An Inventory of Medicinal Products Causing Skin Rash: Clinical and Regulatory Lessons
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EXPERIMENTAL AND THERAPEUTIC MEDICINE 18: 5061-5071, 2019 An inventory of medicinal products causing skin rash: Clinical and regulatory lessons ROBERT ANCUCEANU1, MIHAELA DINU1, FLORENTINA FURTUNESCU2 and DANIEL BODA3,4 1Department of Pharmaceutical Botany and Cell Biology, Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, 020956 Bucharest; 2Department of Public Health and Management, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 050463 Bucharest; 3Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest; 4Carol Medical Center, 010626 Bucharest, Romania Received September 21, 2018; Accepted May 27, 2019 DOI: 10.3892/etm.2019.7837 Abstract. A variety of medicinal products have been homogeneity in reporting rash frequency, by using Council for associated with rash and normally this information should be International Organizations of Medical Sciences classification, available in the Summary of Product Characteristics (SmPCs). and Medical Dictionary for Regu latory Activities coding in a Our study aimed to investigate the frequency of rash as an more standardized manner, and also the need to include more adverse drug reaction, based on the information provided safety endpoints in clinical trials and to use better the safety by SmPCs of 1,048 single active substances (international results for publication and updating the SmPCs. non-proprietary names) authorized in the United Kingdom. Data on rash frequency was collected from each SmPC using Introduction automated searches based on selected keywords. Data analysis was carried out using R, v. 3.4. We found that over 90% of A ‘rash’ is defined as a ‘sudden skin eruption’ and is the main the medicines used orally or by injection may be associated driver of patients to visit a dermatologist. A rash is often the with rash as an adverse event, the most common classes being result of an underlying disease (1), but a variety of medicinal protein kinase inhibitors, anticancer medicinal products, products have also been associated with rashes. An eruptive monoclonal antibodies, biologicals, antivirals and retinoids, skin rash associated with fever or other systemic symptoms is with high variations in rash frequency for products within sometimes described as an ‘exanthema’ (1) or ‘maculopapular the same class, but also for products with the same active rash’, although (as shown below), the term (or its derivation, substance. Analysis of SmPCs revealed the need to increase ‘exanthematous eruptions’) is used to describe the most common form of cutaneous eruption, consisting in an acute and extensive eruption of small fixed erythematous spots that become whitish or pale when applying pressure (2). Correspondence to: Professor Mihaela Dinu, Department of It has been estimated that ~1-7% of all hospital admissions Pharmaceutical Botany and Cell Biology, Faculty of Pharmacy, or referrals from primary care are related to skin adverse drug ‘Carol Davila’ University of Medicine and Pharmacy, 6 Traian Vuia reactions (ADRs) (3,4). Of these, the majority (almost half) are Street, Sector 2, 020956 Bucharest, Romania represented by exanthema (maculopapular rash), as confirmed E-mail: [email protected] by multiple observational studies (4-6) and it has been claimed that almost all medicines have been associated with rash (7). Abbreviations: ACE, angiotensin-converting enzyme; ADHD, attention deficit hyperactivity disorder; ADR, adverse drug reaction; CIOMS, Council for International Organizations of Allergic and non‑allergic hypersensitivity reactions. Medical Sciences; DMARDs, disease-modifying antirheumatic Immune-mediated adverse drug reactions, generally described drugs; DPP4, dipeptidyl peptidase 4; DRESS, drug-reaction with as ‘hypersensitivity reactions’ or ‘allergic reactions/allergy’ eosinophilia and systemic symptoms; eMC, electronic Medicines are not limited to rash, but they may include it, as they may be Compendium; FDC, fixed-dose combination; GLP1, glucagon-like expressed in a variety of clinical forms, from maculopapular peptide 1; MAH, marketing authorization holder; MedDRA, exanthema to urticaria, angioedema or anaphylaxis (8). Equality Medical Dictionary for Regulatory Activities; NSAID, nonsteroidal is often placed between ‘hypersensitivity reactions’ and anti-inflammatory drug; NMDA, N-methyl-D-aspartate; PDE5, ‘allergic reactions’, nevertheless not all drug hypersensitivity phosphodiesterase type 5; SGLT2, sodium-glucose co-transporter 2; reactions are of an allergic nature. The term ‘nonallergic drug SmPC, Summary of Product Characteristics; TNF, tumor necrosis hypersensitivity reactions’ is used in accordance with the factor international consensus to describe drug reactions similar to Key words: rash, summary of product characteristics, regulatory, allergy, but for which no immunological mechanism has been medicinal products, adverse drug reaction proven (9). Instead, the phrase ‘drug allergy’ is reserved for those cases where an immune mechanism involving either antibodies or T cells mediates the reaction. The international 5062 ANCUCEANU et al: AN INVENTORY OF MEDICINAL PRODUCTS CAUSING SKIN RASH consensus recommendation is that for general communication convey, with respect to clinical pharmacology contents (17), purposes in the case of a suspicion of drug allergy the term therapeutic drug monitoring (18,19), dose adjustment in ‘drug hypersensitivity reaction’ should be used (9). In a renal impairment (20,21), drug-drug (16,22) and drug-food cross-sectional study among a general population sample a interactions (23), use of medicinal products in pregnancy and prevalence of 7.8% of ‘drug allergy’ has been found based on lactation (15) or the information provided about biosimilar self-report by the responders (10) (since this was self-reported, medicinal products (24). and thus the allergic nature was only suspected, the term ‘drug Although various narrative reviews have been published on hypersensitivity reaction’ would have been preferable). rash and other adverse drug reactions in general (2,13,25-28), as well as for different therapeutic groups (29-33), no Immediate and delayed allergic reactions. According to their comprehensive review of rash as an adverse effect of medi- onset, drug induced allergic reactions may be immediate and cines has been published. In the present study we report on delayed (non-immediate). Immediate drug induced allergic our investigation of the frequency of rash as an adverse drug reactions occur soon after administration of the causative agent reaction, based on the information provided by SmPC. We and are likely to be mediated by IgE (9). Although periods also critically reflect on shortfalls identified in the way this as short as 1 h have been proposed and are still used (11), it information is included in SmPC and the inconsistencies we has been rightly pointed out that a reasonable period to label have identified. one drug reaction as ‘immediate’ should be longer, up to 6 h (9,12). Immediate allergic reactions may manifest through Materials and methods a diversity of symptoms: urticaria, angioedema, anaphylaxis or anaphylactic shock, conjunctivitis, rhinitis, bronchospasm or SmPCs of medicines corresponding to 1,048 single active even gastrointestinal symptoms (nausea, vomiting, diarrhoea substances (international non-proprietary names) authorized and abdominal pain) (9,11,13). Delayed drug hypersensitivity in the United Kingdom (irrespective of the authorization reactions usually occur after several or many days of treatment, procedure) were retrieved from the electronic Medicines although occurrences as soon as 1 h after the initial drug Compendium (eMC) website (https://www.medicines.org.uk/ administration are possible (9). emc). When more than a quarter of the SmPC were retrieved and analysed, the eMC migrated its website to a new version, Rash classification. Although drug rashes may be classified while still making available the old version of the website. according to their mechanism of action, such classification To have consistency, we have kept using the old version of is usually of little use in diagnosing and managing an the website throughout the data collection and verification. undifferentiated rash in clinical settings. Therefore, a Only medicinal products containing a single active substance morphological classification in seven groups has been were used, excluding fixed-dose combinations (FDCs) or proposed for the cutaneous rashes most frequently encountered products containing various mixtures, such as herbal extracts in the clinical practice, the first three being the most common or blood fractions. Salts of different organic cations have and the last more rare: a) exanthema (maculopapular rash): been considered the same active substance, but esters have simple exanthemas (typically maculopapular rash) or complex been counted as different [e.g., triamcinolone hexacetonide exanthemas (such as DRESS - drug-reaction with eosinophilia and triamcinolone acetonide have been counted as different and systemic symptoms); b) dermatitis (eczema): phototoxic products, because clinical data have indicated that they behave reactions, photoallergic reactions, primary dermatitis similarly only in certain conditions, e.g., the effect of the reactions and drug induced xerosis; c) urticarial reactions: latter is equivalent to that of the former if used at a double anaphylactic and anaphylactoid reactions, acetylsalicylic dose (34)]. Instead,