Do mycophenolate or tacrolimus (immunosuppressants) cause International Normalized Ratio (INR) elevation?

Effect of Mycophenolate and Tacrolimus on INR Elevation

Neither mycophenolate nor tacrolimus causes clinically significant elevation of INR values. According to the available evidence, these immunosuppressants do not appear on lists of medications known to interact with warfarin or affect coagulation parameters.

Evidence Review

Tacrolimus and INR

• The American Heart Association's scientific statement on drug-drug interactions with statins and cardiovascular agents does not list tacrolimus among medications that affect warfarin's INR 1.
• The American College of Chest Physicians guidelines on immunosuppressive drugs do not mention any interaction between tacrolimus and warfarin or any effect on coagulation parameters 1.
• The EASL recommendations on hepatitis C treatment indicate no clinically significant interaction between tacrolimus and warfarin (shown as a "green" interaction in their drug interaction tables) 1.

Mycophenolate and INR

• Similarly, mycophenolate is not listed among medications that interact with warfarin in the comprehensive drug interaction guidelines from the American Heart Association 1.
• The American College of Chest Physicians guidelines on immunosuppressive drugs do not report any effect of mycophenolate on coagulation parameters 1.
• The EASL recommendations also show no clinically significant interaction between mycophenolate and warfarin (also marked as a "green" interaction) 1.

Known Medications That DO Affect INR

For context, medications that are known to significantly affect INR include:

1. Medications that increase INR:

   • Miconazole (mean increase +3.35)
   • Amiodarone (mean increase +1.28)
   • Fluconazole (mean increase +0.79)
   • Metronidazole (mean increase +0.75)
   • Fluoropyrimidines (fluorouracil and capecitabine)
   • Some antibiotics (particularly macrolides)
   • SSRIs (especially fluvoxamine and fluoxetine) 1

2. Medications that decrease INR:

   • Carbamazepine (mean decrease -0.63)
   • Rifampin
   • Phenytoin (after initial increase)
   • Enzalutamide 1

Clinical Implications

When managing patients on warfarin who require immunosuppression with mycophenolate or tacrolimus:

• No preemptive warfarin dose adjustment is necessary when starting either of these immunosuppressants.
• Standard INR monitoring can be maintained without increased frequency.
• Focus monitoring on other potential side effects of these medications:
  • For tacrolimus: nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, and electrolyte abnormalities 1, 2
  • For mycophenolate: GI effects (diarrhea, nausea), hematologic effects (leukopenia), and increased infection risk 1

Common Pitfalls to Avoid

1. Don't confuse with other immunosuppressants: Some clinicians might incorrectly assume all immunosuppressants affect coagulation similarly.

2. Don't overlook other medications: While mycophenolate and tacrolimus don't affect INR, patients on these medications often take multiple drugs that might interact with warfarin.

3. Don't neglect standard monitoring: Even though these specific drugs don't affect INR, regular INR monitoring remains essential for patients on warfarin.

4. Don't ignore drug formulations: Different formulations of mycophenolate (mycophenolate mofetil vs. mycophenolic acid) have similar safety profiles regarding coagulation.

In conclusion, when prescribing mycophenolate or tacrolimus to patients on warfarin, clinicians can be reassured that these immunosuppressants do not require special INR monitoring or warfarin dose adjustments.