Colchicine's Other Indication — Effect of FDA Action

Abstract

The decision by the Food and Drug Administration (FDA) to approve and grant exclusive licensing of an expensive brand-name formulation (Colcrys) of the decades-old generic drug colchicine, has generated much surprise and discussion, as reported by Kesselheim and Solomon in their Perspective article (June 3 issue).1 However, most of the commentary to date has focused on the most familiar indication for colchicine, the treatment of acute gout. We would argue that the drug’s other indication, the longterm treatment of familial Mediterranean fever (FMF),2 deserves equal attention. We direct UCLA’s Familial Mediterranean Fever Clinic, the largest clinic dedicated exclusively to this disease in the Western Hemisphere. Once the diagnosis is established, all patients with FMF are placed on daily colchicine, which they must continue for life to avoid both the periodic attacks of fever and pain and the life-threatening complication of renal amyloidosis. Thus, the increase in cost by a factor of 50 from the generic to the branded form of colchicine causes far more hardship for patients with FMF than for patients with gout, who use the drug only for the treatment of acute attacks. Furthermore, alternative effective therapies are available for gout (e.g., allopurinol and febuxostat), whereas colchicine is the only existing drug that is effective for FMF. We have observed that missing even a single dose of colchicine can precipitate a breakthrough attack of FMF. We fear that the dramatic increase in price will lead to more missed doses and, worse, to unfilled prescriptions, especially among economically disadvantaged populations. This in turn will result in more days absent from work or school, more emergency room visits, more unnecessary exploratory surgeries, more renal amyloidosis, and more patients on lifelong dialysis or dying of an otherwise treatable disease. Although we are sympathetic to the FDA’s legitimate concerns about potential variability in efficacy or toxicity of unregulated drugs that predate the advent of the Food, Drug, and Cosmetic Act of 1938, we would perhaps be more understanding of this action if there were documented evidence of clinically significant variability in efficacy or toxicity of particular generic formulations of colchicine. But we have observed no such problems among hundreds of patients whom we have treated for FMF and who have been adequately maintained on the same dose for decades. Moreover, the few case reports of colchicine toxicity in the literature were the result of accidental overdose,3 inappropriate intravenous administration,4 or interactions with other drugs.5 The effect of colchicine’s licensure on patients with FMF, although far less numerous than those with gout, should be more than just an afterthought. It is especially ironic that the relative rarity of FMF allowed the manufacturer of Colcrys to invoke the Orphan Drug Act of 1983 and thereby receive 7 years of market exclusivity for its use in this disease, as compared with just 3 years for its use in gout. We seriously doubt that this is the sort of “protection” for patients with rare disorders that was envisioned by the framers of that legislation. 1. Kesselheim AS, Solomon DH. Incentives for drug development — the curious case of colchicine. N Engl J Med 2010; 362:2045-7. 2. Goldstein RC, Schwabe AD. Prophylactic colchicine therapy in familial Mediterranean fever: a controlled, double-blind study. Ann Intern Med 1974;81:792-4. 3. Maxwell MJ, Muthu P, Pritty PE. Accidental colchicine overdose: a case report and literature review. Emerg Med J 2002; 19:265-7. 4. Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Deaths associated with inappropriate intravenous colchicine administration. J Emerg Med 2002;22:385-7. 5. Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kélaïdi C, Blanche P. Acute colchicine intoxication during clarithromycin administration. Ann Pharmacother 2004;38:2074-7.