Drug Safety

, Volume 42, Issue 1, pp 55–66 | Cite as

Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Commonly Prescribed Drugs in Outpatient Care Other than Anti-Epileptic Drugs and Antibiotics: A Population-Based Case–Control Study

  • Noel Frey
  • Michael Bodmer
  • Andreas Bircher
  • Susan S. Jick
  • Christoph R. MeierEmail author
  • Julia Spoendlin
Original Research Article



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.


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.


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.


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.



We thank Pascal Egger for programming and technical support.

Compliance with Ethical Standards


This study was supported by the University of Basel Science Foundation (Grant No. DMS2297).

Conflict of Interest

Noel Frey, Michael Bodmer, Andreas Bircher, Susan S. Jick, Christoph R. Meier, and Julia Spoendlin have no conflicts of interest that are directly relevant to the content of this study.

Supplementary material

40264_2018_711_MOESM1_ESM.pdf (244 kb)
Supplementary material 1 (PDF 243 kb)
40264_2018_711_MOESM2_ESM.pdf (289 kb)
Supplementary material 2 (PDF 289 kb)
40264_2018_711_MOESM3_ESM.pdf (282 kb)
Supplementary material 3 (PDF 282 kb)
40264_2018_711_MOESM4_ESM.pdf (325 kb)
Supplementary material 4 (PDF 324 kb)
40264_2018_711_MOESM5_ESM.pdf (206 kb)
Supplementary material 5 (PDF 206 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Noel Frey
    • 1
    • 2
  • Michael Bodmer
    • 3
  • Andreas Bircher
    • 4
  • Susan S. Jick
    • 5
    • 6
  • Christoph R. Meier
    • 1
    • 2
    • 5
    Email author
  • Julia Spoendlin
    • 1
    • 2
  1. 1.Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical SciencesUniversity of BaselBaselSwitzerland
  2. 2.Basel Pharmacoepidemiology Unit, Hospital PharmacyUniversity Hospital BaselBaselSwitzerland
  3. 3.Internal MedicineCantonal HospitalZugSwitzerland
  4. 4.AllergologyUniversity Hospital BaselBaselSwitzerland
  5. 5.Boston Collaborative Drug Surveillance ProgramLexingtonUSA
  6. 6.Boston University School of Public HealthBostonUSA

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