CED
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
Adverse drug reactions in dermatology R. E. Ferner West Midlands Centre for Adverse Drug Reactions, City Hospital Birmingham and School of Clinical and Experimental Medicine, Birmingham, UK doi:10.1111/ced.12572
Summary
Adverse drug reactions (ADRs) – that is, unintended and harmful responses to medicines – are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens–Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs.
Introduction
Definition
ADRs have supplanted syphilis as the ‘great imitator’. They are important to dermatologists as part of the differential diagnosis of skin disease, and as a consequence of its treatment. It is hoped that this brief synopsis will remind practitioners of important aspects of ADRs.
An ADR has been defined as ‘a response to a drug that is noxious and unintended and which occurs in doses normally used for the treatment, prophylaxis, or diagnosis of disease, or the modification of physiological function’. The definition excludes poisoning and unintended but beneficial effects. Newer definitions may be better.1 The European Union definition now encompasses harm from ‘off-label use, overdose, misuse, abuse and medication errors’,2 so any harm from a medicine can (and if serious or unusual should) be reported. Serious here means fatal, life-threatening, or causing or prolonging a stay in hospital. In the UK, details of suspected ADRs can be submitted online to the Yellow Card scheme, and the website provides up-to-date guidance on reporting.3 In addition to
Correspondence: Professor Robin E. Ferner, West Midlands Centre for Adverse Drug Reactions, City Hospital, University of Birmingham, Birmingham BH18 7QH, UK E-mail: [email protected] Conflict of interest: the authors declare no conflict of interest. Accepted for publication 26 August 2014
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology
1
Adverse drug reactions in dermatology R. E. Ferner
healthcare professionals and coroners(!), patients themselves can now report ADRs (Table 1).
Recognising unknown adverse drug reactions The identification of ADRs is often delayed. Diethylstilbesterol, which was given to pregnant mothers to reduce the risk of miscarriage, provides the clearest example. Twenty years after the treatment was introduced, it emerged that post-pubertal women who had been exposed in utero could develop clear-cell carcinoma of the vagina.4 Similarly, it took more than 3 years after thalidomide was marketed to recognize that it caused phocomelia.5 Delay in recognizing ADRs is sometimes, as with diethylstilbestrol, the result of the long latent period before the appearance of the reaction. Delay in recognition may also be due to the unexpected form of the reaction: curly hair from sodium valproate is an example.6 The relative rarity of serious ADRs makes them difficult to detect in the controlled clinical trials that precede market authorization; many of the serious ADRs listed for ustekinumab7 were not detected in the clinical trials.8 Time from the start of treatment to its appearance is one of the defining characteristics of an ADR,9 and dose–response is another. For example, anaphylaxis can be provoked by doses much smaller than those required for treatment. The misconception that Type I immunological hypersensitivity reactions are not doserelated is clearly wrong, as hayfever sufferers who consult the pollen count, or dermatologists who perform skin-prick tests, realise. Some people are more susceptible than others to a reaction: for example, patients with the histocompatibility allele HLA-B*5701 are at high risk of Stevens– Johnson syndrome (SJS) from the anti-human immunodeficiency drug abacavir.10 ADRs can be prevented by identifying susceptible patients, for example, those who are poor metabolizers of thiopurine methyltransferase before azathioprine treatment,11 or those with glucose-6-phosphate dehydrogenase deficiency before dapsone treatment.12 Clinical diagnosis
‘The appearance of the rash itself is often the best guide to the questions to be asked’,13 but failure to consider a possible ADR or to take an adequate drug history makes diagnosis more difficult. Establishing the Dose (extent of exposure), Time-course of events, and patient Susceptibility (DoTS9) may all help.
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Clinical and Experimental Dermatology
Adverse drug reactions in the skin ADRs may be due to the presence of the drug or its metabolites locally (for example, after iron injection or with minocycline14,15) or systemically (for example, amiodarone-induced pigmentation). They can also arise from interactions between drug and dermal components after local exposure (as with lipohypertrophy from insulin injection), or after systemic administration (for example, the acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib).16 Interactions with dermal components can be immunologically mediated.17 While skin prick tests accurately predict IgE-mediated reactions, at least to penicillins, tests for delayed-type hypersensitivity are not generally thought to be helpful.18 ADRs that occur soon after administration of a drug usually present little diagnostic difficulty. They include, for example, urticaria and angio-oedema caused by immediate-type hypersensitivity to penicillins. They also encompass nonimmunological histamine release caused by acetylcysteine infusion or morphine administration, and ‘red person syndrome’, the dramatic toxic effect of rifampicin or vancomycin infused too rapidly, formerly known as ‘red man syndrome’.19,20 Angio-oedema caused by angiotensin-converting enzyme inhibitors has a different time-course, and incidentally, patients with African heritage are much more susceptible.21 Time course is also an important diagnostic indicator for potentially catastrophic T cell-mediated dermatological reactions. SJS/toxic epidermal necrolysis typically appears 10 days to a few weeks after the start of treatment. Acute generalized exanthematous pustulosis (AGEP) occurs hours to days after starting treatment. Drug reaction with eosinophilia and systemic symptoms (DRESS) begins ‘often 2–8 weeks after the introduction of the inciting drug, although rechallenge can result in a reaction within hours to days’.22
Adverse reactions to drugs used by dermatologists ADRs to topically applied medicines are generally obvious, because they are localized to the area of application. Dose, time course and susceptibility may again be important. The dermal atrophy from topical corticosteroids clearly depends on all three, with the skin of the face being more susceptible than that of the scalp, for example. Contact hypersensitivity to topical corticosteroids is rare but well recognized.23 Very rarely, intradermal injection of corticosteroids triggers an anaphylactic reaction.24
ª 2014 British Association of Dermatologists
ª 2014 British Association of Dermatologists
Ampicillin Barbiturates Amiodarone
Amiodarone Minocycline Vancomycin Gadolinium contrast media Carbamazepine
Acetylcysteine used to treat paracetamol overdose
Exanthems Fixed drug eruption Phototoxicity
Pigmentation
‘Red person syndrome’ Scleromyxoedema
Stevens–Johnson syndrome/ toxic epidermal necrolysis
Urticaria due to nonimmune mechanisms
Asthma
Fever, dysphagia, dysuria, conjunctivitis, leucopenia
Hypotension Systemic fibrosis
Scleral pigmentation
Lymphadenopathy, fever, hepatitis, nephritis, pulmonary infiltrates, eosinophilia
Minutes
Days to weeks
Minutes Many months
Days Hours Months (reaction appears minutes to hours after sun exposure) Months Months
Days to weeks
Many months
DoTS, dose, time-course, susceptibility. *The associated features and DoTS analysis may be specific to the drug
Phenytoin
Drug reaction with eosinophilia and systemic symptoms
Infliximab
Penicillin Nerve damage, renal impairment
Weeks Days to weeks (slow time course with diltiazem) Hours to days (rapid time course with antibiotics) Minutes
– Fever > 38 °C, neutrophilia, facial oedema Fever > 38 °C, neutrophilia, facial oedema Anaphylactic shock
Erlotinib Diltiazem
Acneiform rash Acute generalized erythematous pustulosis
Angio-oedema due to Type I hypersensitivity Chronic vasculitis
Time from drug exposure to onset*
Some associated features*
Paradigm cause
Reaction
Erythromycin
Clinical pharmacology (DoTS)
Adverse drug reaction
Table 1 Some examples of drug-induced dermatological injury (DIDI)30
Therapeutic or overdose
Therapeutic
Overdose Therapeutic
High cumulative dose Therapeutic
Therapeutic Therapeutic High cumulative dose
Therapeutic
Therapeutic
Very small
Therapeutic
Therapeutic Therapeutic
Dose*
– Can be localized to inflammatory lesions Rapid infusion Renal impairment; more common with gadodiamide African ancestry; HLAB*1502 in Han Chinese (for carbamazepine); HLAB*5701 (for abacavir) Rapid infusion; high dose; low paracetamol concentration
Infectious mononucleosis Previous exposure Sun exposure
Previous exposure; worse with re-exposure Rheumatoid arthritis (occurs with all tumour necrosis factor-a inhibitors) African ancestry
–
Longer survival from cancer –
Susceptibility factors*
Adverse drug reactions in dermatology R. E. Ferner
Clinical and Experimental Dermatology
3
Adverse drug reactions in dermatology R. E. Ferner
Systemic ADRs from topical preparations used in dermatology must be rare, except perhaps in neonates, who show, for example, significant absorption of hexachlorophane used as a skin antiseptic.25 It seems unlikely, but not impossible, that topical applications containing nanoparticles will cause systemic toxicity.26 Systemic therapy for dermatological disorders can cause serious ADRs. Systemic corticosteroids in supraphysiological doses have well-known ADRs that depend on both the unit dose and cumulative dose, the duration of treatment, and the susceptibility of the patient (for example, to varicella or to diabetes mellitus). Patients taking corticosteroids for longer than a few weeks are now usually given bisphosphonates to protect against osteoporosis. The ADRs of once-weekly oral methotrexate are now well characterized, and a practicable monitoring scheme has made treatment safer.27 Newer systemic biological drugs, which modulate immune reactions, inevitably have widespread effects, and some of these lead to ADRs; everything from immediate Type I hypersensitivity reactions and loss of efficacy caused by circulating antibodies, to progressive multifocal leucoencephalopathy as a consequence of reactivation of latent JC (John Cunningham) virus infections during efalizumab therapy.28 It took several years for ADRs of infliximab to be recognized, and serious ADRs to newer drugs will almost certainly emerge, as experience unmasks rare and delayed reactions. Sometimes it is difficult to distinguish between ADRs and coincidental harm. For example, it is still uncertain whether isotretinoin can cause depression in teenagers smitten with acne. While the relative risk of suicide during isotretinoin exposure in one published study was 0.9, the confidence interval lay between 0.3 (much reduced) and 2.4 (substantially increased).29
Conclusion ADRs can present to dermatologists, and dermatologists’ treatments can cause them. The dose–response relationship, time course of treatment and susceptibility factors can clarify the diagnosis. Unusual or serious ADRs should be reported.
Learning points There is often a long delay between the market-
ing of a drug and the identification of an ADR. An ADR can be characterized by the dose
of drug that causes it, the time at which the
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Clinical and Experimental Dermatology
reaction appears, and the factors that make patients susceptible to it. Dermatological ADRs are characterized by these factors as well as the observable clinical signs. Serious and unusual ADRs to newer biological medicines continue to emerge. Unusual or serious ADRs should be reported.
Acknowledgments I am very grateful to the Dowling Club for persuading me to speak on this subject, and to Professor C. Moss, who aroused my interest in dermatological adverse drug reactions among other things, for very helpful discussions.
References 1 Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28: 851–70. 2 European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) – Annex I. EMA/ 876333/2011 Rev 3. Available at: http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2013/ 05/WC500143294.pdf. (accessed 15 September 2014). 3 Medicines and Healthcare products Regulatory Agency. Yellow Card Website. Available at: https: //yellowcard.mhra.gov.uk/yellowcards/reportmediator/ (accessed 15 September 2014). 4 Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971; 284: 878–81. 5 McBride WG. Thalidomide and congenital abnormalities. Lancet 1961; 2: 1358. 6 Jeavons PM, Clark JE, Harding GF. Valproate and curly hair. Lancet 1977; 1: 359. 7 Anonymous. Summary of Product Characteristics for Stelara 45 mg solution for injection in pre-filled syringe. Available at: https://www.medicines.org.uk/emc/medicine/ 23207/SPC/Stelara+45 + mg+solution+for+injection+ in+pre-filled+syringe/ (accessed 15 September 2014). 8 Meng Y, Dongmei L, Yanbin P et al. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol 2014; 39: 696–707. 9 Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. Br Med J 2003; 327: 1222–5. 10 Mallal S, Nolan D, Witt C et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359: 727–32. 11 Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a
ª 2014 British Association of Dermatologists
Adverse drug reactions in dermatology R. E. Ferner
12
13 14
15 16
17 18 19 20 21
22
pharmacogenomic test whose time has come. J Clin Pathol 2010; 63: 288–95. Todd P, Samaratunga IR, Pembroke A. Screening for glucose-6-phosphate dehydrogenase deficiency prior to dapsone therapy. Clin Exp Dermatol 1994; 19: 217–18. Shuster S. Dermatology in Internal Medicine. Oxford: Oxford Medical Publications, 1978: 24. Bowen ADR, McCalmont TH. The histopathology of subcutaneous minocycline pigmentation. J Am Acad Dermatol 2007; 57: 836–9. Ferner RE, Moss C. Minocycline for acne. Br Med J 1996; 312: 138. Nardone B, Nicholson K, Newman M et al. Istopathologic and immunohistochemical characterization of rash to human epidermal growth factor receptor 1 (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer Res 2010; 16: 4452–60. Ardern-Jones MR, Friedmann PS. Skin manifestations of drug allergy. Br J Clin Pharmacol 2011; 71: 672–83. Gruchalla RS, Pirmohamed M. Clinical practice. Antibiotic allergy. N Engl J Med 2006; 354: 601–9. Newton RW, Forrest ADR. Rifampicin overdosage–”the red man syndrome”. Scott Med J 1975; 20: 55–6. Holliman R. “Red man syndrome” associated with rapid vancomycin infusion. Lancet 1985; 1: 1399–400. McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. Br Med J 2006; 332: 1177–81. Kardaun SH, Sekula P, Valeyrie-Allanore L et al. Drug reaction with eosinophilia and systemic symptoms
CPD questions Question 1
The risk of angio-oedema related to angiotensin-converting enzyme inhibitors is higher in which of the following? a) People of Afro-Caribbean heritage. b) People of Han Chinese heritage. c) People of Inuit heritage. d) People of Europid heritage. e) People of white heritage.
23
24
25
26 27
28
29
30
(DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCADR study. Br J Dermatol 2013; 169: 1071–80. Browne F, Wilkinson SM. Effective prescribing in steroid allergy: Controversies and cross-reactions. Clin Dermatol 2011; 29: 287–94. Downs AM, Lear JT, Kennedy CT. Anaphylaxis to intradermal triamcinolone acetonide. Arch Dermatol 1998; 134: 1163–4. Curley A, Kimbrough RD, Hawk RE et al. Dermal absorption of hexochlorophane in infants. Lancet 1971; 2: 296–7. Landsiedel R, Fabian E, Ma-Hock L et al. Toxico-/biokinetics of nanomaterials. Arch Toxicol 2012; 86: 1021–60. Chalmers RJ, Kirby B, Smith A et al. Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol 2005; 152: 444–50. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9: 425–37. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000; 136: 1231–6. Valeyrie-Allanore L, Roujeau J-C. Dermatological adverse drug reactions. Chapter 32. In: Mann’s Pharmacovigilance, 3rd edn (Andrews EB, Moore N, eds). Chichester: Wiley Blackwell, 2014; 503–511.
Question 3
Adverse drug reaction reports require which of the following? a) No information about the reporter. b) A suspected relation between the harm and the drug. c) That the reaction occurred during use in a licensed indication. d) The name and contact details of the patient. e) That the reaction be previously unknown.
Question 4 Question 2
The acneiform rash caused by erlotinib is related to its action as what? a) A tyrosine kinase antagonist. b) An interleukin-C antagonist. c) An epidermal growth factor receptor antagonist. d) A macrophage-stimulating factor antagonist. e) A CD8 antigen binding antagonist.
ª 2014 British Association of Dermatologists
Acute generalized exanthematous pustulosis after initial exposure to the causative drug usually occurs when? a) Only on re-exposure to the causative agent. b) In 10 days to 10 weeks. c) In 2–8 weeks. d) After cessation of treatment. e) Within the first week.
Clinical and Experimental Dermatology
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Adverse drug reactions in dermatology R. E. Ferner
Question 5
The red person (red man) syndrome occurs with toxic doses of which of the following? a) Gentamicin. b) Pipericillin/tazobactam. c) Linezolid. d) Vancomycin. e) Capreomycin.
Instructions for answering questions This learning activity is freely available online at http://www.wileyhealthlearning.com/ced.
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Clinical and Experimental Dermatology
Users are encouraged to Read the article in print or online, paying particular
attention to the learning points and any author conflict of interest disclosures Reflect on the article Register or login online at www.wileyhealthlearning.com/ced and answer the CPD questions Complete the required evaluation component of the activity Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry.
ª 2014 British Association of Dermatologists
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
Adverse drug reactions in dermatology R. E. Ferner West Midlands Centre for Adverse Drug Reactions, City Hospital Birmingham and School of Clinical and Experimental Medicine, Birmingham, UK doi:10.1111/ced.12572
Summary
Adverse drug reactions (ADRs) – that is, unintended and harmful responses to medicines – are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens–Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs.
Introduction
Definition
ADRs have supplanted syphilis as the ‘great imitator’. They are important to dermatologists as part of the differential diagnosis of skin disease, and as a consequence of its treatment. It is hoped that this brief synopsis will remind practitioners of important aspects of ADRs.
An ADR has been defined as ‘a response to a drug that is noxious and unintended and which occurs in doses normally used for the treatment, prophylaxis, or diagnosis of disease, or the modification of physiological function’. The definition excludes poisoning and unintended but beneficial effects. Newer definitions may be better.1 The European Union definition now encompasses harm from ‘off-label use, overdose, misuse, abuse and medication errors’,2 so any harm from a medicine can (and if serious or unusual should) be reported. Serious here means fatal, life-threatening, or causing or prolonging a stay in hospital. In the UK, details of suspected ADRs can be submitted online to the Yellow Card scheme, and the website provides up-to-date guidance on reporting.3 In addition to
Correspondence: Professor Robin E. Ferner, West Midlands Centre for Adverse Drug Reactions, City Hospital, University of Birmingham, Birmingham BH18 7QH, UK E-mail: [email protected] Conflict of interest: the authors declare no conflict of interest. Accepted for publication 26 August 2014
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology
1
Adverse drug reactions in dermatology R. E. Ferner
healthcare professionals and coroners(!), patients themselves can now report ADRs (Table 1).
Recognising unknown adverse drug reactions The identification of ADRs is often delayed. Diethylstilbesterol, which was given to pregnant mothers to reduce the risk of miscarriage, provides the clearest example. Twenty years after the treatment was introduced, it emerged that post-pubertal women who had been exposed in utero could develop clear-cell carcinoma of the vagina.4 Similarly, it took more than 3 years after thalidomide was marketed to recognize that it caused phocomelia.5 Delay in recognizing ADRs is sometimes, as with diethylstilbestrol, the result of the long latent period before the appearance of the reaction. Delay in recognition may also be due to the unexpected form of the reaction: curly hair from sodium valproate is an example.6 The relative rarity of serious ADRs makes them difficult to detect in the controlled clinical trials that precede market authorization; many of the serious ADRs listed for ustekinumab7 were not detected in the clinical trials.8 Time from the start of treatment to its appearance is one of the defining characteristics of an ADR,9 and dose–response is another. For example, anaphylaxis can be provoked by doses much smaller than those required for treatment. The misconception that Type I immunological hypersensitivity reactions are not doserelated is clearly wrong, as hayfever sufferers who consult the pollen count, or dermatologists who perform skin-prick tests, realise. Some people are more susceptible than others to a reaction: for example, patients with the histocompatibility allele HLA-B*5701 are at high risk of Stevens– Johnson syndrome (SJS) from the anti-human immunodeficiency drug abacavir.10 ADRs can be prevented by identifying susceptible patients, for example, those who are poor metabolizers of thiopurine methyltransferase before azathioprine treatment,11 or those with glucose-6-phosphate dehydrogenase deficiency before dapsone treatment.12 Clinical diagnosis
‘The appearance of the rash itself is often the best guide to the questions to be asked’,13 but failure to consider a possible ADR or to take an adequate drug history makes diagnosis more difficult. Establishing the Dose (extent of exposure), Time-course of events, and patient Susceptibility (DoTS9) may all help.
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Clinical and Experimental Dermatology
Adverse drug reactions in the skin ADRs may be due to the presence of the drug or its metabolites locally (for example, after iron injection or with minocycline14,15) or systemically (for example, amiodarone-induced pigmentation). They can also arise from interactions between drug and dermal components after local exposure (as with lipohypertrophy from insulin injection), or after systemic administration (for example, the acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib).16 Interactions with dermal components can be immunologically mediated.17 While skin prick tests accurately predict IgE-mediated reactions, at least to penicillins, tests for delayed-type hypersensitivity are not generally thought to be helpful.18 ADRs that occur soon after administration of a drug usually present little diagnostic difficulty. They include, for example, urticaria and angio-oedema caused by immediate-type hypersensitivity to penicillins. They also encompass nonimmunological histamine release caused by acetylcysteine infusion or morphine administration, and ‘red person syndrome’, the dramatic toxic effect of rifampicin or vancomycin infused too rapidly, formerly known as ‘red man syndrome’.19,20 Angio-oedema caused by angiotensin-converting enzyme inhibitors has a different time-course, and incidentally, patients with African heritage are much more susceptible.21 Time course is also an important diagnostic indicator for potentially catastrophic T cell-mediated dermatological reactions. SJS/toxic epidermal necrolysis typically appears 10 days to a few weeks after the start of treatment. Acute generalized exanthematous pustulosis (AGEP) occurs hours to days after starting treatment. Drug reaction with eosinophilia and systemic symptoms (DRESS) begins ‘often 2–8 weeks after the introduction of the inciting drug, although rechallenge can result in a reaction within hours to days’.22
Adverse reactions to drugs used by dermatologists ADRs to topically applied medicines are generally obvious, because they are localized to the area of application. Dose, time course and susceptibility may again be important. The dermal atrophy from topical corticosteroids clearly depends on all three, with the skin of the face being more susceptible than that of the scalp, for example. Contact hypersensitivity to topical corticosteroids is rare but well recognized.23 Very rarely, intradermal injection of corticosteroids triggers an anaphylactic reaction.24
ª 2014 British Association of Dermatologists
ª 2014 British Association of Dermatologists
Ampicillin Barbiturates Amiodarone
Amiodarone Minocycline Vancomycin Gadolinium contrast media Carbamazepine
Acetylcysteine used to treat paracetamol overdose
Exanthems Fixed drug eruption Phototoxicity
Pigmentation
‘Red person syndrome’ Scleromyxoedema
Stevens–Johnson syndrome/ toxic epidermal necrolysis
Urticaria due to nonimmune mechanisms
Asthma
Fever, dysphagia, dysuria, conjunctivitis, leucopenia
Hypotension Systemic fibrosis
Scleral pigmentation
Lymphadenopathy, fever, hepatitis, nephritis, pulmonary infiltrates, eosinophilia
Minutes
Days to weeks
Minutes Many months
Days Hours Months (reaction appears minutes to hours after sun exposure) Months Months
Days to weeks
Many months
DoTS, dose, time-course, susceptibility. *The associated features and DoTS analysis may be specific to the drug
Phenytoin
Drug reaction with eosinophilia and systemic symptoms
Infliximab
Penicillin Nerve damage, renal impairment
Weeks Days to weeks (slow time course with diltiazem) Hours to days (rapid time course with antibiotics) Minutes
– Fever > 38 °C, neutrophilia, facial oedema Fever > 38 °C, neutrophilia, facial oedema Anaphylactic shock
Erlotinib Diltiazem
Acneiform rash Acute generalized erythematous pustulosis
Angio-oedema due to Type I hypersensitivity Chronic vasculitis
Time from drug exposure to onset*
Some associated features*
Paradigm cause
Reaction
Erythromycin
Clinical pharmacology (DoTS)
Adverse drug reaction
Table 1 Some examples of drug-induced dermatological injury (DIDI)30
Therapeutic or overdose
Therapeutic
Overdose Therapeutic
High cumulative dose Therapeutic
Therapeutic Therapeutic High cumulative dose
Therapeutic
Therapeutic
Very small
Therapeutic
Therapeutic Therapeutic
Dose*
– Can be localized to inflammatory lesions Rapid infusion Renal impairment; more common with gadodiamide African ancestry; HLAB*1502 in Han Chinese (for carbamazepine); HLAB*5701 (for abacavir) Rapid infusion; high dose; low paracetamol concentration
Infectious mononucleosis Previous exposure Sun exposure
Previous exposure; worse with re-exposure Rheumatoid arthritis (occurs with all tumour necrosis factor-a inhibitors) African ancestry
–
Longer survival from cancer –
Susceptibility factors*
Adverse drug reactions in dermatology R. E. Ferner
Clinical and Experimental Dermatology
3
Adverse drug reactions in dermatology R. E. Ferner
Systemic ADRs from topical preparations used in dermatology must be rare, except perhaps in neonates, who show, for example, significant absorption of hexachlorophane used as a skin antiseptic.25 It seems unlikely, but not impossible, that topical applications containing nanoparticles will cause systemic toxicity.26 Systemic therapy for dermatological disorders can cause serious ADRs. Systemic corticosteroids in supraphysiological doses have well-known ADRs that depend on both the unit dose and cumulative dose, the duration of treatment, and the susceptibility of the patient (for example, to varicella or to diabetes mellitus). Patients taking corticosteroids for longer than a few weeks are now usually given bisphosphonates to protect against osteoporosis. The ADRs of once-weekly oral methotrexate are now well characterized, and a practicable monitoring scheme has made treatment safer.27 Newer systemic biological drugs, which modulate immune reactions, inevitably have widespread effects, and some of these lead to ADRs; everything from immediate Type I hypersensitivity reactions and loss of efficacy caused by circulating antibodies, to progressive multifocal leucoencephalopathy as a consequence of reactivation of latent JC (John Cunningham) virus infections during efalizumab therapy.28 It took several years for ADRs of infliximab to be recognized, and serious ADRs to newer drugs will almost certainly emerge, as experience unmasks rare and delayed reactions. Sometimes it is difficult to distinguish between ADRs and coincidental harm. For example, it is still uncertain whether isotretinoin can cause depression in teenagers smitten with acne. While the relative risk of suicide during isotretinoin exposure in one published study was 0.9, the confidence interval lay between 0.3 (much reduced) and 2.4 (substantially increased).29
Conclusion ADRs can present to dermatologists, and dermatologists’ treatments can cause them. The dose–response relationship, time course of treatment and susceptibility factors can clarify the diagnosis. Unusual or serious ADRs should be reported.
Learning points There is often a long delay between the market-
ing of a drug and the identification of an ADR. An ADR can be characterized by the dose
of drug that causes it, the time at which the
4
Clinical and Experimental Dermatology
reaction appears, and the factors that make patients susceptible to it. Dermatological ADRs are characterized by these factors as well as the observable clinical signs. Serious and unusual ADRs to newer biological medicines continue to emerge. Unusual or serious ADRs should be reported.
Acknowledgments I am very grateful to the Dowling Club for persuading me to speak on this subject, and to Professor C. Moss, who aroused my interest in dermatological adverse drug reactions among other things, for very helpful discussions.
References 1 Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28: 851–70. 2 European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) – Annex I. EMA/ 876333/2011 Rev 3. Available at: http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2013/ 05/WC500143294.pdf. (accessed 15 September 2014). 3 Medicines and Healthcare products Regulatory Agency. Yellow Card Website. Available at: https: //yellowcard.mhra.gov.uk/yellowcards/reportmediator/ (accessed 15 September 2014). 4 Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971; 284: 878–81. 5 McBride WG. Thalidomide and congenital abnormalities. Lancet 1961; 2: 1358. 6 Jeavons PM, Clark JE, Harding GF. Valproate and curly hair. Lancet 1977; 1: 359. 7 Anonymous. Summary of Product Characteristics for Stelara 45 mg solution for injection in pre-filled syringe. Available at: https://www.medicines.org.uk/emc/medicine/ 23207/SPC/Stelara+45 + mg+solution+for+injection+ in+pre-filled+syringe/ (accessed 15 September 2014). 8 Meng Y, Dongmei L, Yanbin P et al. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol 2014; 39: 696–707. 9 Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. Br Med J 2003; 327: 1222–5. 10 Mallal S, Nolan D, Witt C et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359: 727–32. 11 Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a
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pharmacogenomic test whose time has come. J Clin Pathol 2010; 63: 288–95. Todd P, Samaratunga IR, Pembroke A. Screening for glucose-6-phosphate dehydrogenase deficiency prior to dapsone therapy. Clin Exp Dermatol 1994; 19: 217–18. Shuster S. Dermatology in Internal Medicine. Oxford: Oxford Medical Publications, 1978: 24. Bowen ADR, McCalmont TH. The histopathology of subcutaneous minocycline pigmentation. J Am Acad Dermatol 2007; 57: 836–9. Ferner RE, Moss C. Minocycline for acne. Br Med J 1996; 312: 138. Nardone B, Nicholson K, Newman M et al. Istopathologic and immunohistochemical characterization of rash to human epidermal growth factor receptor 1 (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer Res 2010; 16: 4452–60. Ardern-Jones MR, Friedmann PS. Skin manifestations of drug allergy. Br J Clin Pharmacol 2011; 71: 672–83. Gruchalla RS, Pirmohamed M. Clinical practice. Antibiotic allergy. N Engl J Med 2006; 354: 601–9. Newton RW, Forrest ADR. Rifampicin overdosage–”the red man syndrome”. Scott Med J 1975; 20: 55–6. Holliman R. “Red man syndrome” associated with rapid vancomycin infusion. Lancet 1985; 1: 1399–400. McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. Br Med J 2006; 332: 1177–81. Kardaun SH, Sekula P, Valeyrie-Allanore L et al. Drug reaction with eosinophilia and systemic symptoms
CPD questions Question 1
The risk of angio-oedema related to angiotensin-converting enzyme inhibitors is higher in which of the following? a) People of Afro-Caribbean heritage. b) People of Han Chinese heritage. c) People of Inuit heritage. d) People of Europid heritage. e) People of white heritage.
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(DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCADR study. Br J Dermatol 2013; 169: 1071–80. Browne F, Wilkinson SM. Effective prescribing in steroid allergy: Controversies and cross-reactions. Clin Dermatol 2011; 29: 287–94. Downs AM, Lear JT, Kennedy CT. Anaphylaxis to intradermal triamcinolone acetonide. Arch Dermatol 1998; 134: 1163–4. Curley A, Kimbrough RD, Hawk RE et al. Dermal absorption of hexochlorophane in infants. Lancet 1971; 2: 296–7. Landsiedel R, Fabian E, Ma-Hock L et al. Toxico-/biokinetics of nanomaterials. Arch Toxicol 2012; 86: 1021–60. Chalmers RJ, Kirby B, Smith A et al. Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol 2005; 152: 444–50. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9: 425–37. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000; 136: 1231–6. Valeyrie-Allanore L, Roujeau J-C. Dermatological adverse drug reactions. Chapter 32. In: Mann’s Pharmacovigilance, 3rd edn (Andrews EB, Moore N, eds). Chichester: Wiley Blackwell, 2014; 503–511.
Question 3
Adverse drug reaction reports require which of the following? a) No information about the reporter. b) A suspected relation between the harm and the drug. c) That the reaction occurred during use in a licensed indication. d) The name and contact details of the patient. e) That the reaction be previously unknown.
Question 4 Question 2
The acneiform rash caused by erlotinib is related to its action as what? a) A tyrosine kinase antagonist. b) An interleukin-C antagonist. c) An epidermal growth factor receptor antagonist. d) A macrophage-stimulating factor antagonist. e) A CD8 antigen binding antagonist.
ª 2014 British Association of Dermatologists
Acute generalized exanthematous pustulosis after initial exposure to the causative drug usually occurs when? a) Only on re-exposure to the causative agent. b) In 10 days to 10 weeks. c) In 2–8 weeks. d) After cessation of treatment. e) Within the first week.
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Question 5
The red person (red man) syndrome occurs with toxic doses of which of the following? a) Gentamicin. b) Pipericillin/tazobactam. c) Linezolid. d) Vancomycin. e) Capreomycin.
Instructions for answering questions This learning activity is freely available online at http://www.wileyhealthlearning.com/ced.
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Clinical and Experimental Dermatology
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