The Law of Unintended Consequences Rears Its Head

The ACR Advocacy list serve was on fire in December 2009 as members discussed the recent price increase for colchicine. Patients and physicians alike were shocked to discover that Colcrys, a new brand name colchicine, skyrocketed in cost after receiving approval for acute gout and familial Mediterranean fever (FMF), increasing in price from approximately 10 cents a pill to approximately five dollars a pill. For a twice-daily dose, the monthly cost of colchicine increased from $6 to $300! How did this happen, and will our patients be able to manage the sharp price increase for this previously “generic,” technically unapproved, drug?

Colchicine 101

In order to determine how to best respond to this issue, ACR staff researched the use of colchicine and related Food and Drug Administration (FDA) regulatory oversight.

Colchicine was first isolated in 1820 by two French chemists and was included in the first Pharmacopoeia of the United States. Moving ahead almost 120 years to 1938, the Federal Food, Drug, and Cosmetic Act required drugs to be approved by the FDA for safety. Beginning in 1962, Congress required that new drugs must be FDA approved for efficacy as well as safety. The agency also evaluated drugs that had been approved between 1938 and 1962. This did not affect colchicine because it was created prior to 1938. In 2006, the FDA announced a new drug-safety initiative to remove unapproved drugs from the market. The guidance for the initiative, “Marketed Unapproved Drugs—Compliance Policy Guide,” affected colchicine as a marketed unapproved drug that required regulatory approval.

URL Pharma was the first manufacturer to step forward and complete the necessary regulatory testing for FDA approval. During the application process, a significant observation determined for the first time that colchicine toxicity was potentially exacerbated by drugs that inhibit CYP3A4, an enzyme involved in the metabolism of colchicine, and p-gylcoprotein, a protein involved in its oral absorption. Drugs that inhibit CYP3A4 and p-glycoprotein include chlarithromycin, erythromycin, cyclosporine, verapamil, diltiazem, ketaoconcazole, and itraconazole. Many of 169 patients who died presumably due to colchicine toxicity reported to the FDA’s adverse event reporting system (AERS) were on one of these drugs. A placebo-controlled study of colchicine in 184 acute gout patients comparing 1.8 mg over one hour to 4.8 mg over six hours demonstrated similar efficacy in both colchicine treated cohorts with less gastrointestinal toxicity associated with the shorter exposure with reduced dosage. This placebo-controlled study was published in the April 2010 issue of Arthritis & Rheumatism (p. 1060).