Mutual's colchicine product Colcrys approved for gout in US
This article was originally published in Scrip
Mutual Pharmaceutical Company's Colcrys has become the first single-ingredient colchicine product approved by the US FDA for treatment of gout flares. The agency also licensed Colcrys for familial Mediterranean fever, an inherited inflammatory disorder, making it the first drug approved for this condition.
Single-ingredient, oral colchicine has been used by doctors for years to treat gout but has never been approved by the FDA. Consequently, such products on the US market lack approved labelling, dosage recommendations and drug interaction warnings. There are approved combination products containing colchicine and probenecid that are used for treating gout.
The FDA said that during its review of Colcrys it identified two previously uncharacterised safety issues associated with use of oral colchicine. As a result, Colcrys labelling includes a warning about potentially fatal drug-drug interactions and recommends dosing different from colchicine's historical use.
An analysis of safety data from the agency's adverse event reporting system, published literature and company-sponsored pharmacokinetic and drug interaction studies revealed 169 deaths associated with use of oral colchicine. 117 of these fatalities involved doses within the therapeutic range of 2mg or less per day, and more than half of these involved patients who were also taking clarithromycin (Abbott's Biaxin), suggesting a drug-drug interaction that alters colchicine's pharmacokinetics.
The FDA said drugs that are P-gp and CYP3A4 inhibitors increase the potential for colchicine toxicity. It recommends that such inhibitors not be used in renally or hepatically impaired patients who are currently taking colchicine. In patients with normal hepatic and renal function, a colchicine dose reduction should be considered if concomitant treatment with a P-gp or strong CYP3A4 inhibitor is required.
dosing changes
The agency said medical texts typically recommend that patients with acute gout flares take 1.2mg colchicine initially followed by 0.6mg every hour until the flare resolves or gastrointestinal toxicity occurs. In the Colcrys NDA, Mutual, a subsidiary of URL Pharma, submitted data from a placebo-controlled clinical trial comparing the safety and efficacy of the traditional high-dose regimen with a low-dose regimen comprising 1.2mg initially followed by 0.6 mg in one hour.
A significantly greater proportion of patients in the low-dose (38%) and high-dose (33%) colchicine groups achieved a 50% reduction in gout pain compared with placebo (16%). The rate of gastrointestinal events was 26% in the low-dose group and 77% in the high-dose arm. Low-dose patients reported no severe adverse events, while 10 subjects on the high dose experienced severe events.
"These findings suggest that prior use of high-dose colchicine may have exposed patients to increased toxicity with no greater efficacy than the low-dose regimen," the FDA said, recommending the low-dose schedule for gout.
Labelling also includes warnings about fatal overdoses in adults and children, blood disorders and neuromuscular toxicity. The drug was approved with a risk evaluation and mitigation strategy that includes a medication guide.
Familial Mediterranean fever (FMF) is the most common of the hereditary periodic fever syndromes and is characterised by recurrent episodes of fever, arthritis and painful inflammation of the lining of the lungs and abdomen, the FDA said. The condition is rare in the US but more common in Mediterranean countries. Physicians have long prescribed colchicine for FMF based on studies showing it reduced the frequency of attacks, but the drug has never been approved for this condition.