recurrence. • Dose: Treatment of Ocular Surface Squamous Neoplasia. Based on one study, MMC 0.02% was used as one drop three times daily for at least two 1-week courses,

15.4  Mitomycin-C Ophthalmic Solution

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and based on another study 0.04% was used as one drop four times daily for at least two 1-week courses. In both studies, that was in both primary and adjunctive treatments. • Preparation: • Caution: Hazardous medication. Must be prepared in compliance with USP . –– First Formulation: Mitomycin-C 0.02% (0.2 mg/ml)

Ingredients Mitomycin injection 5 mg/vial (Powder) Distilled water used for injection (preservative free)

Quantity 0.2 mg/ml (0.02%) 5 mg 25 ml

–– Second Formulation: Mitomycin-C 0.04% (0.4 mg/ml) Ingredients Mitomycin injection 5 mg/vial (Powder) Distilled water for used injection(preservative free)

Quantity0.4 mg/ml (0.04%) 5 mg 12.5 ml

Procedure: • Under the vertical laminar airflow hood, a high-level disinfectant is sprayed on the outer walls of the filters which contain, respectively, the MMC vial and the distilled water used for injection (preservative-free) to prevent contamination of the laminar flow hood. • Aseptically reconstitute (5 mg) of MMC vial with (25 ml) of distilled water to obtain a concentration of 0.2 mg/ml (0.02%), or (12.5 ml) of distilled water to obtain a concentration of 0.4 mg/ml (0.04%). • From the MMC solution vial, withdraw the whole contents into a syringe by a 0.22-μm filter needle and transfer the solution to the sterile ophthalmic dropper bottle. • Cap the dropper bottle and label with chemotherapy handling and disposal precaution. Expiration Date: 14 days. Storage Conditions: Refrigerator. Protect from light. Packaging: Sterile amber dropper bottle (plastic or glass). Special Instructions: Cytotoxic precaution (special handling and disposal required). Keep out of reach of children. For ophthalmic use only. Keep in the refrigerator. Protect from light.

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15.5  Rituximab Intravitreal Injection [31–35] • Description: Rituximab is a humanized monoclonal mouse anti-CD20 antibody that binds CD20. It is approved for intravenous treatment for B-cell non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma that is refractory to other chemotherapy regimens. However, it is used in the form of an intravitreal injection to treat conditions associated with CD20-positive PVRL without CNS involvement. It is prepared in a concentration of 1 mg/0.1 ml, in terms of one-course protocol, once weekly for four weeks. Intravitreal Rituximab may be an alternative option to intravitreal methotrexate due to the lower level of toxicity. • Use: Off Label CD20-positive PVRL without CNS involvement. • Preparation: –– Rituximab 1 mg/0.1 ml (0.3 ml) Ingredients Rituximab (Rituxan, Genentech, Inc., San Francisco, CA), 10 mg/1 ml

Quantity 0.3 ml

Procedure: • Under a laminar airflow workbench, aseptically withdraw 0.3  ml (1 mg/0.1 ml dose plus overfill) from the Rituximab vial 100 mg/10 ml. • Withdraw a solution into a sterile Luer-Lock® tuberculin syringe, and cap with a tamper-resistant sterile cap. • Label each syringe and place it in an amber bag. Expiration Date: 24 h. Storage Conditions: Refrigerator. Packaging: Sterile Luer-Lock® tuberculin syringe with sterile tamper-evident cap. Special Instruction: For intravitreal injection only. Keep in the refrigerator. Protect from light.

References 1. Fuhrman LC, Godwin DA, Davis RA. Stability of 5-fluorouracil in an extemporaneously compounded ophthalmic solution. Int J Pharm Compd. 2000;4:320–3. 2. Midena E, Angeli CD, Valenti M, de Belvis V, Boccato P. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84(3):268–72.

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Index

A Acetylcysteine, 25–27 Actinomyces, 33, 48, 82 α-hydroxyprogesterone, 46 α-methyl, 46 AmBisome®, 29, 70 Amikacin, 28, 69, 95, 96 Amino acids, 25, 39 Aminoglycoside, 28, 44, 50, 69, 97 Amphotericin B, 28–30, 70 Ampicillin, 44, 51 Amycolatopsis orientalis, 51 Anti-angiogenic, 45 Antibacterial, 33, 36, 37, 41, 73, 82 Antimicrobial, 32, 33, 35, 36, 44, 50, 74 Antineoplastic, 44, 47, 106 Anti-proliferative, 44–45 Artificial tears, 17, 25, 28, 34, 39, 51, 52 Aspergillus, 28, 29, 53, 70, 86 Atopic keratoconjunctivitis (AKC), 50 Atropine, 30–31 Autologous serum, 31–32 B Bacillaceae, 32 Bacillus, 32, 41 Bacitracin, 32–33 Bacterial, 28, 33, 34, 36–38, 41, 48, 51, 52, 69, 73, 86, 95, 98 Bactericidal, 33, 35, 36, 48, 51, 73–75, 82 Balanced salt solution (BSS), 50, 71, 81, 84 Band keratopathy, 42 Benzalkonium chloride (BAK), 11, 13, 26, 54 Beta-lactam, 48, 82

Beta-lactamase, 35, 37, 49, 51, 74 Bevacizumab, 72 Blepharitis, 34, 39 Buffers, 5, 28 C Calcineurin, 39, 49 Calcium, 42 Candida, 28, 29, 53, 70, 86 Carcinoma, 43 Castor oil, 39, 40 Cataract, 36, 75, 83 Cefazolin, 33–35, 73 Ceftazidime, 35–36 Ceftriaxone, 37–38 Cephalosporin, 33, 35–38, 73–75 Cidofovir, 76 Clindamycin, 38–39, 77 Clostridia, 33 CMV, see Cytomegalovirus (CMV) Colistimetate, 41 Colistin, 41 Collagenase, 42, 46 Condyloma acuminate, 45 Conjunctivitis, 34, 39, 45 Corticosteroid, 78 Corynebacterium, 33 Cryptococcus, 28, 70 Curvularia, 29, 70 Cyclic polypeptide, 39 Cyclodextrins, 5 Cyclosporine, 39–40 Cytomegalovirus (CMV), 79, 80 Cytotoxic, 43, 45, 48, 79, 81

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112 D D-Alanyl-D-alanine, 85 Deoxycholate, 28, 29, 70 Dexamethasone, 78 Disodium edetate, 42 Distilled water, 29, 30, 33–37, 41, 42, 45–49, 52, 71, 73, 77, 80, 82, 84 DNA, 43, 78 DNA polymerase, 76 Dysplasia, 43, 45 E Edetate disodium (EDTA), 42 Endophthalmitis, 36, 38, 75 Enzymolysis, 6 Epitheliotrophic, 31 Ergosterol, 53, 86 F 5-Fluorouracil (5-FU), 43, 103 Fluconazole, 53 Foscarnet, 78, 79 Free D-Alanyl-D-alanine, 52 Fungal, 28, 29, 53 Fungi, 41, 52, 85 Fusarium, 28, 29, 53, 70, 86 G Ganciclovir, 79 Gentamicin, 28, 44, 50, 69, 97 Giant papillary conjunctivitis, 50 Glaucoma, 47, 72 Glioblastoma, 72, 96 Glucocorticoid, 78, 97 Glycopeptide, 51 Glycoprotein, 44 Gram-negative, 28, 35, 37, 41, 48, 52, 69, 74, 82, 85 Gram-positive, 33, 37, 41 Growth factors, 31 Guanine, 79 H Haemophilus influenza, 33 Hemolysis, 32 Hemorrhagic conjunctivitis, 45 Hepatitis, 45 H-index, 32 Hydrolyzed, 41 Hydrophilicity, 6 Hyperaemia, 45

Index Hyperplasia, 45 Hypromellose, 26 I Immunobullous, 31 Immunoglobulin, 31 Immunomodulatory, 39 Inserts, 17, 93 Interferon, 44–45 Interleukin, 39 Intracameral, 3, 19, 67, 71, 75, 83, 86 Intravitreal, 3, 19, 63, 64, 70, 71, 76–79, 85, 104–106, 108 Iontophoresis, 18 K Kaposi, 45 Keratoconjunctivitis, 25, 26, 39 Keratopathy, 32 L L-cysteine, 25 Leukemia, 45 Licheniformis, 32 Lipophilic, 39 Lipophilicity, 6 Liposomal, 29, 30 Liposomes, 17 Liquifilm tears, 39, 40 Lymphoid, 45 Lymphoma, 45, 105, 108 M Macrolide, 49 Magnesium, 49 Medroxyprogesterone, 46 Melanoma, 45 Melphalan, 104, 105 Metabolism, 6 Methanesulfonate, 41 Methotrexate, 105, 106, 108 Methyl, 13 Micro-emulsions, 5 Micromonospora Purpura, 44 Mitomycin-C (MMC), 47–48, 106, 107 Mucolytic, 25 Mucopeptide, 35, 36 Mucoproteins, 25 Multi-Drug Resistant Pseudomonas Aeruginosa (MDR-PA), 41

Index N Nanoparticles, 17 Neisseria, 33 Neoplasia, 43, 47, 103, 106 Niosomes, 18 Nocardia, 51 Nucleosides, 41, 79 O Olive oil, 39 P Paecilomyces, 53, 86 Penicillin, 38, 44, 48–49 Penicillinase, 48, 82 Penicillium Chrysogenum, 48 Permeability, 11 Pharmacokinetics, 3 Phenylacetic, 48, 82 Plasmin, 83 Polyaminopropyl biguanide, 13 Polyethylene, 31 Polymerase, 78 Polymyxin, 41 Polyvinyl alcohol, 40 Potassium, 48–49, 82 Povidone, 39, 40 Povidone-iodine, 63, 64, 67, 93 Propylparaben, 13 Pseudomonas, 35 Purine, 76, 79 Pyrimidine, 43, 103 R Retinitis, 76, 79 Retinoblastoma, 104 Ringer, 86 RNA, 43, 78, 103, 104 S Sarcoma, 45 Scedosporium, 53, 86 Sjogren’s syndrome, 25, 31 Sodium chloride, 26, 29, 31, 32, 38, 43, 69, 75, 76, 81, 84, 85, 104, 105

113 Solubility, 5, 11, 21 Spirochetes, 48, 82 Stability, 5, 22, 37 Staphylococci, 33 Stem cell, 47, 104, 106 Sterility, 5, 21 Stevens-Johnson syndrome, 31 Streptococci, 33 Streptomyces, 47, 49, 50, 106 Sulfamethyl, 41 Sulfate, 28, 30, 44, 49, 51, 69, 95 Sulphydryl, 25 T Tacrolimus, 49–50 T-cells, 49, 50 Tertiary amine antimuscarinic alkaloid, 30 Tetrahydrofolates, 105 Tetrahydrofolic acid, 105 Thimerosal, 13 Thymidine, 78 Thymidylate, 105 Thymine, 43, 103 Tissue plasminogen activator (TPA), 83 Tobramycin, 28, 50–51, 69 Tonicity, 5, 11, 21 Toxic anterior segment syndrome (TASS), 68 Treponema pallidum, 33 Triazole, 53 U Uveitis, 63 V Vancomycin, 51–53, 85 Vascular endothelial growth factor (VEGF), 72, 96 Vernal keratoconjunctivitis (VKC), 50 Viral DNA, 79 Viscosity, 6, 11, 17, 34 Vitamins, 31 Voriconazole, 53–54, 86 Y Yeast, 52, 85