European Journal of Clinical Pharmacology

, Volume 75, Issue 2, pp 237–246 | Cite as

Incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis among new users of different individual drugs in a European population: a case-population study

  • Sara Rodríguez-Martín
  • Elisa Martín-Merino
  • Victoria Lerma
  • Antonio Rodríguez-Miguel
  • Olga González
  • Carlos González-Herrada
  • Elena Ramírez
  • Teresa Bellón
  • Francisco J. de AbajoEmail author
Pharmacoepidemiology and Prescription



To estimate the specific incidences of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among new users of drugs frequently reported to be associated with this serious event.


We performed a case-population approach, which combined data from a registry of SJS/TEN cases from the Madrid region (numerator) during the study period 2005–2015 and a primary healthcare database from the same catchment population. The proportion of new users of drugs estimated in the primary healthcare database was stratified by calendar year, sex and age (5-year bands), and then applied to the same strata of Madrid’s population census to compute the number of new users (denominator). Incidences were re-estimated using only cases in which the concerned drug had a probable or very probable causal relationship.


A total of 44 SJS/TEN cases aged > 14 years were registered during the study period. The highest SJS/TEN incidence was found for phenytoin with 68.9 per 100,000 new users (95% CI 27.7–141.9), followed by dexamethasone (5.48; 1.49–14.03), allopurinol (3.29; 1.07–7.67) and cotrimoxazole (3.19; 0.87–8.16). Considering only probable and very probable cases, the incidences hardly changed, except for dexamethasone, which was left without cases. Pantoprazole, levofloxacin and lorazepam showed incidences between 1 per 100,000 and 1 per 1,000,000 new users. Ibuprofen, amoxicillin-clavulanic acid, metamizole, amoxicillin, paracetamol and omeprazole showed incidences around 1 per one million new users.


Phenytoin was the drug with the highest incidence of SJS/TEN, followed by allopurinol and cotrimoxazole. For the rest of the drugs, the estimated incidences were below 1 in 100,000 new users.


Toxic epidermal necrolysis Stevens-Johnson syndrome SCAR Hypersensitivity Case-population study 



We are grateful to all members of the PIELenRed Consortium and patients who take part in this study. The authors would like to acknowledge the excellent collaboration of primary care practitioners taking part in BIFAP and the BIFAP staff for their collaboration and provision of resources to access the database. All views expressed in this article are those of the authors and do not necessarily represent the views of their institutions.

Funding information

The present study was supported by a research grant from the Instituto de Salud Carlos III - Ministerio de Economía y Competitividad (no. PI12/02267), co-founded by FEDER. The Spanish Agency of Medicinal Products and Medical Devices supports the management of the PIELenRed registry and is the owner of the database BIFAP.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all prospective individual participants or legal representatives. For retrospective cases, the Ethics Research Committee granted us an exemption. BIFAP is a fully anonymised database, and according to the Spanish law, an informed consent is not required when no personal data is collected.

Supplementary material

228_2018_2569_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 33 kb)


  1. 1.
    Heng YK, Lee HY, Roujeau JC (2015) Epidermal necrolysis: 60 years of errors and advances. Br J Dermatol 173:1250–1254CrossRefGoogle Scholar
  2. 2.
    Diphoorn J, Cazzaniga S, Gamba C, Schroeder J, Citterio A, Rivolta AL, Vighi GD, Naldi L, REACT-Lombardia study group (2016) Incidence, causative factors and mortality rates of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in northern Italy: data from the REACT registry. Pharmacoepidemiol Drug Saf 25:196–203CrossRefGoogle Scholar
  3. 3.
    Sekula P, Dunant A, Mockenhaupt M, Naldi L, Bouwes Bavinck JN, Halevy S, Kardaun S, Sidorodd A, Liss Y, Schumacher M, Roujeau JC, RegiSCAR syudy group (2013) Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Investig Dermatol 133:1197–1204CrossRefGoogle Scholar
  4. 4.
    Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC, SCAR Study Group. Severe Cutaneous Adverse Reactions (2002) Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 138:1019–1024CrossRefGoogle Scholar
  5. 5.
    Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F, Mockenhaupt M, Paoletti C, Shapiro S, Shear N, Schöpf E, Kaufman DW (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600–1607CrossRefGoogle Scholar
  6. 6.
    Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidorodd A, Schneck J, Roujeau JC, Flahault A (2008) Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Investig Dermatol 128:35–44CrossRefGoogle Scholar
  7. 7.
    Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jové J, Pariente A, Blin P, Bénichou J, Bégaud B (2013) Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France. Pharmacoepidemiol Drug Saf 22:160–167CrossRefGoogle Scholar
  8. 8.
    Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J (2005) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 64:1134–1138CrossRefGoogle Scholar
  9. 9.
    Telfair T, Mohan AK, Shahani S, Klincewick S, Atsma WJ, Thomas A, Fife D (2006) Estimating post-marketing exposure to pharmaceutical products using ex-factory distribution data. Pharmacoepidemiol Drug Saf 15:749–753CrossRefGoogle Scholar
  10. 10.
    Schneeweiss S, Avorn J (2005) A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol 58:323–327CrossRefGoogle Scholar
  11. 11.
    Martín-Merino E, de Abajo FJ, Gil M (2015) Risk of toxic epidermal necrolysis and Stevens-Johnson syndrome associated with benzodiazepines: a population-based cohort study. Eur J Clin Pharmacol 71:759–766CrossRefGoogle Scholar
  12. 12.
    Frey N, Bodmer M, Bircher A, Rüegg S, Jick SS, Meier CR, Spoendlin J (2017) The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs. Epilepsia 58:2178–2185CrossRefGoogle Scholar
  13. 13.
    Frey N, Bircher A, Bodmer M, Jick SS, Meier CR, Spoendlin J (2018) Antibiotic drug use and the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: a population-based case-control study. J Investig Dermatol 138:1207–1209CrossRefGoogle Scholar
  14. 14.
    Keller SF, Lu N, Blumenthal KG, Rai SK, Yokose C, Choi JWJ, Kim SC, Zhang Y, Choi HK (2018) Racial/ethnic variation and risk factors for allopurinol associated severe cutaneous adverse reactions: a cohort study. Ann Rheum Dis 77:1187–1193Google Scholar
  15. 15.
    Yang MS, Lee JY, Kim J, Kim G, Kim BK, Kim JY, Park HW, Cho SH, Min KU, Kang HR (2016) Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis: a nationwide population-based study using National Health Insurance Database in Korea. PLoS One 11(11):e0165933. CrossRefGoogle Scholar
  16. 16.
    Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC (1993) Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92–96CrossRefGoogle Scholar
  17. 17.
    Mittmann N, Knowles SR, Koo M, Shear NH, Rachlis A, Rourke SB (2012) Incidence of toxic epidermal necrolysis and Stevens-Johnson syndrome in an HIV cohort: an observational, retrospective case series study. Am J Clin Dermatol 13:49–54CrossRefGoogle Scholar
  18. 18.
    The RegiSCAR Project Available at: Accessed 30 Jan 2018
  19. 19.
    PIELenRed. ConsorcioPIELenRed Available at: Accessed 24 Mar 2018
  20. 20.
    Agencia Española de Medicamentos y Productos Sanitarios BIFAP: Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria Available at: Accessed 24 Mar 2018
  21. 21.
    Rodríguez-Martín S, Martín-Merino E, Lerma V, Rodríguez-Miguel A, González O, González-Herrada C, Ramírez E, Bellón T, de Abajo FJ (2018) Active surveillance of severe cutaneous adverse reactions: a case-population approach using a registry and a healthcare database. Pharmacoepidemiol Drug Saf:1–9.
  22. 22.
    González-Herrada C, Rodríguez-Martín S, Cachafeiro L, Lerma V, González O, Lorente JA, Rodríguez-Miguel A, González-Ramos J, Roustan G, Ramírez E, Bellón T, de Abajo FJ, PIELenRed Therapeutic Management Working Group (2017) Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: evidence from three different approaches. J Investig Dermatol 137:2092–2100CrossRefGoogle Scholar
  23. 23.
    Huerta C, Abbing-Karahagopian V, Requena G, Oliva B, Alvarez Y, Gardarsdottir H (2013) Prevalence of use of benzodiazepines and related drugs in seven European databases: a cross-national descriptive study from the PROTECT-EU project. Pharmacoepidemiol Drug Saf 22:1–512Google Scholar
  24. 24.
    De Abajo FJ, Gil MJ, García-Poza P, Bryant V, Oliva B, Timoner J, García-Rodríguez LA (2014) Risk of nonfatal acute myocardial infarction associated with non-steroidal antiinflammatory drugs, non-narcotic analgesics and other drugs used in osteoarthritis: a nested case-control study. Pharmacoepidemiol Drug Saf 23:1128–1138CrossRefGoogle Scholar
  25. 25.
    De Abajo FJ, Rodríguez-Martín S, Rodríguez-Miguel A, Gil MJ (2017) Risk of ischemic stroke associated with calcium supplements with or without vitamin D: a nested case-control study. J Am Heart Assoc 6:e005795. CrossRefGoogle Scholar
  26. 26.
    De Abajo FJ, Gil MJ, Bryant V, Timoner J, Oliva B, García-Rodríguez LA (2013) Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case-control study in a new general practice database. Eur J Clin Pharmacol 69:691–701CrossRefGoogle Scholar
  27. 27.
    Instituto de Estadística. Comunidad de Madrid. Available at: Accessed 10 Jan 2018
  28. 28.
    Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, Haustein UF, Vieluf D, Roujeau JC, Le Louet H (2010) ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 88:60–68CrossRefGoogle Scholar
  29. 29.
    Council for International Organisations of Medical Sciences (1995) Guidelines for preparing core clinical safety information on drugs. Geneva: CIOMS. Available at: Accessed 16 June 2018
  30. 30.
    Lee HY, Dunant A, Sekula P, Mockenhaupt M, Wolkenstein P, Valeyrie-Allanore L, Naldi L, Halevy S, Roujeau JC (2012) The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies. Br J Dermatol 167:555–562CrossRefGoogle Scholar
  31. 31.
    Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, Viboud C, Roujeau JC, EuroSCAR Study Group (2008) Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 58:25–32CrossRefGoogle Scholar
  32. 32.
    Yang CY, Chen CH, Deng ST, Huang CS, Lin YJ, Chen YJ, Wu CY, Hung SI, Chung WH (2015) Allopurinol use and risk of fatal hypersensitivity reactions: a nationwide population-based study in Taiwan. JAMA Intern Med 175:1550–1557CrossRefGoogle Scholar
  33. 33.
    Saksit N, Tassaneeyakul W, Nakkam N, Konyoung P, Khunarkornsiri U, Chumworathayi P, Sukasem C, Suttisai S, Piriyachananusorn N, Tiwong P, Chaiyakunapruk N, Sawanyawisuth K, Rerkpattanapipat T, Tassaneeyakul W (2017) Risk factors of allopurinol-induced severe cutaneous reactions in Thai population. Pharmacogenet Genomics 27:255–263CrossRefGoogle Scholar
  34. 34.
    Bachot N, Roujeau JC (2003) Differential diagnosis of severe cutaneous drug eruptions. Am J Clin Dermatol 4:561–572CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sara Rodríguez-Martín
    • 1
    • 2
    • 3
  • Elisa Martín-Merino
    • 4
  • Victoria Lerma
    • 1
    • 3
  • Antonio Rodríguez-Miguel
    • 1
    • 2
    • 3
  • Olga González
    • 5
  • Carlos González-Herrada
    • 5
  • Elena Ramírez
    • 6
  • Teresa Bellón
    • 7
  • Francisco J. de Abajo
    • 1
    • 2
    • 3
    Email author
  1. 1.Clinical Pharmacology UnitPríncipe de Asturias University HospitalAlcalá de HenaresSpain
  2. 2.Department of Biomedical SciencesUniversity of AlcaláAlcalá de HenaresSpain
  3. 3.Pharmacoepidemiology Research GroupInstitute for Health Research IRYCISMadridSpain
  4. 4.Division of Pharmacoepidemiology and PharmacovigilanceSpanish Agency of Medicines and Medical DevicesMadridSpain
  5. 5.Dermatology DepartmentUniversity Hospital of GetafeGetafeSpain
  6. 6.Clinical Pharmacology DepartmentLa Paz University HospitalMadridSpain
  7. 7.Drug Hypersensitivity Laboratory, Institute for Health Research IdiPAZLa Paz University HospitalMadridSpain

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