Noel Frey1,2, Michael Bodmer3, Andreas Bircher4, Susan S Jick5,6, Christoph R Meier7,8,9, Julia Spoendlin1,2. 1. Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. 2. Basel Pharmacoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, 4031, Basel, Switzerland. 3. Internal Medicine, Cantonal Hospital, Zug, Switzerland. 4. Allergology, University Hospital Basel, Basel, Switzerland. 5. Boston Collaborative Drug Surveillance Program, Lexington, MA, USA. 6. Boston University School of Public Health, Boston, MA, USA. 7. Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. christoph.meier@usb.ch. 8. Basel Pharmacoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, 4031, Basel, Switzerland. christoph.meier@usb.ch. 9. Boston Collaborative Drug Surveillance Program, Lexington, MA, USA. christoph.meier@usb.ch.
Abstract
INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with the use of various drugs, but evidence is scarce. We studied the association between new use of outpatient drugs other than anti-epileptic drugs and antibiotics and Stevens-Johnson syndrome and toxic epidermal necrolysis. METHODS: We conducted a matched (1:4) case-control analysis in 480 previously validated Stevens-Johnson syndrome/toxic epidermal necrolysis cases (1995-2013). We calculated odds ratios with 95% confidence intervals for Stevens-Johnson syndrome/toxic epidermal necrolysis in new users of drugs compared to non-users. For cases of Stevens-Johnson syndrome/toxic epidermal necrolysis diagnosed ≤ 84 days after the first use of a drug, we assessed causality between drug exposure and Stevens-Johnson syndrome/toxic epidermal necrolysis using ALDEN (algorithm of drug causality in epidermal necrolysis). We calculated absolute risks by dividing the number of Stevens-Johnson syndrome/toxic epidermal necrolysis cases ≤ 84 days after new drug exposure by the total number of new users of the drug. RESULTS: There was an association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of allopurinol (odds ratio 24.51, 95% confidence interval 2.94-204.04) and cyclooxygenase-2 inhibitors (odds ratio 24.19, 95% confidence interval 2.91-200.92). Proton pump inhibitors, fluoxetine, mirtazapine, and 5-aminosalicylates (sulfasalazine, mesalamine) were also associated with an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis, though with lower odds ratios. ALDEN score application suggests a likely causality for these associations. Absolute risks of Stevens-Johnson syndrome/toxic epidermal necrolysis were 6.0/100,000 new users for allopurinol, and 1.9-4.3/100,000 new users for cyclooxygenase-2 inhibitors and 5-aminosalicylates, and 0.2-1.6/100,000 new users for proton pump inhibitors, fluoxetine, and mirtazapine. We found no association between Stevens-Johnson syndrome/toxic epidermal necrolysis and oxicams, benzodiazepines, citalopram, sertraline, paroxetine, venlafaxine, and phosphodiesterase-5 inhibitors despite > 100,000 new users. CONCLUSIONS: In this observational study, we observed likely causal associations between Stevens-Johnson syndrome/toxic epidermal necrolysis and use of allopurinol, cyclooxygenase-2 inhibitors, and 5-aminosalicylates, and potential associations for proton pump inhibitors, fluoxetine, and mirtazapine.
INTRODUCTION:Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with the use of various drugs, but evidence is scarce. We studied the association between new use of outpatient drugs other than anti-epileptic drugs and antibiotics and Stevens-Johnson syndrome and toxic epidermal necrolysis. METHODS: We conducted a matched (1:4) case-control analysis in 480 previously validated Stevens-Johnson syndrome/toxic epidermal necrolysis cases (1995-2013). We calculated odds ratios with 95% confidence intervals for Stevens-Johnson syndrome/toxic epidermal necrolysis in new users of drugs compared to non-users. For cases of Stevens-Johnson syndrome/toxic epidermal necrolysis diagnosed ≤ 84 days after the first use of a drug, we assessed causality between drug exposure and Stevens-Johnson syndrome/toxic epidermal necrolysis using ALDEN (algorithm of drug causality in epidermal necrolysis). We calculated absolute risks by dividing the number of Stevens-Johnson syndrome/toxic epidermal necrolysis cases ≤ 84 days after new drug exposure by the total number of new users of the drug. RESULTS: There was an association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of allopurinol (odds ratio 24.51, 95% confidence interval 2.94-204.04) and cyclooxygenase-2 inhibitors (odds ratio 24.19, 95% confidence interval 2.91-200.92). Proton pump inhibitors, fluoxetine, mirtazapine, and 5-aminosalicylates (sulfasalazine, mesalamine) were also associated with an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis, though with lower odds ratios. ALDEN score application suggests a likely causality for these associations. Absolute risks of Stevens-Johnson syndrome/toxic epidermal necrolysis were 6.0/100,000 new users for allopurinol, and 1.9-4.3/100,000 new users for cyclooxygenase-2 inhibitors and 5-aminosalicylates, and 0.2-1.6/100,000 new users for proton pump inhibitors, fluoxetine, and mirtazapine. We found no association between Stevens-Johnson syndrome/toxic epidermal necrolysis and oxicams, benzodiazepines, citalopram, sertraline, paroxetine, venlafaxine, and phosphodiesterase-5 inhibitors despite > 100,000 new users. CONCLUSIONS: In this observational study, we observed likely causal associations between Stevens-Johnson syndrome/toxic epidermal necrolysis and use of allopurinol, cyclooxygenase-2 inhibitors, and 5-aminosalicylates, and potential associations for proton pump inhibitors, fluoxetine, and mirtazapine.
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