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

Abstract

Purpose

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.

Methods

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.

Results

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.).

Conclusions

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.

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References

  1. 1.

    Mockenhaupt M (2011) The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol 7(6):803–813. doi:10.1586/eci.11.66, quiz 814–805

    Article  PubMed  Google Scholar 

  2. 2.

    Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J (2005) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of anti-epileptics. Neurology 64(7):1134–1138. doi:10.1212/01.wnl.0000156354.20227.f0

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F et al (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333(24):1600–1607. doi:10.1056/nejm199512143332404

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS (2005) Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol : Off Publ Am Coll Allergy Asthma Immunol 94(4):419–436. doi:10.1016/s1081-1206(10)61112-x, quiz 436–418, 456

    Article  Google Scholar 

  5. 5.

    Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, Sidoroff 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 Invest Dermatol 128(1):35–44. doi:10.1038/sj.jid.5701033

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    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(1):92–96

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC (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(8):1019–1024

    Article  PubMed  Google Scholar 

  8. 8.

    Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flechet ML, Girre JP (1990) Toxic epidermal necrolysis (Lyell syndrome). Incidence and drug etiology in France, 1981–1985. Arch Dermatol 126(1):37–42

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H, Walker AM (1990) The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 126(1):43–47

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Schöpf E, Stühmer A, Rzany B, Victor N, Zentgraf R, Kapp JF (1991) Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 127(6):839–842

    Article  PubMed  Google Scholar 

  11. 11.

    Naldi L, Locati F, Marchesi L, Cainelli T (1990) Incidence of toxic epidermal necrolysis in Italy. Arch Dermatol 126(8):1103–1104

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Strom BL, Carson JL, Halpern AC, Schinnar R, Snyder ES, Shaw M, Tilson HH, Joseph M, Dai WS, Chen D et al (1991) A population-based study of Stevens-Johnson syndrome. Incidence and antecedent drug exposures. Arch Dermatol 127(6):831–838

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J, Holländer N, Bruppacher R, Schöpf E (1996) Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): structure and results of a population-based registry. J Clin Epidemiol 49(7):769–773

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M (2008) Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol 58(1):33–40. doi:10.1016/j.jaad.2007.08.039

    Article  PubMed  Google Scholar 

  15. 15.

    Bakke OM, Manocchia M, de Abajo F, Kaitin KI, Lasagna L (1995) Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: a regulatory perspective. Clin Pharmacol Ther 58(1):108–117. doi:10.1016/0009-9236(95)90078-0

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Tetrazepam containing medicines suspended across the EU (2014) European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Tetrazepam_containing_medicinal_products/human_referral_prac_000015.jsp&mid=WC0b01ac05805c516f. Accessed 4 July 2014

  17. 17.

    Kuepper-Nybelen J, Thuermann P, Schubert I (2014) Frequency of tetrazepam prescription: estimates for Germany. Pharmacoepidemiol Drug Saf. doi:10.1002/pds.3672

    PubMed  Google Scholar 

  18. 18.

    BIFAP Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria. http://bifap.aemps.es/. Accessed 05 March 2015

  19. 19.

    Lamberts H, Wood M (1987) ICPC. International classification of primary care. Oxford University Press, Oxford

    Google Scholar 

  20. 20.

    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(1):60–68. doi:10.1038/clpt.2009.252

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jove J, Pariente A, Blin P, Benichou J, Begaud 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(2):160–167. doi:10.1002/pds.3371

    Article  PubMed  Google Scholar 

  22. 22.

    Greenland S, Rothman KJ (2008) Introduction to stratified data. In: Rothman KJ, Greenland S, Lash TL (eds) Modern epidemiology, 3rd edn. Philadelphia, PA: Lippincott, Williams & Wilkins.

  23. 23.

    Bady B, Trillet M, Aimard G, Girard R (1969) Use of tetrazepam in the treatment of contractures during neurological diseases. J Med Lyon 50(172):1337–1342

    CAS  PubMed  Google Scholar 

  24. 24.

    Boudouresque J, Daniel F (1969) 4261 CB tetrazepam trial in a series of 42 patients with hypertonia of different origin. Mars Med 106(12):1081–1085

    CAS  PubMed  Google Scholar 

  25. 25.

    Pellkofer M, Paulig M (1989) Comparative double-blind study of the effectiveness and tolerance of baclofen, tetrazepam and tizanidine in spastic movement disorders of the lower extremities. Med Klin (Munich, Germany : 1983) 84(1):5–8

    CAS  Google Scholar 

  26. 26.

    Enquete officielle sur les effects indesirables du tetrazepam (2012) Commission Nationale de Pharmacovigilance. Agence nationale de sécurité du médicament et des produits de santé. http://ansm.sante.fr/var/ansm_site/storage/original/application/c9e15dee904acc094f9b909eea1634a2.pdf. Accessed 14 July 2014

  27. 27.

    Proy-Vega B, Aguirre C, de Groot P, Solis-Garcia del Pozo J, Jordan J (2014) On the clinical evidence leading to tetrazepam withdrawal. Expert Opin Drug Saf 13(6):705–712. doi:10.1517/14740338.2014.915023

    CAS  PubMed  Google Scholar 

  28. 28.

    Tetrazepam adverse events and side effects reported to the FDA (AERS). DrugCite. Food and Drug Administration. http://www.drugcite.com/?q=tetrazepam. Accessed 15 July 2014

  29. 29.

    Del Pozo MD, Blasco A, Lobera T (1999) Tetrazepam allergy. Allergy 54(11):1226–1227

    Article  PubMed  Google Scholar 

  30. 30.

    Sanchez I, Garcia-Abujeta JL, Fernandez L, Rodriguez F, Quinones D, Duque S, Lopez R, Jerez J (1998) Stevens-Johnson syndrome from tetrazepam. Allergol Immunopathol 26(2):55–57

    CAS  Google Scholar 

  31. 31.

    Pirker C, Misic A, Brinkmeier T, Frosch PJ (2002) Tetrazepam drug sensitivity—usefulness of the patch test. Contact Dermatitis 47(3):135–138

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Lagnaoui R, Ramanampamonjy R, Julliac B, Haramburu F, Ticolat R (2001) Fatal toxic epidermal necrolysis associated with tetrazepam. Therapie 56(2):187–188

    CAS  PubMed  Google Scholar 

  33. 33.

    Delesalle F, Carpentier O, Guatier S, Delaporte E (2006) Toxic epidermal necrolysis caused by tetrazepam. Int J Dermatol 45(4):480. doi:10.1111/j.1365-4632.2006.02654.x

    Article  PubMed  Google Scholar 

  34. 34.

    Camarasa JG, Serra-Baldrich E (1990) Tetrazepam allergy detected by patch test. Contact Dermatitis 22(4):246

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Loncar C, Franic T, Bilusic M (2005) Toxic epidermal necrolysis caused by flurazepam? Psychiatr Danub 17(3–4):236–239

    PubMed  Google Scholar 

  36. 36.

    Redondo P, Vicente J, Espana A, Subira ML, De Felipe I, Quintanilla E (1996) Photo-induced toxic epidermal necrolysis caused by clobazam. Br J Dermatol 135(6):999–1002

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Huang PH, Tsai WJ (2005) Chlordiazepoxide-induced Stevens-Johnson syndrome. J Chin Med Assoc : JCMA 68(6):276–278. doi:10.1016/s1726-4901(09)70150-9

    Article  PubMed  Google Scholar 

  38. 38.

    Ertam I, Sezgin AO, Unal I (2009) A case with Stevens Johnson syndrome triggered by combination of clobazam, lamotrigine, and valproic acid treatment. Int J Dermatol 48(1):98–99. doi:10.1111/j.1365-4632.2009.03865.x

    Article  PubMed  Google Scholar 

  39. 39.

    Machado VH, Palmini A, Bastos FA, Rotert R (2011) Long-term control of epileptic drop attacks with the combination of valproate, lamotrigine, and a benzodiazepine: a ‘proof of concept’, open label study. Epilepsia 52(7):1303–1310. doi:10.1111/j.1528-1167.2011.03075.x

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    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):1–512. doi:10.1002/pds.3512

    Article  Google Scholar 

  41. 41.

    The RegiSCAR Project. (2014) RegiSCAR. http://www.regiscar.org/. Accessed 3 October 2014

  42. 42.

    Mockenhaupt M, Sekula S, Lebrun-Vignes B, Roujeau JC (2013) The risk of tetrazepam to induce severe cutaneous adverse reactions. Pharmacoepidemiol Drug Saf 22(1):1–521. doi:10.1002/pds.3512

    Article  Google Scholar 

  43. 43.

    PIELenRed (2014) Consorcio PIELenRed. http://pielenred.hol.es/PIELenRed/tag/pielenred/. Accessed 8 October 2014

  44. 44.

    Hanley JA, Lippman-Hand A (1983) If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 249(13):1743–1745

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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

Funding

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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Correspondence to Elisa Martín-Merino.

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Martín-Merino, E., de Abajo, F.J. & Gil, M. Risk of toxic epidermal necrolysis and Stevens-Johnson syndrome associated with benzodiazepines: a population-based cohort study. Eur J Clin Pharmacol 71, 759–766 (2015). https://doi.org/10.1007/s00228-015-1850-y

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Keywords

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