ASHP® Injectable Drug Information™

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A Comprehensive Guide to Compatibility and Stability

2021

Published under the Editorial Authority of ASHP®

Unauthenticated | Downloaded 09/30/21 07:32 AM UTC Published under the editorial authority of ASHP®. Any correspondence regarding this publication should be sent to the publisher, American Society of Health-System Pharmacists, 4500 East-West Highway, Suite 900, Bethesda, MD 20814, attn: ASHP Injectable Drug Information or to [email protected]. The nature of drug information and its applications is constantly evolving because of ongoing research and clinical experience and is often subject to professional judgment and interpretation by the practitioner due to the uniqueness of each clinical situation and patient. While care has been taken to ensure the accuracy of the information presented, the reader is advised that the authors, editors, contributors, reviewers, and publisher cannot be responsible for the continued currency of the information, for any errors or omissions, and/or any consequences arising from the use of this information in a clinical setting. Any reader of this work is cautioned that ASHP makes no representation, guarantee, or warranty, express or implied, as to the accuracy and appropriateness of the information contained in this work and specifically dis- claims any liability to any party for the accuracy and/or completeness of the material contained in the work or for any damages arising out of the use or non-use of any of the information contained in this work. Because of the dynamic nature of drug information, readers also are advised that decisions regarding drug use and patient care must be based on the independent judgment of the clinician, changing information about a drug (e.g., as represented in the literature), and changing professional practices.

Vice President, Publishing Office: Daniel J. Cobaugh, PharmD, DABAT, FAACT Assistant Editor for Injectables: Lisa M. Kohoutek, PharmD, BCPS Project Manager: Elizabeth P. Shannon, BS Production Services/Printing: Sheridan Cover Design: DeVall Advertising Cover Art: iStock-913469346 Page Design: David Wade

© 2021, American Society of Health-System Pharmacists, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or me- chanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without written permission from the American Society of Health-System Pharmacists. ASHP® is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S. Patent and Trademark Office.

ISBN: 978-1-58528-658-4 (hardcover) ISBN: 978-1-58528-685-0 (adobe pdf) ISBN: 978-1-58528-690-4 (ePub) DOI: 10.37573/9781585286850

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TABLE OF CONTENTS

Preface...... vii How to Use ASHP® Injectable Drug Information™ ...... ix AHFS® Pharmacologic-Therapeutic Classification©...... xx

Drug Monographs...... 1

Appendix I: Parenteral Nutrition Formulas...... 1603

References...... 1631

Index...... 1723

DOI: 10.37573/9781585286850.fm

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PREFACE

ASHP® Injectable Drug Information™ 2021 is a collec- mation to the benefit of patients. With increasingly com- tion of compatibility and stability information on par- plex drug therapy regimens, an abundance of new drug enteral drug products and is the most recent contribu- and drug formulation approvals, and ever-present drug tion to this continuing series. With its publication, all shortage issues, pharmaceutics research has important previous editions are considered out of date. implications for patient care in the inpatient, specialty One of the core focuses of ASHP as a professional pharmacy, and home infusion settings. Recent exam- and scientific society has been its long history of pub- ples of inappropriate compounding practices involving lishing internationally recognized, authoritative sources parenteral medications have resulted in increased sterile of drug information. Beginning with publication of the compounding regulation and have reinforced the impor- Society’s ground-breaking work the American Hospital tance of adherence to sterile compounding standards, Formulary Service® (AHFS®; now AHFS Drug Information®) implementation of best practices in the preparation in 1959 and continuing with the definitive works the and administration of parenteral drug products (com- Parenteral Drug Information Guide™ in 1974, the Hand- mercially available or extemporaneously compounded), book on Injectable Drugs® in 1977, and the Medication and application of principles and findings of pharmaceu- Teaching Manual® (now AHFS Patient Medication Infor- tics research to patient care. For additional information mation™) in 1978, ASHP has consistently set the stan- on sterile compounding, ASHP’s Resource Center can be dard for objective drug information focused on safe and consulted (www.ashp.org/sterilecompounding). effective drug therapy. For more than 75 years, ASHP has Beginning with the 18th edition, the Handbook on been at the forefront of efforts to improve medication Injectable Drugs® became an integral component of use and patient safety. Publication of ASHP® Injectable ASHP’s AHFS® resource collection of authoritative drug Drug Information™ 2021 is an important component of information. Applying its expansive drug information those efforts. With the 2021 edition of ASHP® Injectable and informatics expertise, ASHP’s focus with the subse- Drug Information™, ASHP marks 49 years of publishing quent editions has been on the continuing addition and such an invaluable resource on parenteral medications. revision of new and existing drug monographs as well as First published in 1977 as a key outgrowth of phar- important database enhancements to this indispensable maceutics research and pharmacy practice at the US authority on parenteral drugs. ASHP® Injectable Drug Public Health Service and National Institutes of Health Information™ 2021, which was begun to provide a single (NIH), the Handbook on Injectable Drugs® has a long leg- standardized source of the primary research on the sta- acy of translating pharmaceutics research into an essen- bility, compatibilities, and incompatibilities of injectable tial resource for practical patient-care applications. Law- drugs, continues to be the most widely recognized “Gold rence A. Trissel, who served as co-author of ASHP’s first Standard” for such information. resource on injectable drugs—the Parenteral Drug Infor- ASHP® Injectable Drug Information™ 2021 includes mation Guide™, established this legacy by serving as 18 new monographs, bringing the total in this edition the distinguished author of the Handbook on Injectable to 406 monographs on parenteral drugs available in the Drugs® for the first 17 editions. ASHP and the profession United States and in other countries. In addition, more as a whole remain grateful to Mr. Trissel for his contribu- than 500 revisions to existing monographs (affect- tion to the pharmaceutics literature and his unyielding ing nearly 60% of the existing monographs) have been dedication to the science of stability and compatibility accomplished to update information on stability, com- information on parenteral products. patibility, and safety (e.g., Food and Drug Administra- With the publication of the Mirror to Hospital Phar- tion [FDA] MedWatch alerts) and to provide more spe- macy in 1964, ASHP paved the way for a transition from cific referencing of manufacturer information and other nursing-driven to pharmacy-led sterile compounding enhancements to the more than 24,100 compatibility services and has remained an industry leader for both pairs contained in ASHP® Injectable Drug Information™ advocacy and best practices related to parenteral med- 2021. The information cited throughout the text has ications. The mission of ASHP’s reference publications been compiled from 3603 references, including 195 new on compatibility and stability of parenteral products to this edition. Because information from pharmaceuti- has always been to facilitate the use of the vast body of cal manufacturers had not been uniquely cited until the pharmaceutics research on parenteral medications in a 18th edition, the number of unique references supporting way that could enable those who prescribe, prepare, and ASHP® Injectable Drug Information™ 2021 information administer injectable drugs to more fully apply this infor- actually greatly exceeds this number. While primary, DOI: 10.37573/9781585286850.fm

Unauthenticated | Downloaded 09/30/21 07:32 AM UTC viii ASHP INJECTABLE DRUG INFORMATION peer-reviewed literature remains a major source of com- Regular updates, FDA MedWatch alerts and other patibility and stability information, ongoing efforts are guidances, and wall-chart custom views of compatibility underway to provide increased specificity of references information continue to be available for digital versions. to the pharmaceutics research of drug manufacturers. For proper use of this reference work, the reader Other relevant information and pertinent study details must review “How to Use ASHP® Injectable Drug Infor- supplied by corresponding authors of the published liter- mation™,” which immediately follows this Preface. This ature also have been incorporated when available. section will acquaint the user of ASHP® Injectable Drug In addition to the noted enhancements to the 2021 Information™ with its organization, content, structure, print edition of ASHP® Injectable Drug Information™ summarization strategy, interpretation of the informa- 2021, the regularly updated online edition features linked tion presented, and limitations of the published litera- monographs to Extended Stability for Parenteral Drugs, ture upon which this reference text is based. Without a forming a single, comprehensive resource on inject- good working knowledge of these points, ASHP® Inject- able drug information. This extended stability informa- able Drug Information™ 2021 may not be used to its best tion is specifically designed for use in home infusion and advantage or even interpreted correctly. other infusion practices, providing critical stability data to support realistic and cost-effective compounding and patient delivery schedules. ASHP® Injectable Drug Infor- mation™ 2021 also will soon be available as an ebook in a variety of formats (e.g., PDF, EPUB, full-text HTML).

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USERS GUIDE

teral drugs should seek the assistance of more knowl- HOW TO USE ASHP® INJECTABLE edgeable and experienced healthcare professionals to DRUG INFORMATION™ ensure patient safety. Users of ASHP® Injectable Drug Information™ must ® What Is ASHP Injectable Drug recognize that no reference work, including this one, can Information™ ? substitute for adequate decision-making by healthcare professionals. Proper clinical decisions must be made ® ASHP Injectable Drug Information™ is a collection of after considering all aspects of the patient’s condition and summaries of information from the published litera- needs, with particular attention to the special demands ture on the pharmaceutics of parenteral medications imposed by parenteral medications. ASHP® Injectable ® as applied to the clinical setting. ASHP Injectable Drug Drug Information™ cannot make decisions for its users. Information™ is constructed from information derived However, in knowledgeable hands, it is a valuable tool from 3603 references with the information presented in for the proper use of parenteral medications. the standardized structure described below. The purpose of this reference text is to facilitate the use of this clinical Organization of ASHP® Injectable pharmaceutics research by knowledgeable health care Drug Information™ professionals for the benefit of patients. The summary information from published research is supplemented ASHP® Injectable Drug Information™ has been organized with information from the labeling of each product and as a collection of monographs on each of the drugs. The from other references. monographs are arranged alphabetically by nonpropri- The information base summarized in ASHP® Inject- etary (generic) name. The nonproprietary names of the able Drug Information™ is large and highly complex, drugs are the United States Adopted Names (USAN) requiring thoughtful consideration for proper use. This and other official names for drugs as described in the reference text is not, nor should it be considered, ele- USP Dictionary of USAN and International Drug Names. mentary in nature or a primer. A single quick glance in Also included are some of the trade (proprietary, brand) a table is not adequate for proper interpretation of this names and manufacturers of the drug products; this list- highly complex information base. Proper interpretation ing is not necessarily comprehensive and should not be includes the obvious need to consider and evaluate all considered an endorsement of any product or manufac- relevant research information and results. Additionally, turer. information on the formulation components (e.g., excip- All of the information included in ASHP® Injectable ients), product attributes (especially pH), and the known Drug Information™ is referenced so that those who wish stability behaviors of each parenteral drug, as well as the to study the original sources may find them. Efforts are clinical situation of the patient, must be included in a ongoing to provide increased specificity of references to thoughtful, reasoned evaluation of clinical pharmaceu- product labeling as individually cited references to the tics questions. Stability and sterility both must be con- labeling for a drug product, including the proprietary sidered in the assignment of beyond-use dates. name (if available), manufacturer, and revision date of the prescribing information; this will facilitate location Who Should Use ASHP® Injectable of specific labeling that has been used as a reference. In Drug Information™? addition, the full list of the AHFS® Pharmacologic-Ther- apeutic Classification© system and specific classification ® ASHP Injectable Drug Information™ is designed for use numbers within each individual monograph have been as a professional reference and guide to the literature included to facilitate the location of therapeutic infor- on the clinical pharmaceutics of parenteral medica- mation on the drugs. tions. The intended audience consists of knowledge- able healthcare professionals, particularly pharmacists, The monographs have been divided into the sub- who are well versed in the formulation and clinical use headings described below: of parenteral medications and who have the highly Products—lists many of the sizes, strengths, volumes, specialized knowledge base, training, and skill set nec- and forms in which the drug is supplied, along with essary to interpret and apply the information. Prac- other components of the formulation. Instructions titioners who are not well versed in the formulation, for reconstitution (when applicable) are included in essential properties, and clinical application of paren- this section. DOI: 10.37573/9781585286850.fm

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The products described do not necessarily comprise Protection from excessive heat is often required; exces- a comprehensive list of all available products. Rather, sive heat is defined as any temperature above 40°C.17 some common representative products are described. Similarly, protection from freezing may be required Furthermore, dosage forms, sizes, and container con- for products that are subject to loss of strength or figurations of parenteral products may undergo potency or to destructive alteration of their charac- important changes during the lifespan of this edition teristics, in addition to the risk of container breakage, of ASHP® Injectable Drug Information™. upon exposure to freezing temperatures.17 Following the product descriptions, the pH of the Some products may require storage at a cool tempera- drug products, the osmotic value(s) of the drug and/ ture, which is defined as any temperature between or dilutions (when available), and other product infor- 8–15°C, or a cold temperature, which is defined as mation such as the sodium content and definition of any temperature not exceeding 8°C.17 A refrigerator units are presented. is defined as a cold place in which the temperature Practitioners have not always recognized the value is controlled between 2–8°C.17 A freezer refers to a and importance of incorporating product formula- place in which the temperature is controlled between tion information into the thought process that leads -25 and -10°C.17 Some products may have a recom- to their decision on handling drug compatibility mended storage condition below -20°C, and in such and stability questions. Excipients used in the for- cases, the temperature should be controlled to with- mulation of commercially available products may in 10°C of -20°C.17 vary among manufacturers and can influence drug In addition to storage requirements, aspects of compatibility and stability; specific product label- drug stability related to pH, freezing, and expo- ing should be consulted for additional formulation sure to light are presented in this section. Also pre- details. Consideration of the product information sented is information on repackaging of the drugs and formulation components, as well as the proper- or their dilutions in container/closure systems other ties and attributes of the products (especially pH), is than the original package (e.g., prefilling into syring- essential to proper interpretation of the information es or in ambulatory pump reservoirs). Sorption and presented in ASHP® Injectable Drug Information™. filtration characteristics of the drugs are provided as well when this information is available. The informa- Administration—includes route(s) by which the drug tion is derived principally from the primary published can be given, rates of administration (when applica- research literature and is supplemented with infor- ble), and other related administration details. mation from other sources when available. The administration information is a condensation derived principally from product labeling. For com- Compatibility Information—tabulates the compatibili- plete information, including dosage information suf- ty results of the drug about which the monograph ficient for prescribing, the reader should refer to is written with infusion solutions and other drugs product labeling and therapeutically comprehensive based on published reports from the primary research references, such as the AHFS® Drug Information®. as well as the product labeling. The various entries are listed alphabetically by solution or drug name; the Stability—describes the drug’s stability and storage information is completely cross-referenced among requirements. The storage condition terminology of the monographs. The United States Pharmacopeia, 42nd ed., is used in Four types of tables are utilized to present the avail- ASHP® Injectable Drug Information™. able information, depending on the kind of test The United States Pharmacopeia defines controlled being reported. The first type is for information on room temperature as a temperature that encom- the compatibility of a drug in various infusion solu- passes the usual and customary working environ- tions and is depicted in Table 1. The second type of ment of 20–25°C and that results in a mean kinet- table presents information on two or more drugs in 17 ic temperature no greater than 25°C. Temperature intravenous solutions and is shown in Table 2. The excursions between 15–30°C that are experienced in third type of table is used for tests of two or more pharmacies, hospitals, warehouses, and during ship- drugs in syringes and is shown in Table 3. The fourth 17 ping are permitted. Transient temperature eleva- table format is used for reports of simulated or actu- tions up to 40°C also are permitted provided that al injection into Y-sites and manifolds of administra- they do not persist beyond 24 hours and that the tion sets and is shown in Table 4. mean kinetic temperature does not exceed 25°C.17 In Many published articles, especially older ones, do not contrast, room (ambient) temperature is defined sim- include all of the information necessary to complete ply as a temperature prevailing in a working environ- the tables. However, the tables have been complet- ment.17 ed as fully as possible from the original articles; in

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some cases, editorial staff have supplemented the published information based on direct communica- tion with the authors of the published research.

Table 1. Solution Compatibility

Monograph drug name

Solution Mfr Mfr Conc/L or % Remarks Ref C/I (1) (2) (3) (4) (5) (6) (7)

1. Solution in which the test was conducted. 2. Manufacturer of the solution. 3. Manufacturer of the drug about which the monograph is written. 4. Concentration of the drug about which the monograph is written. (See The Listing of Concentration.) 5. Description of the results of the test. 6. Reference to the original source of the information. 7. Designation of the compatibility (C) or incompatibility (I) of the test result according to conventional guidelines.

Table 2. Additive Compatibility

Monograph drug name

Drug Mfr Conc/L or % Mfr Conc/L or % Test Soln Remarks Ref C/I

(1) (2) (3) (4) (5) (6) (7) (8) (9)

1. Monograph title for the test drug. 2. Manufacturer of the test drug. 3. Concentration of the test drug. 4. Manufacturer of the drug about which the monograph is written. 5. Concentration of the drug about which the monograph is written. (See The Listing of Concentration.) Infusion solution in which the test was conducted. 6. Description of the results of the test. 7. Reference to the original source of the information. 8. Designation of the compatibility (C) or incompatibility (I) of the test result according to conventional guidelines. Table 3. Drugs in Syringe Compatibility

Monograph drug name

Drug (in syringe) Mfr Amt Mfr Amt Remarks Ref C/I (1) (2) (3) (4) (5) (6) (7) (8) 1. Monograph title for the test drug. 2. Manufacturer of the test drug. 3. Actual amount of the test drug. 4. Manufacturer of the drug about which the monograph is written. 5. Actual amount of the drug about which the monograph is written. 6. Description of the results of the test. 7. Reference to the original source of the information. 8. Designation of the compatibility (C) or incompatibility (I) of the test result according to conventional guidelines.

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Table 4. Y-Site Injection Compatibility (1:1 Mixture)

Monograph drug name

Drug Mfr Conc Mfr Conc Remarks Ref C/I (1) (2) (3) (4) (5) (6) (7) (8) 1. Monograph title for the test drug 2. Manufacturer of the test drug. 3. Concentration of the test drug prior to mixing at the Y-site. 4. Manufacturer of the drug about which the monograph is written. 5. Concentration of the drug about which the monograph is written prior to mixing at the Y-site. 6. Description of the results of the test. 7. Reference to the original source of the information. 8. Designation of the compatibility (C) or incompatibility (I) of the test result according to conventional guidelines.

Additional Compatibility Information—provides addi- Designating Compatibility or tional information and discussions of compatibility Incompatibility presented largely in narrative form. Each summary of a published research report appearing Other Information—contains any relevant auxiliary infor- in the Compatibility Information tables bears a compati- mation concerning the drug that does not fall into the bility indicator (C, I, or ?). A report receives a designation previous categories. of C when the study results indicate that compatibility of The Listing of Concentration the test samples existed under the test conditions. If the study determined an incompatibility existed under the The concentrations of all admixtures in intravenous solu- test conditions, then an I designation is assigned for the tions in the tables (Table 1 and Table 2) generally have ASHP® Injectable Drug Information™ entry for that study been indicated in terms of concentration per liter (L) result. A designation of ? indicates that the test result to facilitate comparison of the various studies. In some does not clearly fit either the compatibility or incom- cases, this may result in amounts of the drug that are patibility definition. Specific standardized guidelines are greater or lesser than those normally administered (as used to assign these compatibility designations and are when the recommended dose is tested in 100 mL of vehi- described below. The citation is designated as a report cle), but the listings do accurately reflect the actual con- of compatibility when results of the original article indi- centrations tested, expressed in standardized terms. cated one or more of the following criteria were met: Concentration may be expressed as a percentage for cer- tain drugs or solutions (e.g., dextran, hetastarch, manni- 1. Physical or visual compatibility of the combination tol, fat emulsion) to reflect the style commonly used to was reported (no visible or electronically detected express concentration for these products. indication of particulate formation, haze, precipita- For studies involving syringes, the amounts actually tion, color change, or gas evolution). used are indicated. The volumes are also listed if avail- 2. Stability of the components for at least 24 hours able. in an admixture under the specified conditions was For studies of actual or simulated Y-site injection reported (decomposition of 10% or less). of drugs, the concentrations are cited in terms of con- 3. Stability of the components for the entire test peri- centration per mL of each drug solution prior to mix- od, although in some cases it was less than 24 hours, ing at the Y-site. Most published research reports have was reported (time periods less than 24 hours have presented the drug concentrations in this manner, and been noted). ASHP® Injectable Drug Information™ follows this con- vention. For those few published reports that presented The citation is designated as a report of incompat- the drug concentrations after mixing at the Y-site, the ibility when the results of the original article indicated concentrations have been recalculated to be consistent either or both of the following criteria were met: with the more common presentation style to maintain 1. A physical or visual incompatibility was reported the consistency of presentation in ASHP® Injectable Drug (visible or electronically detected particulate forma- Information™. Note that the Y-Site Injection Compati- tion, haze, precipitation, color change, or gas evolu- bility table is designed with the assumption of a 1:1 mix- tion). ture of the subject drug and infusion solution or admix- ture. For citations reporting other than a 1:1 mixture, 2. Greater than 10% decomposition of one or more the actual amounts tested are specifically noted. components in 24 hours or less under the specified

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conditions was reported (time periods of less than 24 The reader must guard against misinterpretation hours have been noted in the table). of research results, which may lead to inappropriate Reports of test results that do not clearly fit into the assumptions of compatibility and stability. As an exam- compatibility or incompatibility definitions cannot be ple, a finding of precipitate formation two hours after designated as either. These are indicated with a question two drugs are mixed does not imply nor should it be mark. interpreted to mean that the combination is compatible until that time point, when a sudden precipitation occurs. Although these criteria have become the conven- Rather, it should be interpreted to mean that precipita- tional definitions of compatibility and incompatibility, tion occurred at some point between mixing and the first the reader should recognize that the criteria may need observation point at two hours. Such a result would lead to be tempered with professional judgment. Inflexible to a designation of incompatibility in ASHP® Injectable adherence to the compatibility designations should be Drug Information™. avoided. Instead, they should be used as aids in the exer- cising of professional judgment. Precipitation reports can be particularly troublesome for practitioners to deal with because of the variability Therapeutic incompatibilities or other drug interac- of the time frames in which they may occur. Apart from tions are not within the scope of ASHP® Injectable Drug combinations that repeatedly result in immediate pre- Information™ and are therefore not addressed. Thera- cipitation, the formation of a precipitate can be unpre- peutically comprehensive references and the product dictable to some degree. Numerous examples of variable labeling should be consulted for such information. precipitation time frames can be found in the literature, Interpreting Compatibility including paclitaxel, etoposide, and sulfamethoxaz- Information in ASHP® Injectable Drug ole-trimethoprim (co-trimoxazole) in infusion solutions and calcium and phosphates precipitation in parenteral Information™ nutrition mixtures (e.g., TNAs, TPNs). Differing drug As mentioned above, the body of information summa- concentrations also can play a role in creating variabil- rized in ASHP® Injectable Drug Information™ is large and ity in results. A good example of this occurs with co-ad- complicated. With the possible exception of a report ministered vancomycin hydrochloride and beta-lactam ® of immediate gross precipitation, it usually takes some antibiotics. Users of the information in ASHP Injectable degree of thoughtful consideration and judgment to Drug Information™ must always be aware that a margin- properly evaluate and appropriately act on the research ally incompatible combination might exhibit precipita- results that are summarized in this book. tion earlier or later than that reported in the literature. In many such cases, the precipitation is ultimately going Nowhere is the need for judgment more obvious than to occur, it is just the timing that is in question. This is of when apparently contradictory information appears in particular importance for precipitate formation because two or more published reports. The body of literature in of the potential for serious adverse clinical consequences, drug-drug and drug-solution compatibility is replete with including death, that have occurred. Certainly, users of apparently contradictory results. Except for study results ASHP® Injectable Drug Information™ information should that have been documented later to be incorrect, the con- always keep in mind and anticipate the possibility of pre- flicting information has been included in ASHP® Injectable cipitation and its clinical ramifications. Furthermore, all Drug Information™ to provide practitioners with all of the injections and infusions should be inspected for particu- information for their consideration. The conflicting infor- late matter and discoloration prior to administration. If mation will be readily apparent to the reader because of found, such injections and solutions should be discarded. the content of the Remarks section as well as the C, I, and ? designations following each citation. In addition, many research reports cite test solutions or concentrations that may not be appropriate for clin- Many or most of the apparently conflicting citations ical use. An example would be a report of a drug’s sta- may be the result of differing conditions or materials bility in unsterile water. Although the ASHP® Injectable used in the studies. A variety of factors that can influence Drug Information™ summary will accurately reflect the the compatibility and stability of drugs must be consid- test solutions and conditions that existed in a study, it is ered in evaluating such conflicting results, and absolute certainly inappropriate to misinterpret a stability report statements are often difficult or impossible to make. Dif- like this as being an authorization to use the product clin- ferences in concentrations, buffering systems, preserva- ically. In such cases, the researchers may have used the tives, vehicles, temperatures, and order of mixing all may clinically inappropriate diluent to evaluate the drug’s play a role. By reviewing a variety of reports, the user of stability for extrapolation to a more suitable vehicle that ASHP® Injectable Drug Information™ is better able to is similar, or they may not have recognized that the dilu- exercise professional judgment with regard to compati- ent is clinically unsuitable. In either event, it is incumbent bility and stability.

Unauthenticated | Downloaded 09/30/21 07:32 AM UTC xiv ASHP INJECTABLE DRUG INFORMATION on the practitioner in the clinical setting to use profes- And, finally, contemporary practitioners have come sional judgment to apply the information in an appropri- to expect that the analytical methods used in reports ate manner and recognize what is not acceptable clini- on the chemical stability of drugs will be validated, sta- cally. bility-indicating methods. However, many early studies Further, it should be noted that many of the citations used methods that were not demonstrated to be stabil- designated incompatible are not absolute. While a par- ity indicating. ticular admixture may incur more than 10% decompo- Biological drugs (therapeutic proteins [e.g., enzymes, sition within 24 hours, the combination may be useful monoclonal antibodies, immune globulins]) are partic- for a shorter time period. The concept of “utility time” or ularly sensitive to environmental factors and undergo the time to 10% decomposition may be useful in these more complex and numerous degradation pathways than cases. Unfortunately, such information is often not avail- classical drugs.3207 3208 3212 In addition to physicochemical able. Included in the Remarks columns of the tables are instability issues similar to those observed with classical the amount of decomposition, the time period involved, drugs (e.g., precipitation, decomposition), such proteins and the temperature at which the study was conducted are subject to other stability issues (e.g., protein confor- when this information is available. mation, biologic activity) that must be considered.3207 Users of ASHP® Injectable Drug Information™ should 3208 3209 3212 Therefore, a single analytic method that only always keep in mind that the information contained in assesses protein concentration is insufficient to deter- this reference text must be used as a tool and a guide to mine stability of biological products.3209 3210 Interpreta- the research that has been conducted and published. It tion of the results of compatibility and stability studies is not a replacement for thoughtfully considered profes- of such proteins poses a challenge because both ana- sional judgment. It falls to the practitioner to interpret lytic methods and meaningful acceptance criteria should the information in light of the clinical situation, includ- be specific to the biologic; official compendial stan- ing the patient’s needs and status. What is certain is that dards (e.g., The United States Pharmacopeia monographs relying solely on the C or I designation without the appli- and analytic methods) should be consulted when avail- cation of professional judgment is inappropriate. able.3206 3209 3212 Although many experts agree that mul- tiple complementary methods should be used to assess Limitations of the Literature the physical and chemical stability as well as assessment of biologic activity, no clear guideline or recommenda- In addition to conflicting information, many of the pub- tion for in-use stability studies for therapeutic proteins lished articles have provided only partial evaluations, not is available.3208 3210 3211 3212 looking at all aspects of a drug’s stability and compati- bility. This is not surprising considering the complexity, Literature Search for Updating ASHP® difficulty, and costs of conducting such research. There are, in fact, articles that do provide evaluations of both Injectable Drug Information™ physical stability/compatibility and chemical stability. To gather the bulk of the published compatibility and But some are devoted only to physical issues, while oth- stability information for updating ASHP® Injectable Drug ers examine only chemical stability. Although a finding Information™, a literature search is performed using the of precipitation, haze, or other physical effects may con- International Pharmaceutical Abstracts™ (IPA™) data- stitute an incompatibility (unless transient), the lack of base and PubMed. By using key terms (e.g., stability), a such changes does not rule out chemical deterioration. listing of candidate articles for inclusion in ASHP® Inject- In some cases, drugs initially designated as compatible able Drug Information™ is generated. From this list, rel- because of a lack of visual change were later shown to evant articles are critically evaluated and prioritized for undergo chemical decomposition. Similarly, the deter- inclusion. As a supplement to this automated literature mination of chemical stability does not rule out the pres- searching, a manual search of the references of the arti- ence of unacceptable levels of particulates and/or tur- cles is also conducted, and any articles not included pre- bidity in the combination. In a classic case, the drugs viously are similarly evaluated for inclusion. In addition, leucovorin calcium and fluorouracil were determined pharmaceutical manufacturers may be contacted for to be chemically stable for extended periods by stabil- additional in-house (unpublished) data. ity-indicating HPLC assays in several studies, but years later, repeated episodes of filter clogging led to the dis- covery of unacceptable quantities of particulates in com- binations of these drugs. The reader must always bear in mind these possibilities when only partial information is available.

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ABBREVIATIONS MANUFACTURER AND COMPENDIUM ABBREVIATIONS AA Amino acids (percentage specified) AB Abbott D Dextrose solution (percentage unspecified) ABV AbbVie D5LR Dextrose 5% in Ringer’s injection, lactated ABX Abraxis D5R Dextrose 5% in Ringer’s injection ACA Acacia D-S Dextrose-saline combinations ACC American Critical Care D2.5½S Dextrose 2.5% in sodium chloride 0.45% ACD Accord Healthcare D2.5S Dextrose 2.5% in sodium chloride 0.9% ACH Achaogen D5¼S Dextrose 5% in sodium chloride 0.225% ACT Actavis D5½S Dextrose 5% in sodium chloride 0.45% AD Adria D5S Dextrose 5% in sodium chloride 0.9% AFT AFT D10S Dextrose 10% in sodium chloride 0.9% AGT Aguettant D5W Dextrose 5% AH Allen & Hanburys D10W Dextrose 10% AHP Ascot Hospital Pharmaceuticals IM Isolyte M AKN Akorn IP Isolyte P ALL Allergan IS10 Invert sugar 10% ALP Alpharma I.U.a International unit(s) ALT Altana Pharma LR Ringer’s injection, lactated ALV Alveda Pharma NM Normosol M ALZ Alza NR Normosol R AM ASTA Medica NRD5W Normosol R in dextrose 5% AMA AMAG NS Sodium chloride 0.9% AMB Amneal Biosciences R Ringer’s injections AMD Amdipharm REF Refrigeration AMG Amgen RT Room temperature AMP Amphastar S Saline solution (percentage unspecified) AMR American Regent ½S Sodium chloride 0.45% AMS Amerisource SL Sodium lactate (1/6) M AND Andromaco TNA Total nutrient admixture (3-in-1) ANT Antigen TPN Total parenteral nutrition (2-in-1) AP Asta-Pharma W Sterile water for injection APC Apothecon APN Aspen a It is well accepted that “IU” is not a preferred abbreviation for international units. There is some difference of opinion among medication safety stakeholders APO Apotex on whether such units should be referred to simply as “units” or as APP American Pharmaceutical Partners “International Units.” Throughout the text of this reference, we generally have used the term international units to describe such units; however, because of APR Aspri space limitations within the columns of the Compatibility Information tables, the APT Aspen Triton term international units has been abbreviated as I.U. where necessary. AQ American Quinine AR Armour ARC American Red Cross ARD Ardeapharm ARR Arrow AS Arnar-Stone ASC Ascot ASP Astellas Pharma AST Astra

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ASZ AstraZeneca CEL Celgene AT Alpha Therapeutic CEN Centocor AUB Aurobindo CER Cerenex AUR Auromedics CET Cetus AVD Avadel Legacy Pharmaceuticals CH Lab. Choay Societe Anonyme AVE Aventis CHI Chiron AVG Alvogen CHS Chiesi AW Asta Werke CHU Chugai AY Ayerst CI Ciba AZV Laboratórios Azevedos CIS CIS US BA Baxter CL Clintec BB B & B Pharmaceuticals CLA Claris Lifesciences BAN Banyu Pharmaceuticals CLN Clinigen BAY Bayer CMB Cumberland BC Bencard CMP CMP Pharma BCT BioCryst Pharmaceuticals CN Connaught BD Becton Dickinson CNF Centrafarm BE Beecham CO Cole BED Bedford COM CommScope BEH Behring COR COR Therapeutics BEL R. Bellon COV Covis BFM Bieffe Medital CP Continental Pharma BI Boehringer Ingelheim CPP CP Pharmaceuticals BIO Bioniche Pharma CPR Cooper BK Berk CR Critikon BKN Baker Norton CRC Caraco BM Boehringer Mannheim CSL CSL Ltd. BMS Bristol-Myers Squibb CTI Cell Therapeutics Inc. BN Breon CU Cutter BP British Pharmacopoeia CUB Cubist BPC British Pharmaceutical Codexb CUP Cura Pharmaceuticals BPI BPI Labs CUR Curomed BR Bristol CY Cyanamid BRD Bracco Diagnostics DAK Dakota BRK Breckenridge DB David Bull Laboratories BRN B. Braun DCC Dupont Critical Care BRT Britianna DGL Douglas BT Boots DI Dista BTK Biotika DIA Diamant BV Ben Venue DM Dome BW Burroughs Wellcome DME Dupont Merck Pharma BX Berlex DMX Dumex BXT Baxalta DRA Dr. Rentschler Arzneimittel CA Calmic DRT Durata Therapeutics CAD Cadence Pharmaceuticals DRX Draxis CAR Cardinal Health DU DuPont CBH CSL Behring DUR Dura CDM CDM Lavoisier DW Delta West CE Carlo Erba EA Eaton

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EBE Ebewe HC Hillcross ECL Éclat HE Hengrui Medicine Co. EGL Eagle HEL Helsinn EI Eisai HER Heritage ELN Elan HIK Hikma EN Endo HMR Hoechst Marion Roussel ENZ Enzon HO Hoechst-Roussel ERF Erfa HOS Hospira ERM Erempharma HQS HQ Specialty Pharma ES Elkins-Sinn HR Horner ESL ESI Lederle HRN Heron ESP ESP Pharma HY Hyland EST Esteve ICI ICI Pharmaceuticals EV Evans ICN ICN Pharmaceuticals EX Essex IMM Immunex EXL Exela IMS IMS Ltd. FA Farmitalia IN Intra FAC Facta Farmaceutical INT Intermune FAN Fandre Laboratories IV Ives FAU Faulding IVX Ivex FC Frosst & Cie IX Invenex FED Federa JAZ Jazz FER Ferring JC Janssen-Cilag FI Fisons JHP JHP Pharmaceuticals FOR Forest Laboratories JJ Johnson & Johnson FP Faro Pharma JN Janssen FRE Fresenius JP Jones Pharma FRK Fresenius Kabi KA Kabi FUJ Fujisawa KED Kedrion GEI Geistich Pharma KEY Key Pharmaceuticals GEM Geneva-Marsam KN Knoll GEN Genentech KP Kabi Pharmacia GG Geigy KV Kabi-Vitrum GH Generic Health KY Kyowa GIL Gilead LA Lagap GIU Giulini LE Lederle GL Glaxo LEM Lemmon GLT Generics Limited LEO Leo Laboratories GNS Gensia-Sicor LFB Laboratoire Français du Fractionnement et des GO Goedecke Biotechnologies GRI Grifols LI Lilly GRP Gruppo LIF Lifeshield GRU Grunenthal LJ La Jolla GSK GlaxoSmithKline LME Laboratoire Meram GVA Geneva LUN Lundbeck GW Glaxo Wellcome LY Lyphomed GZ Genzyme LZ Labaz Laboratories HAE Haemonetics MA Mallinckrodt HB Hoechst-Biotika MAC Maco Pharma

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MAR Marsam OR Organon MAY Mayne Pharma ORC Orchid MB May & Baker ORP Orphan Medical MCD Merck Chibret Dohme ORT Ortho MDI Medimmune OTS Otsuka MDX Medex OVA Ovation MDZ Medicianz PAD Paddock ME Merck PAL Paladin MEL Melinta Therapeutics PAN Panpharma Laboratory MER Merus Labs PAR Par MG McGaw PB Pohl-Boskamp MGI MGI Pharma PD Parke-Davis MI Miles PE Pentagone MIL Millimed PF Pfizer MJ Mead Johnson PFM Pfrimmer MM Merrimack PH Pharmacia MMD Marion Merrell Dow PHC Pharmachemie MMT Meridian Medical Technologies PHM Pharmacosmos MN McNeil PHS Pharmascience MON Monarch PHT Pharma-Tek MRD Merrell-Dow PHU Pharmacia & Upjohn MRN Merrell-National PHX Phoenix MSD Merck Sharp & Dohme PNN Pantheon MTN Marathon PNT Parenta MUN Mundi Pharma PO Poulenc MY Maney PP Pharmaceutical Partners MYL Mylan PPC Pharmaceutical Partners of Canada MYR Mayrhofer Pharmazeutika PPR Premier Pro Rx NA National PR Pasadena Research NAB Nabi PRF Pierre Fabre NAP NAPP Pharmaceuticals PRK Parkfields NCI National Cancer Institute PRM Premier NE Norwich-Eaton PRP Premier Pro NIN Ningbo Team PTK Paratek NF National Formularyb PX Pharmax NO Nordic QI Qilu NOP Novopharm QLM Qualimed Labs NOV Novo Pharm QU Quad NVA Novartis RB Robins NVN Novo Nordisk RBP Ribosepharm NVP Nova Plus RC Roche NVX Novex Pharma REN Renaudin NYC Nycomed RI Riker OCT Octapharma RKB Reckitt & Benckhiser OHM Ohmeda RKC Reckitt & Colman OM Omega ROR Rorer OMJ OMJ Pharmaceuticals ROX Roxane OMN Ortho-McNeil RP Rhone-Poulenc ON Orion RPR Rhone-Poulenc Rorer

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RR Roerig TE Teva RS Roussel TEC Teclapharm RU Rugby TEL Teligent SA Sankyo TES Tesaro SAA Sanofi Aventis TET Tetraphase SAG Sageant TL Tillotts TMC The Medicines Company SAN Sanofi TO Torigian SB Sintetica Bioren TR Travenol SC Schering UCB UCB SCI Scios UP Upjohn SCN Schein USB US Bioscience SCS SCS Pharmaceuticals USP United States Pharmacopeiab SE Searle USV USV Pharmaceuticals SEQ Sequus UT United Therapeutics SER Servier VHA VHA Plus SGS SangStat VI Vitarine SGT Sagent VIC Vicuron Pharmaceuticals SHI Shionogi VT Vitrum SIA Siam Pharmaceutical WAS Wasserman WAT Watson SIC Sicor WAY Wyeth-Ayerst SIG Sigma Tau WB Winthrop-Breon SKB SmithKline Beecham WC Warner-Chilcott SKF Smith Kline & French WED Weddel SM Smith WEL Wellcome SMX SteriMax WI Winthrop SN Smith + Nephew WG WG Critical Care SO SoloPak WL Warner Lambert SP Spectrum Pharmaceuticals WOC Wockhardt SQ Squibb WW Westward SRB Serb WY Wyeth SS Sanofi-Synthelabo XGN X-Gen ST Sterilab XU Xudong Pharmaceutical Co. YAM Yamanouchi STP Sterop ZEN Zeneca STR Sterling ZLB ZLB Biopharma STS Steris STU Stuart ZNS Zeneus Pharma SUN Sun ZY ZyGenerics SV Savage ZYD Zydus SW Sanofi Winthrop SX Sabex b While reference to a compendium does not indicate the specific manufacturer of SY Syntex a product, it does help to indicate the formulation that was used in the test. SYN Synergen SYO Synthelabo REFERENCES SZ Sandoz For a list of references cited in the text of this monograph, TAK Takeda search the monograph titled References. TAL Talon Therapeutics TAP TAP Holdings TAR Targanta Therapeutics TAY Taylor

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AHFS® Pharmacologic-Therapeutic Classification©

AHFS CLASSIFICATION 8:12.28.20 - Lincomycins 4:00 - Antihistamine Drugs 8:12.28.24 - Oxazolidinones 12:00 - Autonomic Drugs 8:12.28.26 - Pleuromutilins 4:04 - First Generation Antihistamines 12:04 - Parasympathomimetic 8:12.28.28 - Polymyxins (Cholinergic) Agents 4:04.04 - Ethanolamine Derivatives* 8:12.28.30 - Rifamycins 4:04.08 - Ethylenediamine Derivatives* 8:12.28.32 - Streptogramins 12:08 - Anticholinergic Agents 4:04.12 - Phenothiazine Derivatives* 8:12.28.92 - Other Miscellaneous 12:08.04 - Antiparkinsonian Agents* Antibacterials* 4:04.16 - Piperazine Derivatives* 12:08.08 - Antimuscarinics/Antispasmodics 8:14 - Antifungals 4:04.20 - Propylamine Derivatives* 12:12 - Sympathomimetic (Adrenergic) 4:04.92 - Miscellaneous Derivatives* 8:14.04 - Allylamines Agents 8:14.08 - Azoles 4:08 - Second Generation 12:12.04 - α-Adrenergic Agonists Antihistamines 8:14.16 - Echinocandins 12:12.08 - β-Adrenergic Agonists 4:92 - Other Antihistamines* 8:14.28 - Polyenes 12:12.08.04 - Nonselective β-Adrenergic 8:14.32 - Pyrimidines Agonists 8:00 - Anti-infective Agents 8:14.92 - Antifungals, Miscellaneous 12:12.08.08 - Selective β1-Adrenergic 8:16 - Antimycobacterials Agonists 8:08 - Anthelmintics 8:16.04 - Antituberculosis Agents 12:12.08.12 - Selective β2-Adrenergic 8:12 - Antibacterials 8:16.92 - Antimycobacterials, Miscellaneous Agonists 12:12.12 - α- and β-Adrenergic Agonists 8:12.02 - Aminoglycosides 8:18 - Antivirals 8:12.06 - Cephalosporins 8:18.04 - Adamantanes 12:16 - Sympatholytic (Adrenergic Blocking) Agents 8:12.06.04 - First Generation Cephalosporins 8:18.08 - Antiretrovirals 8:12.06.08 - Second Generation 8:18.08.04 - HIV Entry and Fusion Inhibitors 12:16.04 - α-Adrenergic Blocking Agents Cephalosporins 8:18.08.08 - HIV Protease Inhibitors 12:16.04.04 - Nonselective 8:12.06.12 - Third Generation Cephalosporins 8:18.08.12 - HIV Integrase Inhibitors α-Adrenergic Blocking Agents 8:12.06.16 - Fourth Generation Cephalosporins 8:18.08.16 - HIV Nonnucleoside Reverse 12:16.04.08 - Nonselective 8:12.06.20 - Fifth Generation Cephalosporins Transcriptase Inhibitors α1-Adrenergic Blocking Agents* 8:12.06.28 - Siderophore Cephalosporins 8:18.08.20 - HIV Nucleoside and Nucleotide 8:12.07 - Miscellaneous β-Lactams Reverse Transcriptase Inhibitors 12:16.04.12 - Selective α1-Adrenergic 8:12.07.04 - Carbacephems* 8:18.08.92 - Antiretrovirals, Miscellaneous* Blocking Agents 8:12.07.08 - Carbapenems 8:18.20 - Interferons 12:16.08 - β-Adrenergic Blocking Agents* 12:16.08.04 - Nonselective β-Adrenergic 8:12.07.12 - Cephamycins 8:18.24 - Monoclonal Antibodies 8:12.07.16 - Monobactams Blocking Agents* 8:18.28 - Neuraminidase Inhibitors 12:16.08.08 - Selective β-Adrenergic Blocking 8:12.08 - Chloramphenicol 8:18.32 - Nucleosides and Nucleotides Agents* 8:12.12 - Macrolides 8:18.40 - HCV Antivirals 12:20 - Skeletal Muscle Relaxants 8:12.12.04 - Erythromycins 8:18.40.04 - HCV Cyclophilin Inhibitors* 12:20.04 - Centrally Acting Skeletal Muscle 8:12.12.12 - Ketolides* 8:18.40.08 - HCV Entry Inhibitors* Relaxants 8:12.12.92 - Other Macrolides 8:18.40.16 - HCV Polymerase Inhibitors 12:20.08 - Direct-acting Skeletal Muscle 8:12.16 - Penicillins 8:18.40.20 - HCV Protease Inhibitors Relaxants 8:12.16.04 - Natural Penicillins 8:18.40.24 - HCV Replication Complex 12:20.12 - GABA-derivative Skeletal Muscle 8:12.16.08 - Aminopenicillins Inhibitors Relaxants 8:12.16.12 - Penicillinase-resistant Penicillins 8:18.40.92 - HCV Antivirals, Miscellaneous* 12:20.20 - Neuromuscular Blocking Agents 8:12.16.16 - Extended-spectrum Penicillins 8:18.92 - Antivirals, Miscellaneous 8:12.18 - Quinolones 12:20.92 - Skeletal Muscle Relaxants, 8:30 - Antiprotozoals Miscellaneous 8:12.20 - Sulfonamides 8:30.04 - Amebicides 12:92 - Autonomic Drugs, 8:12.24 - Tetracyclines 8:30.08 - Antimalarials Miscellaneous 8:12.24.04 - Aminomethylcyclines 8:12.24.08 - Fluorocyclines 8:30.92 - Antiprotozoals, Miscellaneous 8:12.24.12 - Glycylcyclines 8:36 - Urinary Anti-infectives 16:00 - Blood Derivatives 8:12.28 - Antibacterials, Miscellaneous 8:92 - Anti-infectives, Miscellaneous* 8:12.28.04 - Aminocyclitols* 8:12.28.08 - Bacitracins 10:00 - Antineoplastic Agents 8:12.28.12 - Cyclic Lipopeptides 8:12.28.16 - Glycopeptides DOI: 10.37573/9781585286850.fm

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24:08.12.92 - Calcium-Channel Blocking 28:08.04 - Nonsteroidal Anti-inflammatory 20:00 - Blood Formation, Agents, Miscellaneous* Agents Coagulation, and Thrombosis 24:08.16 - Central α-Agonists 28:08.04.08 - Cyclooxygenase-2 (COX-2) 24:08.20 - Direct Vasodilators Inhibitors 20:04 - Antianemia Drugs 28:08.04.24 - Salicylates 24:08.20 - Direct Vasodilators 20:04.04 - Iron Preparations 28:08.04.92 - Other Nonsteroidal Anti- 24:08.24 - Diuretics* inflammatory Agents 20:04.08 - Liver and Stomach Preparations* 24:08.24.04 - Carbonic Anhydrase Inhibitors* 28:08.08 - Opiate Agonists 20:12 - Antithrombotic Agents 24:08.24.08 - Loop Diuretics* 28:08.12 - Opiate Partial Agonists 20:12.04 – Anticoagulants 24:08.24.12 - Osmotic Diuretics* 28:08.92 - Analgesics and Antipyretics, 20:12.04.08 - Coumarin Derivatives 24:08.24.16 - Potassium-sparing Diuretics* Miscellaneous 20:12.04.12 - Direct Thrombin Inhibitors 24:08.24.20 - Thiazide Diuretics* 20:12.04.14 - Direct Factor Xa Inhibitors 24:08.24.24 - Thiazide-like Diuretics* 28:10 - Opiate Antagonists 20:12.04.16 - Heparins 24:08.24.92 - Diuretics, Miscellaneous* 28:12 - Anticonvulsants 20:12.04.92 - Anticoagulants, Miscellaneous 24:08.32 - Peripheral Adrenergic Inhibitors 28:12.04 - Barbiturates 20:12.14 - Platelet-reducing Agents 24:08.44 - Renin-Angiotensin-Aldosterone 28:12.08 - Benzodiazepines 20:12.18 - Platelet-aggregation Inhibitors System Inhibitors* 28:12.12 - Hydantoins 20:12.20 - Thrombolytic Agents 24:08.44.04 - Angiotensin-Converting Enzyme Inhibitors* 28:12.16 - Oxazolidinediones* 20:12.92 - Antithrombotic Agents, 24:08.44.08 - Angiotensin II Receptor 28:12.20 - Succinimides Miscellaneous Antagonists* 28:12.92 - Anticonvulsants, Miscellaneous 20:16 - Hematopoietic Agents 24:08.44.20 - Mineralocorticoid (Aldosterone) 28:16 - Psychotherapeutic Agents 20:24 - Hemorrheologic Agents Receptor Antagonists* 24:08.92 - Hypotensive Agents, Miscellaneous* 28:16.04 - Antidepressants 20:28 - Antihemorrhagic Agents 24:12 - Vasodilating Agents 28:16.04.12 - Monoamine Oxidase Inhibitors 20:28.08 - Antiheparin Agents 28:16.04.16 - Selective Serotonin- and 24:12.08 - Nitrates and Nitrites 20:28.16 - Hemostatics Norepinephrine-reuptake Inhibitors 24:12.12 - Phosphodiesterase Type 5 Inhibitors 28:16.04.20 - Selective-serotonin Reuptake 20:28.92 - Antihemorrhagic Agents, 24:12.92 - Vasodilating Agents, Miscellaneous Inhibitors Miscellaneous 28:16.04.24 - Serotonin Modulators 20:92 - Blood Formation, Coagulation, 24:16 - Sclerosing Agents 28:16.04.28 - Tricyclics and Other and Thrombosis Agents, 24:20 - α-Adrenergic Blocking Agents Norepinephrine-reuptake Inhibitors Miscellaneous 24:24 - β-Adrenergic Blocking Agents 28:16.04.92 - Antidepressants, Miscellaneous 28:16.08 - Antipsychotics 24:28 - Calcium-Channel Blocking 24:00 - Cardiovascular Drugs 28:16.08.04 - Atypical Antipsychotics Agents 28:16.08.08 - Butyrophenones 24:04 - Cardiac Drugs 24:28.08 - Dihydropyridines 28:16.08.24 - Phenothiazines 24:28.92 - Calcium-Channel Blocking Agents, 28:16.08.32 - Thioxanthenes 24:04.04 - Antiarrhythmic Agents Miscellaneous 28:16.08.92 - Antipsychotics, Miscellaneous 24:04.04.04 - Class Ia Antiarrhythmics 24:04.04.08 - Class Ib Antiarrhythmics 24:32 - Renin-Angiotensin-Aldosterone 28:16.92 - Psychotherapeutic Agents, 24:04.04.12 - Class Ic Antiarrhythmics System Inhibitors Miscellaneous* 24:04.04.16 - Class II Antiarrhythmics* 24:32.04 - Angiotensin-Converting Enzyme 28:20 - Anorexigenic Agents and 24:04.04.20 - Class III Antiarrhythmics Inhibitors Respiratory and CNS 24:04.04.24 - Class IV Antiarrhythmics 24:32.08 - Angiotensin II Receptor Antagonists Stimulants 24:04.04.92 - Antiarrhythmics, Miscellaneous 24:32.20 - Mineralocorticoid (Aldosterone) 28:20.04 - Amphetamines 24:04.08 - Cardiotonic Agents Receptor Antagonists 28:20.08 - Anorexigenic Agents 24:04.92 - Cardiac Drugs, Miscellaneous 24:32.40 - Renin Inhibitors 28:20.08.04 - Amphetamine Derivatives 24:06 - Antilipemic Agents 24:32.92 - Renin-Angiotensin-Aldosterone 28:20.08.32 - Selective Serotonin Receptor System Inhibitors, Miscellaneous Agonists 24:06.04 - Bile Acid Sequestrants 28:20.08.92 - Anorexigenic Agents, 24:06.05 - Cholesterol Absorption Inhibitors Miscellaneous 24:06.06 - Fibric Acid Derivatives 26:00 - Cellular Therapy* 28:20.32 - Respiratory and CNS Stimulants 24:06.08 - HMG-CoA Reductase Inhibitors 28:20.80 - Wakefulness-promoting Agents 24:06.24 - Proprotein Convertase Subtilisin 28:00 - Central Nervous System 28:20.92 - Anorexigenic Agents and Stimulants, Kexin Type 9 (PCSK9) Inhibitors Miscellaneous* Agents 24:06.92 - Antilipemic Agents, Miscellaneous 28:24 - Anxiolytics, Sedatives, and 24:08 - Hypotensive Agents 28:04 - General Anesthetics Hypnotics 24:08.04 - α-Adrenergic Blocking Agents* 28:04.04 - Barbiturates 28:24.04 - Barbiturates 24:08.08 - β-Adrenergic Blocking Agents* 28:04.16 - Inhalation Anesthetics* 28:24.08 - Benzodiazepines 24:08.12 - Calcium-Channel Blocking Agents* 28:04.92 - General Anesthetics, Miscellaneous 28:24.92 - Anxiolytics, Sedatives, and Hypnotics, 24:08.12.08 - Dihydropyridines* 28:08 - Analgesics and Antipyretics Miscellaneous

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28:28 - Antimanic Agents 36:56 - Myasthenia Gravis 44:00 - Enzymes 28:32 - Antimigraine Agents 36:58 - Ocular Disorders* 28:32.12 - Calcitonin Gene-related Peptide 36:60 - Thyroid Function* (CGRP) Antagonists 36:61 - Pancreatic Function 48:00 - Respiratory Tract Agents 28:32.28 - Selective Serotonin Agonists 36:62 - Phenylketonuria* 28:32.92 - Antimigraine Agents, Miscellaneous* 48:02 - Antifibrotic Agents 36:64 - Pheochromocytoma* 28:36 - Antiparkinsonian Agents 48:04 - Antihistamines* 36:66 - Pituitary Function 28:36.04 - Adamantanes 48:04.04 - First Generation Antihistamines* 28:36.08 - Anticholinergic Agents 36:68 - Roentgenography* 48:04.08 - Second Generation Antihistamines* 28:36.12 - Catechol-O-Methyltransferase 36:70 - Respiratory Function* 48:08 - Antitussives (COMT) Inhibitors 36:72 - Scarlet Fever* 48:10 - Anti-inflammatory Agents 28:36.16 - Dopamine Precursors 36:76 - Sweating* 48:10.08 - Corticosteroids* 28:36.20 - Dopamine Receptor Agonists 36:80 - Trichinosis* 48:10.08.04 - Nasal Preparations* 28:36.20.04 - Ergot-derivative Dopamine 48:10.08.08 - Orally Inhaled Preparations* 36:84 - Tuberculosis Receptor Agonists 48:10.20 - Interleukin Antagonists 28:36.20.08 - Nonergot-derivative Dopamine 36:88 - Urine and Feces Contents* 48:10.24 - Leukotriene Modifiers Receptor Agonists 36:88.12 - Ketones* 28:36.32 - Monoamine Oxidase B Inhibitors 48:10.32 - Mast-cell Stabilizers 36:88.20 - Occult Blood* 48:12 - Bronchodilators* 28:40 - Fibromyalgia Agents 36:88.24 - pH* 28:56 - Vesicular Monoamine 48:12.04 - Adrenergic Agents* 36:88.28 - Protein* 48:12.04.08 - Nonselective β-Adrenergic Transporter 2 (VMAT2) 36:88.40 - Sugar* Agonists* Inhibitors 48:12.04.12 - Selective β2-Adrenergic Agonists* 28:92 - Central Nervous System 38:00 - Disinfectants (for agents Agents, Miscellaneous 48:12.04.16 - α- and β-Adrenergic Agonists* used on objects other than skin)* 48:12.08 - Anticholinergic Agents* 32:00 - Nonhormonal 48:12.12 - Xanthine Derivatives* Contraceptives* 40:00 - Electrolytic, Caloric, and 48:14 - Cystic Fibrosis Transmembrane Water Balance Conductance Regulator Modulators 34:00 - Dental Agents* 40:04 - Acidifying Agents 48:14.04 - Cystic Fibrosis Transmembrane 40:08 - Alkalinizing Agents Conductance Regulator Correctors 40:10 - Ammonia Detoxicants 48:14.12 - Cystic Fibrosis Transmembrane 36:00 - Diagnostic Agents Conductance Regulator Potentiators 40:12 - Replacement Preparations 48:16 - Expectorants 36:04 - Adrenocortical Insufficiency 40:18 - Ion-removing Agents 48:24 - Mucolytic Agents 36:06 - Allergenic Extracts* 40:18.16 - Sodium-removing Agents* 48:32 - Phosphodiesterase Type 4 36:08 - Amyloidosis* 40:18.17 - Calcium-removing Agents Inhibitors 36:10 - Appendicitis* 40:18.18 - Potassium-removing Agents 48:36 - Pulmonary Surfactants 36:12 - Blood Volume* 40:18.19 - Phosphate-removing Agents 48:48 - Vasodilating Agents 36:16 - Brucellosis* 40:18.92 - Other Ion-removing Agents 40:20 - Caloric Agents 48:92 - Respiratory Agents, 36:18 - Cardiac Function Miscellaneous 36:24 - Circulation Time* 40:24 - Salt and Sugar Substitutes* 36:26 - Diabetes Mellitus* 40:28 - Diuretics 52:00 - Eye, Ear, Nose, and Throat 36:28 - Diphtheria* 40:28.04 - Carbonic Anhydrase Inhibitors* (EENT) Preparations 36:30 - Drug Hypersensitivity* 40:28.08 - Loop Diuretics 40:28.12 - Osmotic Diuretics 52:02 - Antiallergic Agents 36:32 - Fungi 40:28.16 - Potassium-sparing Diuretics 52:04 - Anti-infectives 36:34 - Gallbladder Function 40:28.20 - Thiazide Diuretics 52:04.04 - Antibacterials 36:36 - Gastric Function* 40:28.24 - Thiazide-like Diuretics 52:04.16 - Antifungals 36:38 - Intestinal Absorption* 40:28.28 - Vasopressin Antagonists 52:04.20 - Antivirals 36:40 - Kidney Function 40:28.92 - Diuretics, Miscellaneous* 52:04.92 - Anti-infectives, Miscellaneous 36:44 - Liver Function 40:36 - Irrigating Solutions 52:08 - Anti-inflammatory Agents 36:46 - Lymphatic System* 40:40 - Uricosuric Agents 52:08.08 - Corticosteroids 36:48 - Lymphogranuloma Venereum* 40:92 - Electrolytic, Caloric, and Water 52:08.20 - Nonsteroidal Anti-inflammatory 36:52 - Mumps Balance Agents, Miscellaneous Agents

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52:08.92 - Anti-inflammatory Agents, 68:34 - Other Corpus Luteum Miscellaneous 68:00 - Hormones and Synthetic Hormones* Substitutes 52:12 - Contact Lens Solutions* 68:36 - Thyroid and Antithyroid Agents 52:16 - Local Anesthetics 68:04 - Adrenals 68:36.04 - Thyroid Agents 52:24 - Mydriatics 68:08 - Androgens 68:36.08 - Antithyroid Agents 52:28 - Mouthwashes and Gargles 68:12 - Contraceptives 68:40 - Leptins 52:32 - Vasoconstrictors 68:16 - Estrogens, Antiestrogens, and 68:44 - Renin-Angiotensin-Aldosterone 52:40 - Antiglaucoma Agents Estrogen Agonist-Antagonists System 52:40.04 - α-Adrenergic Agonists 68:16.04 - Estrogens 52:40.08 - β-Adrenergic Blocking Agents 68:16.08 - Antiestrogens 72:00 - Local Anesthetics 52:40.12 - Carbonic Anhydrase Inhibitors 68:16.12 - Estrogen Agonist-Antagonists 52:40.20 - Miotics 68:18 - Gonadotropins and 76:00 - Oxytocics 52:40.24 - Osmotic Agents* Antigonadotropins 52:40.28 - Prostaglandin Analogs 68:18.04 - Antigonadotropins 52:40.32 - Rho Kinase Inhibitors 68:18.08 - Gonadotropins 78:00 - Radioactive Agents* 52:40.92 - Antiglaucoma Agents, Miscellaneous* 68:20 - Antidiabetic Agents 68:20.02 - α-Glucosidase Inhibitors 52:92 - EENT Drugs, Miscellaneous 80:00 - Antitoxins, Immune 68:20.03 - Amylinomimetics Globulins, Toxoids, and Vaccines 56:00 - Gastrointestinal Drugs 68:20.04 - Biguanides 68:20.05 - Dipeptidyl Peptidase IV (DDP-4) 80:02 - Allergenic Extracts* 56:04 - Antacids and Adsorbents Inhibitors 80:04 - Antitoxins and Immune 56:08 - Antidiarrhea Agents 68:20.06 - Incretin Mimetics Globulins 56:10 - Antiflatulents 68:20.08 - Insulins 80:08 - Toxoids 68:20.08.04 - Rapid-acting Insulins 56:12 - Cathartics and Laxatives 80:12 - Vaccines 68:20.08.08 - Short-acting Insulins 56:14 - Cholelitholytic Agents 68:20.08.12 - Intermediate-acting Insulins 56:16 - Digestants 68:20.08.16 - Long-acting Insulins 84:00 - Skin and Mucous 56:20 - Emetics* 68:20.16 - Meglitinides Membrane Agents 56:22 - Antiemetics 68:20.17 - Sodium-glucose Cotransporter 1 (SGLT1) Inhibitors* 84:04 - Anti-infectives 56:22.08 - Antihistamines 68:20.18 - Sodium-glucose Cotransporter 2 84:04.04 - Antibacterials 56:22.20 - 5-HT3 Receptor Antagonists (SGLT2) Inhibitors 84:04.06 - Antivirals 56:22.32 - Neurokinin-1 Receptor 68:20.20 - Sulfonylureas 84:04.08 - Antifungals Antagonists 68:20.28 - Thiazolidinediones 84:04.08.04 - Allylamines 84:04.08.08 - Azoles 56:22.92 - Antiemetics, Miscellaneous 68:20.92 - Antidiabetic Agents, Miscellaneous* 84:04.08.12 - Benzylamines 56:24 - Lipotropic Agents* 68:22 - Antihypoglycemic Agents 84:04.08.16 - Echinocandins* 56:28 - Antiulcer Agents and Acid 68:22.12 - Glycogenolytic Agents 84:04.08.20 - Hydroxypyridones Suppressants 68:22.92 - Antihypoglycemic Agents, 84:04.08.24 - Oxaboroles Miscellaneous 84:04.08.28 - Polyenes 56:28.12 - Histamine H2-Antagonists 84:04.08.32 - Pyrimidines* 56:28.28 - Prostaglandins 68:24 - Parathyroid and Antiparathyroid Agents 84:04.08.40 - Thiocarbamates 56:28.32 - Protectants 84:04.08.92 - Antifungals, Miscellaneous 68:24.04 - Antiparathyroid Agents 56:28.36 - Proton-pump Inhibitors 84:04.12 - Scabicides and Pediculicides 68:24.08 - Parathyroid Agents 56:28.92 - Antiulcer Agents and Acid 84:04.92 - Local Anti-infectives, Miscellaneous 68:28 - Pituitary Suppressants, Miscellaneous* 84:06 - Anti-inflammatory Agents 68:29 - Somatostatin Agonists and 56:32 - Prokinetic Agents 84:06.08 - Corticosteroids Antagonists 56:36 - Anti-inflammatory Agents 84:06.20 - Nonsteroidal Anti-inflammatory 68:29.04 - Somatostatin Agonists Agents 56:92 - GI Drugs, Miscellaneous 68:29.08 - Somatostatin Antagonists* 84:06.92 - Anti-inflammatory Agents, 68:30 - Somatotropin Agonists and Miscellaneous 60:00 - Gold Compounds Antagonists 84:08 - Antipruritics and Local 68:30.04 - Somatotropin Agonists Anesthetics 64:00 - Heavy Metal Antagonists 68:30.08 - Somatotropin Antagonists 84:12 - Astringents 68:32 - Progestins 84:16 - Cell Stimulants and Proliferants

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84:20 - Detergents 88:24 - Vitamin K Activity 84:24 - Emollients, Demulcents, and 88:28 - Multivitamin Preparations Protectants* 84:24.04 - Basic Lotions and Liniments* 92:00 - Miscellaneous Therapeutic 84:24.08 - Basic Oils and Other Solvents* Agents 84:24.12 - Basic Ointments and Protectants* 84:24.16 - Basic Powders and Demulcents* 92:04 - Alcohol Deterrents 84:28 - Keratolytic Agents 92:08 - 5-α-Reductase Inhibitors 84:32 - Keratoplastic Agents 92:12 - Antidotes 84:50 - Depigmenting and Pigmenting 92:16 - Antigout Agents Agents 92:18 - Antisense Oligonucleotides 84:50.04 - Depigmenting Agents 92:20 - Immunomodulatory Agents 84:50.06 - Pigmenting Agents 92:22 - Bone Anabolic Agents 84:80 - Sunscreen Agents 92:24 - Bone Resorption Inhibitors 84:92 - Skin and Mucous Membrane 92:26 - Carbonic Anhydrase Inhibitors Agents, Miscellaneous 92:28 - Cariostatic Agents 92:32 - Complement Inhibitors 86:00 - Smooth Muscle Relaxants 92:36 - Disease-Modifying 86:08 - Gastrointestinal Smooth Antirheumatic Drugs Muscle Relaxants* 92:40 - Gonadotropin-releasing 86:12 - Genitourinary Smooth Muscle Hormone Antagonists* Relaxants 92:44 - Immunosuppressive Agents 86:12.04 - Antimuscarinics 92:56 - Protective Agents

86:12.08 - β3-Adrenergic Agonists 92:92 - Other Miscellaneous Therapeutic Agents 86:12.08.12 - Selective β3-Adrenergic Agonists 86:16 - Respiratory Smooth Muscle 94:00 - Devices* Relaxants 96:00 - Pharmaceutical Aids* 88:00 - Vitamins

88:04 - Vitamin A * Category is currently not in use in . 88:08 - Vitamin B Complex the printed version of AHFS Drug 88:12 - Vitamin C Information® 88:16 - Vitamin D 88:20 - Vitamin E

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