Colchicine Tablets were approved by FDA on 7/29 & 7/30/09 (approval letters not yet posted as of this writing). Two NDA’s were submitted, one for the treatment of acute gout and the other for familial Mediterranean fever (FMF). Pretty amazing and interesting for a number of reasons. First, it is a DESI (meaning, a previously unapproved product) to NDA. Second, there have been huge safety issues (including several deaths) that caused FDA to take enforcement action against the injectable versions. Third, this approval will cause a big change in how this product is used and dosed (see MedWatch announcement) . Fourth, the product was approved based only on literature for efficacy for the treatment of familial Mediterranean fever (FMF) and a single Phase III study for the treatment of acute gout.
During the review of this product the sponsor (Mutual Pharmaceuticals) and FDA determined that, historically, the dose was too high and that concomitant medications produced unacceptable and sometimes fatal toxicity. FDA is certain to use this example in its justification of enforcement action against DESI drugs.
FDA has ramped up its efforts to remove unapproved drugs (DESI) from the market making highest priority those drugs where there are safety or efficacy concerns. Colchicine injection was removed from the market in February, 2008 because of often fatal toxicity. The development work done by Mutual showed that this toxicity was due to excessive dose and/or concomitant medications. At the time, FDA did not take action against the DESI tablet products because they were titrated. Now we know that the titration was flawed, since Mutual showed that a lower dose was just as effective as the higher doses.
What studies did Mutual need to conduct for approval? As of this writing, the FDA review information is not available. The label that covers only the FMF indication indicates that efficacy was based on literature:
“The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.”
Given that the drug is used in pediatric patients aged 4 and older and that the dose is based on age, it is somewhat surprising that no pediatric pharmacokinetic studies were performed (label: “Pediatric Patients: Pharmacokinetics of colchicine was not evaluated in pediatric patients”) ; pk studies were conducted in only healthy adults.
For acute gout, Mutual had previously presented posters at the October 2008 annual meeting of the American College of Rheumatology showing that they had conducted a Phase III study(Low Dose (1.8 mg) vs High Dose (4.8 mg) Oral Colchicine Regimens in Patients with Acute Gout Flare in a Large, Multicenter, Randomized, Double-Blind, Placebo-Controlled Parallel Group Study) as well as a drug-drug interaction study (A One Sequence, Two-Period Pharmacokinetic Drug-Drug Interaction Study With Colchicine Reveals Profound Effects of Clarithromycin (A Macrolide Antibiotic) On The Pharmacokinetic Profile of Colchicine in Healthy Adults). The label for acute gout indicates a single phase 3 study was conducted.