Guidelines Issued for Combining Colchicines and Calcium-Channel Blockers
By Alice Goodman
Medscape Medical News
October 29, 2009 (Philadelphia, Pennsylvania) — New dosing guidelines for colchicine (Colcrys) provide important information about drug–drug interactions with calcium-channel blockers commonly used to treat hypertension. These guidelines are also applicable to other drugs that inhibit CYP450 3A4 and P-glycoprotein when used concomitantly with colchicine.
"This study is an extension of a previous study that looked at verapamil and diltiazem for drug–drug interactions. Gout affects more than 5 million adults in the United States, and 50% of people with gout have hypertension, so this information can affect a huge number of patients. These data provide critical guidance for physicians about previously unknown drug–drug interactions and will help prevent toxicity and optimize use of this drug," said Robert Terkeltaub, MD, who presented the results of this and a related study here at American College of Rheumatology (ACR) 2009. Dr. Terkeltaub is section chief of rheumatology/allergy at the VA Medical Center in San Diego and professor at the University of California at San Diego.
Colcrys is the only form of colchicine approved by the US Food and Drug Administration for the treatment of acute gout. Generic forms of colchicine have been used off-label for several years. The results of this study on verapamil are similar to those on drug interactions between diltiazem and colchicine, Dr. Terkeltaub explained.
The first study to evaluate drug–drug interactions between verapamil and colchicine found that verapamil increased the blood concentration of colchicine by 30%, increased exposure by 99%, and increased clearance by 52%.
Thus, when treating an acute flare of gout, the dose of oral colchicine should be reduced from 3 to 2 tablets for patients receiving verapamil or diltiazem. When administered chronically, colchicine doses should be reduced by 50% in patients receiving concomitant verapamil or diltiazem.
"The dose [of colchicine] should be adjusted for tolerance, age, and renal function," Dr. Terkeltaub added.
The phase 1 open-label 2-period study was an analysis of blood samples from healthy volunteers taking a single oral dose of colchicine 0.6 mg on day 1. Blood samples were obtained on days 2, 3, 4, and 5. After a washout period, subjects received verapamil once daily for 5 days on day 15, followed by a second dose of colchicine on day 19. Blood samples were obtained again on days 20, 21, 22, and 23.
Based on this study, similar dose adjustments should be made when colchicine is given concomitantly with strong CYP3A4 inhibitors like verapamil, clarithromycin, ketoconazole, and nefazodone, Dr. Terkeltaub emphasized.
"This study represents the first evidence-based dosing guidelines in a regular prophylactic setting where colchicine is given for 6 months or more," he added.
"These new guidelines are very important because many patients with gout have a great deal of comorbidity and are taking other medications, which limits their treatment options. These guidelines will help optimize the use of this drug for patients with gout," said
Anthony Reginato, PhD, from Rhode Island Hospital in Providence, made these remarks while giving attendees a tour of important poster presentations, including these studies.
Dr. Terkeltaub was also first author of a separate study of 75 healthy volunteers showing that low-dose (1.2 mg + 0.6 mg after 1 hour) and high-dose (1.2 mg + 0.6 mg for 6 doses) colchicine achieved similar steady-state plasma concentrations and blood levels. Following a gout flare, peak colchicine blood levels of around 6 ng/mL provide adequate pain relief within the first 24 hours. Dr. Terkeltaub said that on the basis of this study, low-dose colchicine is recommended for early acute gout flare treatment, and that additional exposure to high-dose colchicine could increase unwanted adverse effects.
The study was sponsored by URL Pharma. Dr. Terkeltaub reports financial relationships with NIH, Altus, Ardea, BioCryst, Novartis Pharmaceutical Corporation, Pfizer Inc, Proctor and Gamble, Regeneron, Savient, EnzymeRx, Takeda, URL Pharma, and UCB. Dr. Reginato has disclosed no relevant financial relationships.
American College of Rheumatology (ACR) 2009. Abstract 1107. Presented October 19, 2009.