Rationale

Colchicine has a long history of use for treatment and prevention of gout, and it is also used for familial Mediterranean fever (FMF), Behcet disease, secondary amyloidosis, primary biliary cirrhosis, well as cardiac and dermatologic disorders.1-5 It is currently being tested in clinical trials involving patients with COVID-19 infections.1,6,7 Colchicine has a narrow therapeutic index.4,5 Therapeutic doses are 1.2-2.4 mg/day for FMF, 1.2 mg/day for acute gout and 0.5-0.6 mg/day three to four times a weeks for gout prophylaxis.8 Elevated levels of colchicine can be fatal. For example, colchicine dose between 0.5 and 0.8 mg/kg has been associated with 10% mortality and colchicine dose greater than 0.8 mg/kg has been associated with 100% mortality.9-12 Even at therapeutic dose, up to 80% of patients reported experiencing gastrointestinal adverse events, and a few reported experiencing serious adverse events.9,10,13-15 Symptoms of colchicine toxicity range from mild (e.g., abdominal pain, diarrhea, nausea, vomiting) to moderate (e.g., muscle pain, muscle weakness) to fatal (e.g., cardiac failure, renal failure).4,16,17 Although there are many reports of serious drug interactions with colchicine, published recommendations on management of these interactions tend to be suboptimal. Thus, we proposed a management algorithm to provide warnings to prescribers and their patients who are at risk of harm.

Algorithm

Logic flow diagram for colchicine drug interactions

Explanation

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp).8,16 In patients with normal physiological functioning, up to 20% of colchicine dose is eliminated unchanged in urine, and approximately 50% of the absorbed colchicine dose is metabolized through CYP3A4.5 Inhibition of CYP3A4 and P-gp may increase concentration of colchicine, which lead to toxicity.8,9,14 For example, use in combination with cyclosporine, a strong CYP3A4/P-gp inhibitor, significantly increased colchicine concentration by 270 %.8 Concomitant use of colchicine and erythromycin, a moderate CYP3A4 inhibitor, has also been linked to serious adverse events.18 Example of strong CYP3A4 inhibitors includes clarithromycin, ketoconazole, itraconazole, and ritonavir; moderate CYP3A4 inhibitors are erythromycin, fluconazole, verapamil, and diltiazem; and strong P-gp inhibitors include cyclosporine.8,19

Since both CYP3A4 and P-gp inhibitors are commonly prescribed for a wide variety of disease states, concurrent use of colchicine and  CYP3A4 and P-gp inhibitors is common in clinical practice settings. Fatal adverse events have been reported with concomitant use of colchicine with strong CYP3A4 or P-gp inhibitors (e.g., clarithromycin, itraconazole, cyclosporine and some protease inhibitor).14,16,20 For example, a retrospective study reported that nine (10.2%) of the 88 patients who received  clarithromycin and colchicine concomitantly died.20 In addition, FDA Adverse Event Reporting System (FAERS) received reports of 58 serious cases with 30 fatal outcomes resulting from concurrent use of colchicine and clarithromycin.5

Furthermore, concurrent use of colchicine with P-gp or strong CYP3A4 inhibitors is contraindicated in patients with renal impairment.9 Colchicine is partially excreted through kidneys4,8,21 and may requires dose adjustment in patients with renal impairment.4 Renal impairment has been reported in literature to be a risk factor for colchicine toxicity that can be fatal in some cases.4,5,21-27 A retrospective study has found that in patients who have taken clarithromycin and colchicine concurrently, the presence of renal impairment at baseline (creatinine level of >140 µmol/L) increased the risk of death by 9-fold (RR=9.1; 95% CI, 1.75-47.06.06; P<0.001).20 Moreover, renal disease was reported in 8 out of the 20 literature case reports of colchicine-clarithromycin interaction.5

Overall, co-administration of colchicine and strong CYP3A4 or P-gp inhibitors significantly increase colchicine toxicity and should be avoided. To minimize the adverse events, a viable alternative to CYP3A4 or P-gp inhibitors should be used with colchicine. Pausing colchicine treatment during acute treatment CYP3A4 or P-gp inhibitors may also be an appropriate option. However, if co-administration of colchicine and CYP3A4 or P-gp inhibitors are necessary, then a dosage adjustment plan should be used. For example, the original intended dose of colchicine for gout prophylaxis is 0.6 mg twice daily), colchicine dose of colchicine should be reduced to 0.3 mg daily when used with strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole) and to 0.3 mg twice daily when used with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole).19 In addition, patient should be monitor for evidence of colchicine toxicity.

Artifacts for implementers

Drug interaction algorithm implementation survey

Supporting documentation

Webinar on 1/20/21

References

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