FDA MedWatch - Colchicine

Colchicine (marketed as Colcrys)
Audience: Rheumatological healthcare professionals

FDA notified healthcare professionals of the approval of the first single-ingredient oral colchicine product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares and of two previously uncharacterized safety concerns associated with the use of colchicine. Oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.

FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity. Data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose.

Based on this information, FDA has included important safety considerations in the approved prescribing information to assure safe use of Colcrys and is providing background information, a data summary and recommendations in this alert.

Read the complete MedWatch Safety summary, including a link the the Information for Healthcare Professionals page with a data summary and patient management recommendations, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm174596.htm

Colchicine (marketed as Colcrys)Audience: Rheumatological healthcare professionals

[Posted 07/30/2009] FDA notified healthcare professionals of the approval of the first single-ingredient oral colchicine product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares and of two previously uncharacterized safety concerns associated with the use of colchicine. Oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.

FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity. Data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose.

Based on this information, FDA has included important safety considerations in the approved prescribing information to assure safe use of Colcrys and is providing background information, a data summary and recommendations in this alert.

[07/30/2009 - Information for Healthcare Professionals - FDA]


Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys)


FDA ALERT [07/30/2009]: FDA has now approved the first single-ingredient oral colchicine product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares. Oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.
During the drug application review, FDA identified two previously uncharacterized safety concerns associated with the use of colchicine (marketed as Colcrys).

First, FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity.

Second, data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose.

Based on this information, FDA is highlighting important safety considerations found in the approved prescribing information to assure safe use of Colcrys.

FDA recommends:

Healthcare professionals not use P-glycoprotein (P-gp) or strong CYP3A4 inhibitors in patients with renal or hepatic impairment who are currently taking colchicine.
Healthcare professionals consider a dose reduction or interruption of colchicine treatment in patients with normal renal and hepatic function if treatment with a P-gp or a strong CYP3A4 inhibitor is required.
Healthcare professionals prescribe the FDA-approved Colcrys dose for the treatment of acute gout flares: 1.2 mg followed by 0.6mg in 1 hour (total 1.8mg).
Healthcare professionals refer to Colcrys’ approved prescribing information for specific dosing recommendations and additional drug interaction information.
Patients review the Medication Guide for important safety information
This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch programusing the information at the bottom of this page.


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Additional Considerations for Healthcare Professionals

Be aware that there is now an FDA-approved single-ingredient colchicine product, Colcrys
Understand that the recommended dose of Colcrys (colchicine) for Familial Mediterranean Fever (FMF) and acute gout flares are different
Be aware that concomitant use of P-gp and strong CYP3A4 inhibitors may cause severe drug interactions with colchicine, including death
Evaluate patients’ underlying susceptibility for colchicine toxicity due to renal and hepatic impairment or age
Understand that concomitant use of colchicine and P-gp or strong CYP3A4 inhibitors is contraindicated in patients with renal or hepatic impairment.
Be aware that Colcrys has a Medication Guide and urge patients, their families, and caregivers to review the Medication Guide carefully
Inform patients who are taking colchicine to check with healthcare professionals before taking any new medicine
Information for patients, family members, and caregivers:

Understand that colchicine (Colcrys) is not a pain medication and should not be used for other causes of pain
Understand that life-threatening and fatal drug interactions can occur with Colcrys if it is given with certain medications. These interactions can occur even at prescribed Colcrys doses, and with medications that are given for a limited time, such as antibiotics
Review the Medication Guide that accompanies Colcrys.
Discuss with healthcare professionals all medications being taken and check with them before starting any new medications
Avoid consuming grapefruit and grapefruit juice while using colchicine
Pay close attention for any signs or symptoms of colchicine toxicity such as muscle weakness or pain, numbness or tingling in the fingers or toes, unusual bleeding or bruising, severe diarrhea or vomiting, feeling weak or tired, increased infections, and pale or gray color of the lips, tongue, or palms of hands. If any of these symptoms occur, seek medical attention right away
Background and Data Summary: Severe Drug Interactions
During the drug application review, FDA analyzed safety data for colchicine-related deaths described in the published literature, adverse events reported to FDA’s Adverse Event Reporting System (AERS), and company-sponsored pharmacokinetic and drug interaction studies. The analysis found 169 deaths associated with the use of oral colchicine.

Of the 169 deaths, 117 were not reported as overdoses; i.e., the majority of reported deaths had colchicine doses within the therapeutic range of less than or equal to 2 mg per day. The reported death cases did not contain information regarding patients’ renal or hepatic function. Sixty of the 117 reported deaths (51%) involved patients who were concomitantly using clarithromycin.* These reports suggest alterations in the pharmacokinetics of colchicine played a central role in the development of toxicity.

The pharmacokinetics of colchicine may be affected in several ways. The absorption of colchicine from the gastrointestinal tract is thought to be limited by the multidrug resistance efflux transporter P-glycoprotein (P-gp). Additionally, colchicine is a substrate of intestinal and hepatic cytochrome P450 3A4 (CYP3A4), which catalyzes demethylation of colchicine to inactive metabolites. Colchicine is primarily eliminated by hepatobiliary excretion through the stool. Renal excretion accounts for 10-20% of colchicine elimination in patients with normal renal function.

Consistent with the current understanding of colchicine metabolism, certain drugs increase the potential for colchicine toxicity via modulation of P-gp and CYP3A4 activity. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine when P-gp and strong CYP3A4 inhibitors, particularly clarithromycin, were also being used. In the majority of cases, the doses of colchicine were within the therapeutic range.

Fatal and non-fatal cases of colchicine toxicity have also been reported in the literature with concomitant use of other CYP3A4 and P-gp inhibitors, such as cyclosporine, erythromycin, and calcium channel antagonists such as verapamil and diltiazem. Other examples of P-gp and strong CYP3A4 inhibitors include telithromycin, ketoconazole, itraconazole, HIV protease inhibitors, and nefazodone. Toxicity has also been reported in a patient who began to regularly consume a liter of grapefruit juice daily while being treated chronically with colchicine. Additionally, cases of myopathy and/or rhabdomyolysis in patients receiving colchicine have been reported with concomitant use of statins, fenofibrate/gemfibrozil, cyclosporine, or digoxin.

Based on this information, FDA concludes there is a risk for severe drug interactions in certain patients treated with colchicine and concomitant P-gp or strong CYP3A4 inhibitors. FDA recommends that P-gp or strong CYP3A4 inhibitors not be used in patients with renal or hepatic impairment who are currently taking colchicine. Furthermore, FDA recommends that healthcare professionals consider a dose reduction or interruption of colchicine in patients with normal renal and hepatic function if treatment with a P-gp or a strong CYP3A4 inhibitor is required. The FDA-approved prescribing information for Colcrys contains recommended dosage adjustments.

* The FDA approved prescribing information for clarithromycin (marketed as Biaxin, Biaxin Filmtab, Biaxin XL) was updated in 2005 and 2006 to include this warning: There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients.

Data Summary: Acute Gout

For the treatment of acute gout flares, medical texts typically recommend that patients take orally 1.2mg of colchicine followed by 0.6mg every hour until the flare resolves or until gastrointestinal toxicity occurs. However, adequate studies to determine the optimal dose of colchicine in acute gout flares have never been conducted. As part of the application for approval, the manufacturer of Colcrys submitted data from a clinical trial to evaluate the safety and efficacy of a low-dose regimen of oral colchicine for treatment of acute gout flares compared to the traditional high-dose regimen.

The trial was a multicenter, randomized, double-blind, placebo-controlled trial of patients meeting American College of Rheumatology criteria for gout who were assigned to one of three treatment groups within 12 hours of a gout flare, as follows:

Group 1: high-dose colchicine (1.2 mg, then 0.6 mg hourly for 6 hours [4.8 mg total])
Group 2: low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by 5 placebo doses hourly)
Group 3: placebo (2 capsules, then 1 capsule hourly for 6 hours).
The trial found that a statistically significantly greater proportion of patients in the low-dose (38%) and high-dose (33%) colchicine groups achieved a 50% reduction in pain in the target joint compared to placebo (16%). Additionally, the rate of gastrointestinal adverse events (diarrhea, nausea, vomiting, abdominal pain) was considerably lower in low-dose patients (26%) compared to high-dose patients (77%). In addition, there were no severe adverse events reported in low-dose patients compared to 10 reported in high-dose patients.

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. Based on this trial, FDA recommends that healthcare professionals prescribe the approved Colcrys dose of 1.2mg at onset of acute gout flare followed by 0.6mg in 1 hour, for a total of 1.8mg, and carefully consider the need for additional subsequent dosing. Healthcare professionals should also monitor patients for signs and symptoms of colchicine toxicity.