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(cid:1) (> DRUG ERUPTION & REACTION MANUAL 29th EDITION 2023 Neil H. Shear, MD, FRCPC, FACP Professor of Dermatology and Clinical Pharmacology and Toxicology University of Toronto, Canada 0 CRC Press Taylor &.Francis Group Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business Twenty Ninth edition published 2023 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2023 Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. 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ISBN: 9781032413617 (hbk) ISBN: 9781032413594 (pbk) ISBN: 9781003357728 (ebk) DOI: 10.1201/9781003357728 CONTENTS Introductory notes v Drug profiles: generic names A–Z 1 Descriptions of important reactions 383 Drugs that cause important reactions 389 Main classes of drugs 423 Class reactions 429 ACE inhibitors 429 Antiarrhythmics 431 Antibiotics, macrolide 433 Anticonvulsants 435 Antidepressants, tricyclic 438 Antifungal, Imidazole 439 Antimalarials 440 Antineoplastics 442 Antipsychotics 447 Antiretrovirals 450 Benzodiazepines 453 Beta blockers 455 Bisphosphonates 456 Calcium channel blockers 457 Cephalosporins 459 Corticosteroids, topical 460 Dipeptidyl-Peptidase 4 (DPP4) inhibitors 461 Disease-modifying antirheumatic drugs (DMARDS) 462 Epidermal growth factor receptor (EGFR) inhibitors 465 Fluoroquinolones 468 H1 receptor antagonists 470 HMG-CoA reductase inhibitors/statins 472 Immune checkpoint inhibitors 474 Monoclonal antibodies 476 Non-steroidal anti-inflammatories (NSAIDS) 481 Proton pump inhibitors (PPI) 484 TNF inhibitors 486 Tyrosine-kinase inhibitors 489 Genetic tables 493 Concordance of synonyms and trade names with generic names 507 iii A Note from the Editor Patients frequently ask about their prescribed drug: “Is it safe?” This text is meant to help all prescribers, dispensers and patients understand what the risk of harm might be; whether it is from a drug reaction or interaction, Litt’s D.E.R.M. is the go to information source. How does this information help answer the unanswerable? Simply put, safety is a process, not a question. With the right information at hand a safe environment can thrive; the most up-to-date relevant data help peel away background noise from a seemingly infinite number of sources. This new edition adds additional support to a risk management environment, and we will continue to provide the most up-to-date and relevant information; so we include known genetic risks that are associated with drug reactions and can be screened prior to drug therapy. Litt’s D.E.R.M. is more than a text. It is part of a community of resources to make prescribing safe and to help optimize therapy. To that end remember that the on-line information in the database is almost double what you see in the text. And it too is kept up-to-date on a regular basis! For me I am in love with the Litt app – an easy portal to the online data base, particularly if you are moving between various work spaces. One patient on three critical drugs developed a rash on day 8 of treatment; the Litt app gave me easy access to the likelihood of an exanthematous rash for each, and I could provide a clear, quantitative, and thoughtful direction for the immediate future. Drug eruptions are still very important in all aspects of medicine. And the number of drugs and reactions continues to increase with great diversity! Systemic effects are also more commonly recognized; the skin is just the beginning. I am so grateful to the team at CRC Press who continue to keep the Litt manual and database current and to provide the best breadth and relevant information to support a safer environment in medicine. Thank you for supporting our activities. Neil H. Shear, MD, FRCPC, FACP Litt’s Drug Eruption & Reaction Manual – at a glance This 29th edition has been revised and updated throughout to present a quick clinical reference guide to adverse drug reactions (ADRs), side effects, drug interactions and other safety information for prescription and over-the-counter medications. There is material on reactions caused by classes of drugs, enabling you to see at a glance whether a reaction is common to all the drugs in that particular class, or to a majority of them, or only to a significant few. The aims of this edition remain: 1. To help medical practitioners make informed and safe decisions when diagnosing and prescribing, and also when generally seeking information. 2. To help healthcare professionals remain pharmacovigilant. 3. To provide all physicians, lecturers, educators, and pharmacists with an easy-to-use and reliable quick reference tool. Space in the manual is, unfortunately, constrained. The full and comprehensive picture for all drugs – from which our informa tion derives – can be found in the Litt database (www.drugeruptiondata.com), which is updated continually. The Litt database was originated by Jerome Z. Litt; and is now edited by Neil H. Shear, with advice and input by Rupert Purchase, DPhil, CChem, FRSC. v A note on ADRs The incidence and severity of ADRs are influenced by a number of factors: 1. Patient-related factors: • Age – geriatric, pediatric, adolescent . . . older patients are taking more medications-hence more of a possibility of develop ing reactions; pediatric patients have more delicate skins; hormonal changes occur in adolescents . . . All these factors play roles in the development of possible adverse reactions. • Gender – male or female – and if the latter, then pregnant/breast-feeding/menopausal . . . • Disease – not only the disease being treated, but also other pre-existing health conditions and comorbid diseases. For example, atopic patients are at increased risk for serious allergic reactions; also, there would be an increased risk for hyper sensitivity drug reactions if the patient has asthma or lupus erythematosus. • Genetics – a patient could have abnormal drug metabolism due to inheriting abnormal alleles (see further the section of Genetic Tables). • Geography – patients living in sunny climes could develop phototoxicities from photosensitizing drugs more readily than those who inhabit cooler, less sunny climates. 2. Drug-related factors: • Type/class of drug – for example, there is a heightened risk of angioedema with the use of ACE inhibitors (see further the section of tables of class reactions). • Duration of therapy – the longer a patient maintains the therapy, the more possible it becomes that he/she could develop a reaction due to their changes in drug metabolism (e.g. renal insufficiency) or drug interactions. • Dosage – the greater the dosage, the more likely an adverse side effect. • Bioavailability – the extent to and rate at which the drug enters systemic circulation, thereby accessing the site of action. • Interactions with other drugs – for example, synergistic QT prolongation can occur when two QT prolonging agents, such as erythromycin + ritonavir, are used together. • Route of administration – intramuscular, intravenous, subcutaneous, and topical administrations are more likely to cause hypersensitivity reactions; oral medications are less likely to result in drug hypersensitivity. The terms “drug allergy,” “drug hypersensitivity,” and “drug reaction” are often used interchangeably. “Drug allergy” specifi cally refers to a reaction mediated by IgE; “drug hypersensitivity” is an immune-mediated response to a drug agent in a sensi tized patient; and “drug reactions” comprise all adverse events related to drug administration, regardless of etiology. Vigilance at point of care: While the possibilities for adverse drug reactions seem endless, we must be on the lookout for any new medication(s) the patient might be taking. A thorough, detailed history of all medications must be made in order to elicit any remote possibility that the drug in question might be the culprit for the side effect. People do not often realize that the common over-the counter analgesics – aspirin, Tylenol, Advil, Motrin, Naprosyn, and others – are actually medications. Herbals and supple ments such as St. John’s wort, ginkgo biloba, and echinacea can be responsible for various hypersensitivity reactions. For example, St. John’s wort, in particular, interacts adversely with SSRIs and tricyclic antidepressants. vi Contents of the book, and how to use them 1. The A–Z The major portion of the manual lists in alphabetical order the 1500 most consulted and most important generic drugs, biologics, and supplements, and the adverse reactions that can arise from their use. If you do not find a drug in the main A–Z listing under the name you know it by, you can turn to the concordance of synonyms and trade names to find the generic name it will be listed under. Trade (brand) name(s) are listed alphabetically. When there are many trade names, the ten (or so) most commonly recognized ones are listed. Following the trade names is – in parentheses – the latest name of the pharmaceutical company that markets the drug. Many of the names of companies have changed from earlier editions of this manual because of acquisitions, mergers, and other factors in the pharmaceutical industry. Next appear the Indication(s), the Class in which the drug belongs, and the Half-life of each drug, where known. Drug interactions: many severe, hazardous drug-drug interactions are recorded. Only clinically significant drug inter actions that have been reported to trigger potential harm and that could be life threatening have been included here in the profile. These interactions are predictable and well documented in controlled studies; they should be avoided. Pregnancy category: for new drugs approved on or after 30 June 2015 this field gives (where available) a brief summary of the full statement reflecting the risk for pregnant women as given in the prescribing guidelines; health care providers are advised to check the individual label where necessary. An explanation of the categories for older drugs (A, B, C, D and X) can be found on our website – www.drugeruptiondata.com. Any “Black box” Warning required by the FDA or Notes on use then follow. Adverse Drug Reactions: under each drug profile is a list of related ADRs. These adverse events have been classified under the following categories: Skin, Hair, Nails, Mucosal; Cardiovascular, Central Nervous System, Endocrine/ Metabolic, Gastrointestinal/Hepatic, Genitourinary, Hematologic, Local, Neuromuscular/Skeletal, Ocular, Otic, Renal, Respiratory, Other. Within each category, the reactions are listed alphabetically. Thus, the order of listing does not reflect severity or frequency in any way. The terminology used to list reaction patterns has been simplified as far as possible by eliminating, for the most part, tags such as “like” (as in “-Psoriasis-like”), “-reactivation,” “-syndrome,” “-dissemination,” “-iform,” etc. The number of reports is given for each reaction in square brackets. The incidence of the most important reactions is given in parentheses where indicated (usually from the full prescribing information for the relevant drug). For example, the profile for Amoxicillin begins: Skin AGEP [28] Anaphylactoid reactions/anaphylaxis (includes anaphylactic shock) [17] Angioedema (<10%) [5] This means that we have 28 journal articles referring to occurrence of AGEP (acute generalized exanthematous pustulosis); 17 articles mentioning the occurrence of anaphylaxis; and 5 articles discussing angioedema, as reactions to Amoxicillin within the Skin category. All these articles appear on our website – www.drugeruptiondata.com – together with links to the article abstracts on PubMed®. Additionally, the incidence of angioedema as a reaction has been reported as up to 10%. On some occasions, there are very few adverse reactions to a specific drug. These drugs are still included in the manual as there is a positive significance in knowing there are no adverse reports. vii 2. Important eruptions / reactions i) This section of the manual includes a listing of descriptions of important eruption and reaction patterns. Over 40 eruptions/reactions are described here in alphabetical order, from Acanthosis nigricans to Xerostomia. (Descriptions of several other reactions, and lists of drugs associated with these reactions, can be found on our website – www.drugeruptiondata.com.) ii) There follows the list of drugs that cause the most important reactions, as a quick reference guide. iii) We then have a list of the main classes of drugs, from 5-HT1 agonists to Xanthine alkaloids, as a quick reference guide. iv) There follows a newly enlarged section of tables of class reactions, enabling you to see at a glance whether a reaction is common to all the drugs in that particular class, or to a majority of them, or only to a significant few. v) Next are tables of reported genetic associations with cutaneous adverse drug reactions and recommendations from various sources regarding genetic screening to prevent cutaneous adverse drug reactions. 3. The Concordance The final part of the manual is a concordance to match synonyms (noted in italic) and trade names with the generic drug name. If you know only the synonym or trade name, you can use this list to find the corresponding generic name to look up in the main A–Z listing section of the book. viii Being a drug reaction sleuth! Neil H Shear I’ll start off with a real referral sent to me a few years ago (I expect it will sound familiar to all dermatologists): “Dear Neil, I am just seeing a patient at the hospital. The patient took amoxicillin and clarithromycin 1 week before & ceftriaxone 45 min before getting a rash. I think it very unlikely that ceftriaxone is the cause. As far as I know he never had it before. The reason for this note is that our Respiratory Physician feels strongly that ceftriaxone is the cause. What do you think?” What I do like about this is the fact that this is a written (email) request, so any reply I give has some demonstrable existence, as against a phone call or hall chat relying on memory only. However, a common mistake would be to answer the question “What do you think?” There is very limited information about this patient whom I did not see and will never see. The first step in a proper consultation is DIAGNOSIS of the possible drug reaction. There are 3 key components for making a diagnosis: – Appearance of the rash – Systemic issues – Histology My mnemonic is Remember: Appearance, Systemic, Histology (RASH). Thinking back on the referral sent to me I have very little information to help make a diagnosis. What was the “rash” and were there systemic symptoms and signs? I don’t know. So I will need to ask for more detailed infor mation if this consultation continues. The second step is to determine CAUSALITY. Note the referral is focused on an assumption that I will pick a single drug that caused the “rash”. Unfortunately, that is not how life works. There are at a minimum 3 possible causes that we know of from the history of drugs given. We don’t know if the patient was on other drugs or has a drug allergy history. In this case I will have to assume there are NO systemic features and that the “rash” is a “simple exanthem”. Causality assessments demand: –A quantitative approach (numbers matter) – Using a Bayesian type of approach we can generate probabilities that each drug we know of might have caused a reaction. So now I need to see what the baseline rate of “rash” is for each drug. This is where Litt comes in . . . Amoxicillin Looking at the Amoxicillin listing in the database (Fig 1) or the Amoxicillin summary in the manual I can see that there are 33 reports of the reaction and that the background rate is estimated at >5%. This is not the final step, but it gives me some evidence to demonstrate that, although each of these drugs could cause rash, one is much more likely than the others. Figure 1 ix