Risk Profile for

The patient is currently taking colchicine 0.6 mg oral capsule

The medication [itraconazole 200 mg oral tablet] will interact with colchicine by inhibition of CYP3A4/PGP.

GFR Function (ml/Min)
Kidney failure Severely decreased Moderately to severely decreased Mildly to moderately decreased Normal to high
Summary

Warning

Consider a dose reduction or alternative:
  • Colchicine has a narrow therapeutic index.
  • Patients who take colchicine and inhibitors of its primary metabolic clearance pathway have a risk of colchicine toxicity.
Alternative Options

The antifungal terbinafine does not appear to affect CYP3A4, and is unlikely to interact with colchicine. However, there are some clinical situations where terbinafine would not be a suitable substitute for an azole antifungal. Voriconazole is less likely to interact with colchicine than itraconazole, ketoconazole, or posaconazole. Fluconazole has been studied in healthy subjects, and found to produce a 40% increase in colchicine AUC (See the Mitigare Product Label Section 7 & Section 12).

Clinical Explanation

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Fatal adverse events have been reported with concomitant use of colchicine with strong CYP3A4 or P-gp inhibitors. The medication [itraconazole 200 mg oral tablet] is one of these strong inhibitors (see the evidence summary below). The risk of a serious adverse event might be reduced by switching to a alternative drug that is not a strong inhibitor or stop colchicine (see the "Alternative Options" box). If switching is not an option, monitoring for colchicine toxicity might help avoid a potentially serious adverse event. 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). A strong monitoring strategy would include advising the patient to monitor for these symptoms.

What is a drug-drug interaction?
  • When two or more drugs react with each other and cause unwanted side effects
  • Co-administration of colchicine and strong CYP3A4 or P-gp inhibitors significantly increase colchicine toxicity and should be avoided

"Colchicine's toxicity impairs protein assembly, decreases endocytosis and exocytosis, alteres cell morphology, decreases cellular motility, arrests mitosis, and interrupts cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure." https://pubmed.ncbi.nlm.nih.gov/20586571/

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).

Literature

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp).3,6 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 CYP3A4.2 Inhibition of CYP3A4 and P-gp may increase concentration of colchicine, which lead to toxicity.3,4,5 For example, use in combination with cyclosporine, a strong CYP3A4/P-gp inhibitor, significantly increased colchicine concentration by 270 %.3 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.3,7

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 be 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).5,6,8 For example, a retrospective study reported that nine (10.2%) of the 88 patients who received clarithromycin and colchicine concomitantly died.8 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.2

Furthermore, concurrent use of colchicine with P-gp or strong CYP3A4 inhibitors is contraindicated in patients with renal impairment.4 Colchicine is partially excreted through kidneys1,3,9 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.4,5,9-15 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).8 Moreover, renal disease was reported in 8 out of the 20 literature case reports of colchicine-clarithromycin interaction.5

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Dupont P, Hunt I, Goldberg L, Warrens A. Colchicine myoneuropathy in a renal transplant patient. Transpl Int. 2002;15(7):374-376.
  10. 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.
  11. Le Quintrec JS, Le Quintrec JL. Drug-induced myopathies. Baillieres Clin Rheumatol. 1991;5(1):21-38.
  12. 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.
  13. Pirzada NA, Medell M, Ali, II. Colchicine induced neuromyopathy in a patient with normal renal function. J Clin Rheumatol. 2001;7(6):374-376.
  14. Medani S, Wall C. Colchicine toxicity in renal patients – Are we paying attention? Clin Nephrol. 2016;86(2):100-105.
  15. 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.