European Journal of Clinical Pharmacology

, Volume 71, Issue 6, pp 759–766 | Cite as

Risk of toxic epidermal necrolysis and Stevens-Johnson syndrome associated with benzodiazepines: a population-based cohort study

  • Elisa Martín-MerinoEmail author
  • Francisco J. de Abajo
  • Miguel Gil
Pharmacoepidemiology and Prescription



We aim to estimate the incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among tetrazepam users and compare it with benzodiazepine users in a Spanish primary care database (BIFAP). The incidence in the general population (GenPop) and among phenytoin new users (as a positive control) was also estimated.


We identified a cohort of GenPop free of SJS/TEN (N = 3,155,364). Cohort entry was the date after 1 year of register with the physician during 2001–2011. No age restrictions were applied. Patients were followed from entry up to the first of the following: a record of SJS/TEN (potential cases), death, end of information, or December 2011. History of potential cases were manually reviewed blinded to exposure and considered “probable” when diagnosed in referral reports. Three cohorts of patients newly prescribed with benzodiazepines (N = 531,813), tetrazepam (N = 343,568), or phenytoin (N = 4993) were extracted from the GenPop cohort. Incidence rate (cases per million person-years (py)) for the GenPop and cumulative incidence (per million new users) during the first 9 weeks after each drug prescription were computed.


In the GenPop, 48 probable cases (38 SJS and 10 TEN) were identified (3.21/million py; 3.37 in men and 2.94 in women). In the benzodiazepines cohort, 2 probable TEN cases was identified (3.76/mill.). In the tetrazepam cohort, 1 probable SJS/TEN case was identified (2.91/mill.). In the phenytoin cohort, 4 probable cases (2 SJS and 2 TEN) were identified (801.12/mill.).


The incidence of SJS/TEN in tetrazepam users was very rare and similar to benzodiazepines users. The incidence in the GenPop and among users of phenytoin agreed with the literature.


Stevens-Johnson syndrome Toxic epidermal necrolysis Tetrazepam Benzodiazepines Phenytoin Incidence Cohort study 



The authors would like to acknowledge the excellent collaboration of general practitioners and pediatricians taking part in BIFAP.


FdA collaboration was supported by a research grant from the Instituto de Salud Carlos III—Ministerio de Ciencia e Innovación (Grant No. PI12/02267).

Conflict of interest

The authors declare that they have no conflict of interest. The views expressed here do not necessarily represent the views of the co-authors’ respective companies or organizations.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Elisa Martín-Merino
    • 1
    Email author
  • Francisco J. de Abajo
    • 2
    • 3
  • Miguel Gil
    • 1
  1. 1.BIFAP Research UnitSpanish Agency on Medicines and Medical Devices (AEMPS)MadridSpain
  2. 2.Department of Biomedical Sciences, School of MedicineUniversity of AlcaláMadridSpain
  3. 3.Clinical Pharmacology UnitUniversity Hospital Príncipe de AsturiasMadridSpain

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