See the App for this algorithm here!
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.
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
- See the app for the algorithm here
- Click to download a PDF of the flow diagram
- Click to view the colchicine value sets
- Click to view the CYP3A4/P-gP inhibitor value sets
- Serum potassium – LOINC 2823-3
- Kidney function – LOINC 48642-3 or 48643-1
- Click to add comments or ask questions on the Discussion forum
Drug interaction algorithm implementation survey
- Click to provide your feedback about algorithm implementation
Webinar on 1/20/21
- Leung YY, Yao Hui LL, Kraus VB. Colchicine–Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45(3):341-350.
- Chen K, Schenone AL, Borges N, Militello M, Menon V. Teaching an Old Dog New Tricks: Colchicine in Cardiovascular Medicine. Am J Cardiovasc Drugs. 2017;17(5):347-360.
- Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505.
- Solak Y, Atalay H, Biyik Z, et al. Colchicine toxicity in end-stage renal disease patients: a case-control study. Am J Ther. 2014;21(6):e189-195.
- Villa Zapata L, Hansten PD, Horn JR, et al. Evidence of Clinically Meaningful Drug-Drug Interaction With Concomitant Use of Colchicine and Clarithromycin. Drug Saf. 2020;43(7):661-668.
- Parra-Medina R, Sarmiento-Monroy JC, Rojas-Villarraga A, Garavito E, Montealegre-Gómez G, Gómez-López A. Colchicine as a possible therapeutic option in COVID-19 infection. Clin Rheumatol. 2020;39(8):2485-2486.
- Nasiripour S, Zamani F, Farasatinasab M. Can Colchicine as an Old Anti-Inflammatory Agent Be Effective in COVID-19? J Clin Pharmacol. 2020;60(7):828-829.
- Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011;63(8):2226-2237.
- Finkelstein Y, Aks SE, Hutson JR, et al. Colchicine poisoning: the dark side of an ancient drug. Clin Toxicol (Phila). 2010;48(5):407-414.
- Herrán-Monge R, Muriel-Bombín A, García-García M, Dueñas-Laita A, Fernández-Rodríguez ML, Prieto de Lamo AM. [Accidental fatal colchicine overdose]. Med Intensiva. 2013;37(6):434-436.
- Aghabiklooei A, Zamani N, Hassanian-Moghaddam H, Nasouhi S, Mashayekhian M. Acute colchicine overdose: report of three cases. Reumatismo. 2014;65(6):307-311.
- Erden A, Karagoz H, Gümüscü HH, et al. Colchicine intoxication: a report of two suicide cases. Ther Clin Risk Manag. 2013;9:505-509.
- Maxwell MJ, Muthu P, Pritty PE. Accidental colchicine overdose. A case report and literature review. Emerg Med J. 2002;19(3):265-267.
- Todd BA, Billups SJ, Delate T, et al. Assessment of the association between colchicine therapy and serious adverse events. Pharmacotherapy. 2012;32(11):974-980.
- Essame J, Grossberg S, Mahomed A. Colchicine overdose: A South African experience, a case report. Afr J Emerg Med. 2020;10(3):167-169.
- Imai S, Momo K, Kashiwagi H, Miyai T, Sugawara M, Takekuma Y. Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database. Biol Pharm Bull. 2020;43(10):1519-1525.
- Eleftheriou G, Bacis G, Fiocchi R, Sebastiano R. Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. Clin Toxicol (Phila). 2008;46(9):827-830.
- Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine intoxication–possible role of erythromycin administration. J Rheumatol. 1992;19(3):494-496.
- Davis MW, Wason S, Digiacinto JL. Colchicine-antimicrobial drug interactions: what pharmacists need to know in treating gout. Consult Pharm. 2013;28(3):176-183.
- Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis. 2005;41(3):291-300.
- Dupont P, Hunt I, Goldberg L, Warrens A. Colchicine myoneuropathy in a renal transplant patient. Transpl Int. 2002;15(7):374-376.
- Wallace SL, Singer JZ, Duncan GJ, Wigley FM, Kuncl RW. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol. 1991;18(2):264-269.
- Le Quintrec JS, Le Quintrec JL. Drug-induced myopathies. Baillieres Clin Rheumatol. 1991;5(1):21-38.
- van der Velden W, Huussen J, Ter Laak H, de Sévaux R. Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin. Neth J Med. 2008;66(5):204-206.
- Pirzada NA, Medell M, Ali, II. Colchicine induced neuromyopathy in a patient with normal renal function. J Clin Rheumatol. 2001;7(6):374-376.
- Medani S, Wall C. Colchicine toxicity in renal patients – Are we paying attention? Clin Nephrol. 2016;86(2):100-105.
- Garrouste C, Philipponnet C, Kaysi S, Enache I, Tiple A, Heng AE. Severe colchicine intoxication in a renal transplant recipient on cyclosporine. Transplant Proc. 2012;44(9):2851-2852.