What medications interact with colchicine (CYP3A4 inhibitors)?

Medications That Interact with Colchicine (CYP3A4/P-gp Inhibitors)

Strong CYP3A4 and/or P-glycoprotein inhibitors should not be co-administered with colchicine due to risk of serious and potentially fatal toxicity. 1

Major Interacting Medications

Strong CYP3A4/P-gp Inhibitors (Contraindicated):

• Macrolide antibiotics:

  • Clarithromycin
  • Telithromycin
  • Erythromycin (moderate inhibitor)

• Antifungals:

  • Ketoconazole
  • Itraconazole

• Protease inhibitors:

  • Ritonavir
  • Atazanavir
  • Indinavir
  • Nelfinavir
  • Saquinavir
  • Tipranavir/ritonavir
  • Darunavir/ritonavir
  • Lopinavir/ritonavir

• Other medications:

  • Cyclosporine
  • Nefazodone
  • Ranolazine

Moderate CYP3A4 Inhibitors (Require Dose Adjustment):

• Verapamil
• Diltiazem
• Aprepitant
• Fluconazole
• Fosamprenavir
• Amprenavir
• Grapefruit juice

Mechanism of Interaction

Colchicine is a substrate for both CYP3A4 enzymes and P-glycoprotein (P-gp) transporters 2. When co-administered with inhibitors of these pathways, colchicine plasma concentrations can increase significantly, leading to:

1. Increased risk of colchicine toxicity
2. Potential for fatal outcomes, especially in patients with renal impairment 3

Dose Adjustments for Necessary Co-administration

If co-administration with CYP3A4/P-gp inhibitors cannot be avoided, the FDA-approved colchicine label recommends the following dose adjustments 2:

For Strong CYP3A4/P-gp Inhibitors:

• Gout flare prophylaxis: Reduce from 0.6mg twice daily to 0.3mg once daily
• Gout flare treatment: Reduce from 1.2mg followed by 0.6mg to 0.6mg followed by 0.3mg
• FMF treatment: Maximum daily dose of 0.6mg (may be given as 0.3mg twice daily)

For Moderate CYP3A4 Inhibitors:

• Gout flare prophylaxis: Reduce from 0.6mg twice daily to 0.3mg twice daily or 0.6mg once daily
• Gout flare treatment: Reduce to 1.2mg once (no second dose)
• FMF treatment: Maximum daily dose of 1.2mg (may be given as 0.6mg twice daily)

Special Risk Factors

Renal Impairment

Patients with renal impairment are at significantly higher risk of colchicine toxicity when taking interacting medications 3. The 2016 EULAR guidelines specifically note that colchicine should be avoided in patients with severe renal impairment (GFR <30 mL/min) 1.

Hepatic Impairment

Co-administration of colchicine with CYP3A4/P-gp inhibitors is contraindicated in patients with hepatic impairment 2.

Statin Co-administration

Concomitant use of colchicine with statins (particularly atorvastatin, simvastatin, lovastatin, fluvastatin, and pravastatin) increases the risk of myopathy and rhabdomyolysis 1, 2. This interaction appears to be due to:

• Competitive inhibition of CYP3A4
• Competition for P-gp-mediated efflux
• Synergistic muscle-related toxicity

Signs of Colchicine Toxicity

When monitoring patients on colchicine with potential interacting medications, watch for:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea)
• Myelosuppression (leukopenia, thrombocytopenia, pancytopenia)
• Neuromuscular toxicity (myopathy, rhabdomyolysis)
• Multi-organ failure in severe cases

Clinical Pearls

1. Even short-term co-administration of colchicine with clarithromycin has been associated with fatal outcomes, particularly in patients with renal impairment 3.

2. Azithromycin appears to be the safest macrolide to use with colchicine, as it does not require dose adjustment 4.

3. The European League Against Rheumatism (EULAR) specifically warns against co-administration of colchicine with cyclosporin, clarithromycin, verapamil, and ketoconazole 1.

4. Approximately 1% of patients prescribed colchicine receive inappropriate co-prescriptions with interacting medications 5.

5. The risk of fatal colchicine toxicity is particularly high when combined with clarithromycin in patients with renal insufficiency 3.