Colchicine-Tacrolimus-Myfortic Drug Interaction
Colchicine requires significant dose reduction (50-75% for prophylaxis, 33-66% for acute gout treatment) when combined with tacrolimus due to life-threatening toxicity risk, while myfortic (mycophenolic acid) does not directly interact with colchicine but requires monitoring when used with tacrolimus. 1, 2
Critical Interaction: Colchicine and Tacrolimus
Mechanism of Interaction
- Tacrolimus is a moderate CYP3A4 inhibitor and affects P-glycoprotein (P-gp), both of which are the primary pathways for colchicine metabolism and elimination 1, 3
- When these pathways are blocked, colchicine blood levels can increase by 200-300%, leading to potentially fatal toxicity even in patients with normal renal function 2, 4
- Colchicine undergoes hepatic demethylation by CYP3A4 and is a substrate for P-gp, making it highly vulnerable to accumulation when combined with tacrolimus 5
Clinical Evidence of Toxicity
- A documented case report describes colchicine-induced myopathy in a tacrolimus-treated renal transplant recipient who developed 4-fold elevated liver enzymes and elevated creatine phosphokinase within days of starting standard-dose colchicine (0.6 mg twice daily) 6
- Pharmacokinetic studies demonstrate that colchicine AUC is 3-fold higher in kidney transplant recipients using tacrolimus compared to controls, with significantly elevated maximum concentrations 3
- Life-threatening complications include pancytopenia, multiorgan failure, rhabdomyolysis, and cardiac arrhythmias 4
Mandatory Dose Adjustments
For acute gout treatment:
- Reduce loading doses to no more than 0.6-1.2 mg total (33-66% reduction from standard dosing) 2, 5
- Avoid repeated dosing within 24 hours 2
For prophylaxis or chronic use:
- Reduce maintenance doses to 0.3-0.6 mg daily (50-75% reduction) 2, 5
- Never exceed 3 mg daily maximum in any circumstance 1
Monitoring Requirements
- Monitor for early gastrointestinal symptoms (diarrhea, abdominal cramping, vomiting) as the first warning signs of toxicity 5, 4
- Check creatine phosphokinase (CPK) and liver enzymes for muscle-related toxicity 6
- Monitor complete blood counts for myelosuppression 4
- Assess renal function regularly, as dysfunction dramatically increases toxicity risk 3
Tacrolimus and Myfortic (Mycophenolic Acid) Interaction
Pharmacokinetic Effect
- When tacrolimus is prescribed with mycophenolic acid (MPA), exposure to MPA is higher compared to cyclosporine co-administration, because cyclosporine interrupts enterohepatic recirculation of MPA while tacrolimus does not 1
- This is a unidirectional interaction where tacrolimus increases MPA levels, but MPA does not significantly affect tacrolimus levels 5
Management Strategy
- Monitor for MPA-associated adverse reactions including bone marrow suppression, gastritis, nausea, diarrhea, and abdominal pain 5, 1
- Reduce the dose of mycophenolic acid products as needed based on clinical tolerance 1
- This interaction is clinically relevant but manageable with dose adjustment, unlike the potentially fatal colchicine-tacrolimus interaction 5
No Direct Colchicine-Myfortic Interaction
- Mycophenolic acid does not inhibit CYP3A4 or P-glycoprotein, so it does not directly interact with colchicine metabolism 5, 7
- However, both drugs can cause bone marrow suppression independently, requiring monitoring of complete blood counts when used together 7
- Aluminum/magnesium hydroxide antacids can reduce mycophenolic acid bioavailability, but this does not involve colchicine 7
Common Pitfalls to Avoid
- Do not use standard colchicine dosing (0.6 mg twice daily) in patients on tacrolimus—this has resulted in documented toxicity 6
- Do not attribute muscle symptoms solely to tacrolimus or statins if the patient is also on colchicine; colchicine independently causes myotoxicity and may be the culprit 5
- Do not assume azithromycin requires colchicine dose adjustment—unlike clarithromycin, azithromycin does not significantly interact with colchicine 2
- Early and frequent monitoring of tacrolimus levels should occur within 1-3 days when starting or stopping interacting medications 1