New Restrictions on Celecoxib (Celebrex) Use and the Withdrawal of Valdecoxib (Bextra)

Early release, published at www.cmaj.ca on April 15, 2005. Subject to revision.

HEALTH AND DRUG ALERTS P RACTICE New restrictions on celecoxib (Celebrex) use and the withdrawal of valdecoxib (Bextra)

Early release, published at www.cmaj.ca on Apr. 15, 2005. Subject to revision.

Reason for posting: Coxibs, v. 0.5%; risk ratio 3.7, 95% CI the class of NSAIDs that selec- 1.0–13.5).2 Amid concerns about Table 1: The degree of inhibition of COX-2 relative tively inhibit cyclooxygenase 2 reports of severe cutaneous reac- to COX-1 for various NSAIDs (COX-2), were designed to re- tions (Stevens–Johnson syn- NSAID type COX-2 selectivity* duce joint pain and inflamma- drome, erythema multiforme, tion without causing the gastric toxic epidermal necrolysis) COX-2 selective inhibitors epithelial adverse effects typical among patients taking valde- Rofecoxib 80 of nonselective NSAIDs. Rofe- coxib,5 the drug was removed Etodolac 23 coxib (Vioxx) was withdrawn from the market. Meloxicam 11 from the market in September Celecoxib 9 2004 over concerns about car- What to do: COX-2 inhibitors Nonselective NSAIDs diovascular adverse effects, and appear to increase the risk of car- Diclofenac 4 key safety trials involving cele- diovascular adverse events in a Sulindac 3 coxib (Celebrex)1 and valdecoxib dose-related fashion, and all pa- Piroxicam 2 (Bextra)2 have recently been tients should be informed of this. Ibuprofen 0.4 published. Health Canada now Calculating the patient’s baseline Naproxen 0.3 recommends new restrictions on risk of cardiovascular disease Indomethacin 0.2 celecoxib use, and valdecoxib (e.g., with Framingham risk cal- Ketorolac 0.003 has been taken off the market.3 culators) may be wise, and cele- Note: COX = cyclooxygenase. The US Food and Drug Ad- coxib should not be prescribed to *The 80% inhibitory concentration ratios of COX-2 relative to COX-1 in ministration has gone further, patients with cardiovascular dis- human whole blood assays.6 directing that all prescription ease or diabetes or those at in- and over-the-counter NSAIDs creased risk of cardiovascular include specific information re- events. Celecoxib should be used References 1. Solomon SD, McMurray JJ, Pfeffer garding potential cardiovascular, in the lowest effective doses for MA, Wittes J, Fowler R, Finn P, et al. gastrointestinal and other risks.4 short periods (weeks) only. A Cardiovascular risk associated with risk–benefit discussion is neces- celecoxib in a clinical trial for col- orectal adenoma prevention. N Engl J The drugs: The results of re- sary for those requiring the drug Med 2005;352:1071-80. cent trials have raised concerns for a longer period. Of note, pa- 2. Nussmeier NA, Whelton AA, Brown 1 MT, Langford RM, Hoeft A, Parlow that coxib use increases the risk tients in the APC study who JL, et al. Complications of the Cox-2 of cardiovascular adverse events. used celecoxib for 3 years at a inhibitors parecoxib and valdecoxib In the APC study, a trial on col- dose double that recommended after cardiac surgery. N Engl J Med 2005;352:1081-91. orectal adenoma prevention, for osteoarthritis had an increase 3. Health Canada. Advisory: Health 2035 patients were randomly as- in absolute risk of cardiovascular Canada has asked Pfizer to suspend signed to celecoxib 200 mg events of about 1.3% (number sales of its drug Bextra and informs Canadians of new restrictions on the twice daily or 400 mg twice needed to harm of 77). use of Celebrex. 07 Apr 2005. Available daily or placebo. After about 3 The only NSAID known to at: www.hc-sc.gc.ca/english/protection /warnings/2005/2005_17.html (ac- years, cardiovascular events reduce primary and secondary cessed 2005 Apr 12). (death from cardiovascular cardiovascular events is ASA. The 4. US Food and Drug Administration. causes, myocardial infarction, absolute risk of other NSAIDs is FDA Public Health Advisory: FDA an- nounces important changes and addi- stroke, heart failure) had oc- unclear. Appreciating the relative tional warnings for COX-2 selective curred in 1% of patients receiv- degree of COX-2 selectivity of and non-selective non-steroidal anti-in- ing placebo, 2.3% of the group some commonly used NSAIDs flammatory drugs (NSAIDs). Available at: www.fda.gov/cder/drug/advisory taking 200 mg celecoxib (hazard (Table 1) may be useful. Alterna- /COX2.htm (accessed 2005 Apr 13). ratio [HR] 2.3, 95% confidence tive pharmacologic and nonphar- 5. Health Canada. Health Canada en- dorsed important safety information interval [CI] 0.9–5.5), and 3.4% macologic approaches to pain on BEXTRA (valdecoxib) tablets [let- (HR 3.4, 95% CI 1.4–7.8) of the management should be reviewed ter]. Dec. 10, 2004. Available at: group taking 400 mg.1 and strongly considered. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt /bextra2_hpc_e.html (accessed 2005 In a trial involving 1671 pa- Apr 14). tients who underwent coronary 6. Warner TD, Giuliano F, Vojnovic I, Jill Cotter artery bypass grafting, cardiovas- Bukasa A, Mitchell JA, Vane JR. Resident Nonsteroid drug selectivities for cy- cular events were more frequent Department of Family Medicine clo-oxygenase-1 rather than cyclo- among those taking valdecoxib University of Ottawa oxygenase-2 are associated with human gastrointestinal toxicity: a full and parecoxib for pain than Eric Wooltorton in-vitro analysis. Proc Natl Acad Sci

DOI:10.1503/cmaj.050456 among those taking placebo (2% CMAJ USA 1999;96:7563-8.

CMAJ • MAY 10, 2005; 172 (10) 1299