What is the risk of anaphylactoid reactionsto COX-2 inhibitors?Assessing the riskof anaphylaxis withCOX-2 inhibitors Selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, rofecoxib, and valdecoxib, are an effective and commonly used class of drugs for the management of pain. They are particularly useful in patients who are unable to tolerate aspirin or traditional NSAIDs because of side effects. Many physicians are appropriately concerned about the risk of anaphylactoid reactions from COX-2 inhibitors. The manufacturers' warning labels for all 3 state that COX-2 inhibitors may cause severe anaphylactoid reactions, particularly in patients who have experienced asthma or allergic-type reactions to aspirin or NSAIDs. Warning labels on celecoxib and valdecoxib also list sulfonamide allergy as a contraindication. Anaphylaxis and anaphylactoid reactions to selective COX-2 inhibitors are rare. There are 2 case reports describing patients who became sensitized to celecoxib and suffered an anaphylactic episode on subsequent exposure.1,2 There also have been rare case reports of anaphylactoid reactions to celecoxib3 and rofecoxib4 on first exposure. In these cases, the patients did not have sulfonamide allergy or aspirin-exacerbated respiratory disease (AERD). Valdecoxib has not been described in the published literature to cause anaphylaxis or anaphylactoid reactions. A fair amount of research has been conducted on the risk of anaphylactoid reactions from selective COX-2 inhibitors in patients with AERD. In a double-blind, placebo-controlled trial, Stevenson and Simon5 challenged 60 such patients with rofecoxib; none of them reacted with 12.5 or 25 mg. Martin-Garcia and associates6 and Szczeklik and associates7 challenged a total of 52 AERD patients with up to 25 mg of rofecoxib. None reacted during single-blind oral challenges. Woessner and associates8 challenged 60 AERD patients with an even higher dose of rofecoxib (50 mg), and none had any adverse reactions. Celecoxib has also been studied in patients with AERD. In one placebo-controlled study, 60 patients with AERD were given 200 mg of celecoxib; none of the patients reacted.9 Similarly, Yoshida and associates10 challenged 17 patients with AERD using 200 mg of celecoxib, and Gyllfors and associates11 challenged 32 AERD patients with 400 mg of celecoxib, and no anaphylactoid reactions occurred. Valdecoxib is the third and most recent selective COX-2 inhibitor to enter the US market. Woessner and associates12 recently completed a double-blind, placebo-controlled study of 70 patients with AERD. None of the patients had adverse reactions to the full dose (20 mg) of valdecoxib. Because celecoxib and valdecoxib contain a sulfonamide moiety, they are considered by the FDA to be contraindicated in patients with sulfonamide allergy. However, there are no reports in the literature of sulfonamide-allergic patients experiencing anaphylaxis to either celecoxib or valdecoxib. This is not surprising, since both drugs lack the aromatic amine portion and the N1-substituent of the sulfonamide antimicrobial, which are considered to be responsible for the adverse reactions in sulfonamide-allergic patients.13 In summary, anaphylaxis and anaphylactoid reactions from selective COX-2 inhibitors are rare. Well-designed studies support the safety of these agents in patients with AERD. There is very little evidence supporting cross-reactivity between selective COX-2 inhibitors and sulfonamide antibiotics. However, because of the warning label on these drugs, we recommend administering a full therapeutic dose of a COX-2 inhibitor in the physician's office for patients with AERD or sulfonamide allergy. References: REFERENCES 1. Levy MB, Fink JN. Anaphylaxis to celecoxib. Ann Allergy Asthma Immunol. 2001;87:72-73. 2. Grob M, Pichler WJ, Wuthrich B. Anaphylaxis to celecoxib. Allergy. 2002;57:264-265. 3. Gagnon R, Julien M, Gold P. Selective celecoxib- associated anaphylactoid reaction. J Allergy Clin Immunol. 2003;111:1404-1405. 4. Schellenberg RR, Isserow SH. Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who had a reaction to a cyclooxygenase-1 inhibitor. N Engl J Med. 2001;345:1856. 5. Stevenson DD, Simon RA. Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma. J Allergy Clin Immunol. 2001;108: 47-51. 6. Martin-Garcia C, Hinojosa M, Berges P, et al. Safety of a cyclooxygenase-2 inhibitor in patients with aspirin-sensitive asthma. Chest . 2002;121:1812-1817. 7. Szczeklik A, Nizankowska E, Bochenek G, et al. Safety of a specific COX-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy . 2001;31:219-225. 8. Woessner KM, Simon RA, Stevenson DD. Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol . 2004;93:339-344. 9. Woessner KM, Simon RA, Stevenson DD. The safety of celecoxib in patients with aspirin-sensitive asthma. Arthritis Rheum . 2002;46:2201-2206. 10. Yoshida S, Ishizaki Y, Onuma K, et al. Selective cyclo-oxygenase 2 inhibitor in patients with aspirin- induced asthma. J Allergy Clin Immunol. 2000;106: 1201-1202. 11. Gyllfors P, Bochenek G, Overholt J, et al. Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2- selective analgesic drug celecoxib. J Allergy Clin Immunol . 2003;111:1116-1121. 12. Woessner KM, Simon RA, Stevenson DD. Tolerability of selective cyclooxygenase inhibitors in asthma: valdecoxib. In press. 13. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy. Drug Saf. 2001;24:239-247.
