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Comparison of Reporting of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors

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Abstract

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides.

Objective: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate.

Methods: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature.

Results: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8–9 times that of celecoxib and approximately 25 times that of the background rate.

Conclusion: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.

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References

  1. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997; 24(11): 726–9

    PubMed  CAS  Google Scholar 

  2. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994 Nov 10; 331(19): 1272–85

    Article  PubMed  CAS  Google Scholar 

  3. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, et al, editor. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 2005; 153(2): 241–53

    Google Scholar 

  4. Mockenhaupt M, Schopf E. Epidemiology of drug-induced severe skin reactions. Semin Cutan Med Surg 1996; 15(4): 236–43

    Article  PubMed  CAS  Google Scholar 

  5. Roujeau JC, Kelly JP, Naldi N, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333: 1600–7

    Article  PubMed  CAS  Google Scholar 

  6. Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353(9149): 307–14

    Article  PubMed  CAS  Google Scholar 

  7. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001 Aug 9; 345(6): 433–42

    Article  PubMed  CAS  Google Scholar 

  8. Jüni P, Rutjes AWS, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287–8

    Article  PubMed  Google Scholar 

  9. FDA Public Health Advisory: safety of Vioxx [online]. Available from URL: http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm [Accessed 2004 Oct 4]

  10. COX-2 selective (includes Bextra, Celebrex, and Vioxx) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Available from URL: http://www.fda.gov/cder/drug/infopage/COX2/default.htm [Accessed 2005 May 11]

  11. Mockenhaupt M, Kelly JP, Kaufman D, et al. SCAR Study Group. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with nonsteroidal antiinflammatory drugs: a multinational perspective. J Rheumatol 2003; 30(10): 2234–40

    PubMed  CAS  Google Scholar 

  12. Celebrex™. Physicians’ Desk Reference. 55th ed. Montvale (NJ): Medical Economics Company, 2001: 2482–2484

  13. Jones JB, Wabba MM. Important drug warning (‘Dear Healthcare Professional’ letter). Peapack (NJ) and New York (NY): Pharmacia/Pfizer, 2002 Nov 13 [online]. Available from URL: http://www.fda.gov/medwatch/SAFETY/2002/safety02.htm#bextra. [Accessed 2004 Oct 1]

  14. Tubert P, Begaud B, Pere JC, et al. Power and weakness of spontaneous reporting: a probabilistic approach. J Clin Epidemiol 1992; 45(3): 283–6

    Article  PubMed  CAS  Google Scholar 

  15. Schroeder DR. Statistics: detecting a rare adverse drug reaction using spontaneous reports. Reg Anesth Pain Med 1998; 23(6 Suppl. 2): 183–9

    PubMed  CAS  Google Scholar 

  16. Giglio P. Toxic epidermal necrolysis due to administration of celecoxib (Celebrex). South Med J 2003 Mar; 96(3): 320–1

    Article  PubMed  Google Scholar 

  17. Glasser DL, Burroughs SH. Valdecoxib-induced toxic epidermal necrolysis in a patient allergic to sulfa drugs. Pharmacotherapy 2003 Apr; 23(4): 551–3

    Article  PubMed  Google Scholar 

  18. Layton D, Riley J, Wilton LV, et al. Safety profile of rofecoxib as used in general practice in England: results of a prescription- event monitoring study. Br J Clin Pharmacol 2003 Feb; 55(2): 166–74

    Article  PubMed  CAS  Google Scholar 

  19. Schopf E, Stuhmer A, Rzany B, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Germany. Arch Dermatol 1991; 127(6): 839–42

    Article  PubMed  CAS  Google Scholar 

  20. Fritsch PO, Ruiz-Maldonado R. Stevens-Johnson syndrometoxic epidermal necrolysis. In: Freedberg IM, Eisen AZ, Wolff K, et al., editors. Fitzpatrick’s dermatology in general medicine. New York: McGraw-Hill, 1999

    Google Scholar 

  21. Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther 1998; 20Suppl. C: C40–4

    Article  PubMed  CAS  Google Scholar 

  22. Hartmann K, Doser AK, Kuhn M. Postmarketing safety information: how useful are spontaneous reports? Pharmacoepidemiol Drug Saf 1999; 8Suppl. 1: S65–71

    Article  PubMed  Google Scholar 

  23. Mittman N, Knowles SR, Gomez M, et al. Evaluation of the extent of under-reporting of serious adverse drug reactions the case of toxic epidermal necrolysis. Drug Saf 2004; 27(7): 477–87

    Article  Google Scholar 

  24. Sachs RM, Bortnichak EA. An evaluation of spontaneous adverse drug reaction monitoring systems. Am J Med 1986; 81Suppl. 5B: 49–55

    PubMed  CAS  Google Scholar 

  25. Garcia-Doval I, LeCleach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000; 136(3): 323–7

    Article  PubMed  CAS  Google Scholar 

  26. Correia O, Delgado L, Barbosa IL, et al. Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol 2002; 47(1): 58–62

    Article  PubMed  Google Scholar 

  27. Abe R, Shimizu T, Shibaki A, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol 2003; 162(5): 1515–20

    Article  PubMed  CAS  Google Scholar 

  28. Chung W-H, Hung S-I, Hong H-S, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004, 428, 486

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors were employees of the United States Government at the time this study was conducted and received no directed funding nor declare any conflict of interest relevant to this research effort. The views expressed are those of the authors and do not necessarily represent those of the US Food and Drug Administration or imply its endorsement.

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Correspondence to Lois La Grenade.

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La Grenade, L., Lee, L., Weaver, J. et al. Comparison of Reporting of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors. Drug-Safety 28, 917–924 (2005). https://doi.org/10.2165/00002018-200528100-00008

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