A new set of evidence-based guidelinesprovides an algorithm for reducing colchicine doses to prevent toxicity in patients who are also taking drugs such as cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil extended release (ER), or diltiazem ER. The research group was led by Robert A. Terkeltaub, MD, from the Veterans Administration San Diego Medical Center in California, and the new report appears in the August issue of Arthritis & Rheumatism.
The researchers conducted a series of studies designed to show the effects of single-dose colchicine given with known inhibitors of CYP3A4 or P-glycoprotein. The 168 study participants were healthy, nonsmoking young adults who were not taking other medications. Twenty-four patients were enrolled in each of the 7 studies.
Tests of colchicine taken with a macrolide antibiotic produced different results, depending on the antibiotic used. Clarithromycin, a potent CYP3A4 inhibitor, boosted the mean maximum concentration of colchicine by about 230%, reduced apparent oral clearance by 75%, and extended the terminal elimination half-life from 9 hours to about 30 hours. The authors note that there have been "numerous deaths attributed to the combination of colchicine with this drug."
Azithromycin (a weak CYP3A4 inhibitor) had minimal effects on colchicine concentration and terminal elimination half-life, and decreased total apparent oral clearance by 30%. The authors recommend azithromycin as a safer alternative to clarithromycin in patients taking colchicine.
Dr. Terkeltaub told Medscape Medical News, "We were pleasantly reassured by the lack of significant drug interaction with azithromycin. This is a major point in clinical practice."
The calcium channel blockers verapamil ER and diltiazem ER also had different effects on colchicine levels. Verapamil ER, a moderate inhibitor of CYP3A4 and P-glycoprotein, increased mean colchicine concentrations by about 40%, increased mean total colchicine exposure by about 103%, reduced total apparent oral clearance by 52%, and extended the terminal elimination half-life from 4.3 hours to about 17 hours.
Diltiazem ER increased mean colchicine concentrations by 44%, decreased total apparent oral clearance by about 40%, and doubled the terminal elimination half-life from about 6 hours to about 12 hours. "These data suggest that a minimal drug interaction occurs when diltiazem ER and colchicine are coadministered, and that, in general, a dose adjustment for colchicine is not required," the authors conclude.
Ketoconazole, known to be a strong CYP3A4/P-glycoprotein inhibitor, increased mean maximum colchicine by about 100%, increased total colchicine exposure by about 210%, decreased apparent oral clearance by 70%, and extended the terminal elimination half-life from about 6.3 hours to 26 hours. The recommendation for colchicine dose reduction in patients also taking ketoconazole is outlined in the table.
Rotinavir increased the mean maximum concentration of colchicine by about 185%, increased mean total colchicine exposure by about 290%, decreased total apparent oral clearance by 70%, and extended the terminal elimination half-life from about 5 hours to about 17 hours.
The authors note: "The importance of understanding colchicine drug–drug interactions...is exemplified when one considers the clinical profile of the average patient with gout. Many patients with gout are obese and have multiple comorbid conditions, including hypertension, diabetes, metabolic syndrome, and renal insufficiency, that also require medication."
In general terms, authors recommend reducing the dose of colchicine by two thirds for acute gout flares and three fourths for flare prophylaxis if the patient is also taking a strong P-glycoprotein inhibitor such as cyclosporine or tacrolimus. They recommend reducing the colchicine dose by one third for acute gout flare or one half for gout flare prophylaxis in patients taking a moderate CYP3A4 inhibitor.
Dr. Terkeltaub added, "Regarding subgroups of gout patients requiring further [colchicine] dose reduction, more study is needed. Renal impairment at the level of stage 3 and worse is the area of greatest interest for upcoming study, as is moderate liver disease."
Table. Recommended Colchicine Dose Reductions With Concomitant Drugs
| Concomitant Drug | Colchicine Dose | ||
| Acute Gout Flare | Prophylaxis of Gout Flare | Familial Mediterranean Fever | |
| Cyclosporine | 0.6 mg/day, to be repeated no earlier than 3 days | 0.3 mg/day, or 0.3 mg every other day | 0.6 mg maximum daily dose, may be given as 03 mg twice daily |
| Clarithromycin, ketoconazole, ritonavir | 0.6 mg/day, or 0.3 mg twice a day, to be repeated no earlier than 3 days | 0.3 mg/day, or 0.3 mg every other day | 0.6 mg maximum daily dose, may be given as 0.3 mg twice daily |
| Diltiazem, verapamil | 1.2 mg, dose to be repeated no earlier than 3 days | 0.3 mg twice a day or 0.6 mg/day, or 0.3 mg/day | 1.2 mg maximum daily dose, may be given as 0.6 mg twice daily |
| Azithromycin | No dose reduction required | No dose reduction required. | No dose reduction required |
The study was supported by URL Pharma. Dr. Terkeltaub has received consulting fees from Altus, Ardea Biosciences, BioCryst, Novartis, Pfizer, Procter & Gamble, Regeneron, Savient, EnzymeRx, Takeda, URL Pharma, and UCB, and grants from the Research Service of the Department of Veterans Affairs
Arthritis Rheum. 2011;63:2226-2237. Abstract
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