Pharmacists and their patients may notice a change in one of the oldest medications in the U.S. Pharmacopeia: colchicine. A derivative of the plant Colchicum autumnale, colchicine has been used for centuries to treat a variety of inflammatory conditions, and for at least the last 200 years to treat acute gout. Even today, colchicine’s mechanism of action is not fully understood, but probably involves inhibiting the migration of leukocytes and proinflammatory cytokines into affected tissues, thereby relieving inflammation.
Despite its widespread use, the drug was never officially approved by the FDA for any indication. Because colchicine was an older drug, manufacturers did not have to demonstrate its safety and efficacy per the requirements of the 1938 Food, Drug, and Cosmetic Act (FDCA). Realizing that older drugs should be held to the same standard of efficacy and safety as all other medications, the FDA began a variety of activities to study agents “grandfathered” into the market by the FDCA. In 2006, the agency launched the Unapproved Drugs Initiative, a program that developed incentives for (largely generic) drug companies to perform adequate studies on these older drugs.
As part of the Unapproved Drugs Initiative, Philadelphia-based URL Pharma supported a Phase III study to compare two dosing regimens of colchicine with placebo in 185 patients suffering flares of acute gouty arthritis. Patients in the study self-initiated treatment within 12 hours of an attack of gout. The low dose consisted of 1.2 mg colchicine followed by 0.6 mg one hour later. The high dose consisted of 1.2 mg, followed by 0.6 mg hourly × 6 hours (4.8 mg total). The primary outcome of the study was response, which was defined an improvement in pain scores of 50% or more within 24 hours.
The study revealed the low dose to be superior to placebo and roughly equal to the high dose in attaining the primary outcome (15.5%, 37.8% and 32.7% in the placebo, low-dose and high-dose arms, respectively).The low-dose colchicine caused fewer gastrointestinal adverse events (AEs) than the high-dose regimen (25.7% vs 76.9% in the low-dose and high-dose groups, respectively). The authors concluded that low-dose colchicine was an effective treatment for acute gout and the efficacy results were in line with the only other placebo-controlled trial of colchicine for gout, which was published in 1987.
Some have criticized the outcomes of the study, for three reasons: The primary efficacy end point was examined only at 24 hours; 30% to 50% of patients in all three arms required other medication for “rescue” pain relief, usually nonsteroidal anti-inflammatory drugs (NSAIDs), and these patients were considered nonresponders in the trial; and the results of the trial indicated that colchicine would not displace NSAIDs or corticosteroids as the first choice for treating gouty arthritis flares.
Despite these criticisms, the FDA approved URL Pharma’s proprietary version of colchicine (Colcrys) for the treatment of acute gout, based largely on the results of this trial. The FDA also approved this drug for chronic prophylaxis of gout attacks and for the treatment of familial Mediterranean fever (FMF), a rare hereditary autoimmune disease for which colchicine is the only agent available. Existing legislation gave the FDA the authority to grant URL Pharma three years of market exclusivity for the gout indications and seven years of market exclusivity for FMF. Last September, the FDA ordered companies that manufactured, distributed or marketed unapproved, single-ingredient oral colchicine to stop their activities with respect to the drug.
The immediate impact of this decision is a dramatic increase in cost. Colcrys is roughly 50 times more expensive that unapproved colchicine ($4.85 per tablet of Colcrys compared with roughly 10 cents per tablet of colchicine). Patients and third-party payers alike are trying to make sure patients continue to receive colchicine despite the massive price increase. Patients with FMF or those who take colchicine routinely for gout prophylaxis could be the hardest hit, with some patients now paying about $300 per month for an agent for which they paid only $6 per month just a few months ago.
Several patient groups and physician organizations have been critical of URL Pharma and the FDA. The American College of Rheumatology (ACR) has urged the FDA to “grandfather” unbranded versions of colchicine to help rein in the financial burden. URL Pharma has defended the price of Colcrys by pointing out the costs involved in conducting the research necessary to bring a drug to the U.S. market. The company also has developed and implemented a patient assistance program that can be accessed by going to http://www.colcrys.com/healthcare-professional/patient-assistance-program.htm. URL Pharma notes that patients with incomes up to $132,000 per year may qualify to obtain Colcrys for $25 per month. Finally, the company points out that its research demonstrated that low-dose colchicine—a drug known to have several dose-related AEs, including nausea, diarrhea, myopathy and neutropenia—is not only as effective as high-dose colchicine, but safer. The possibility of significant drug–drug interactions may be reduced in patients using the low-dose regimen.
The most current clinical guidelines for gout developed by a large body of clinicians are those published in 2006 by the European League Against Rheumatism (EULAR). These guidelines recommend either NSAIDs or colchicine as the first line of treatment for acute gouty arthritis. They also suggest that NSAIDs may be a safer option. How EULAR or the ACR would view the new low-dose colchicine regimen compared with NSAIDs remains to be seen. Certainly a head-to-head study comparing NSAIDs with colchicine would give clinicians the most robust information concerning both efficacy and safety, but such a study is unlikely.
For now, pharmacists may find themselves explaining the saga of Colcrys’ approval and helping patients enroll in URL Pharma’s patient assistance program. Colcrys may treat acute gouty arthritis pain, but its potential for producing headaches for pharmacists may be significant. Those headaches may multiply as other drug companies follow in URL Pharma’s footsteps and undertake the process with other drugs that have been used for decades, including nitroglycerin tablets and certain forms of morphine.
Colcrys Product Information. www.colcrys.com. Accessed March 10, 2011.
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