Precautions for Taking Fluconazole (Diflucan) with Warfarin (Coumadin)
Fluconazole significantly increases warfarin's anticoagulant effect and requires close INR monitoring, dose adjustment, and possible separation of administration times to prevent dangerous bleeding complications. 1, 2
Mechanism of Interaction
- Fluconazole inhibits CYP2C9 and other cytochrome P450 enzymes that metabolize warfarin 1
- The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation due to its long half-life 1
- This interaction leads to increased prothrombin time and INR values, significantly increasing bleeding risk 1, 2
Clinical Impact
- INR can increase by 0.83-1.27 points on average after initiating fluconazole 3
- Risk of INR exceeding 5.0 increases from 4.3% to 15.3% with systemic fluconazole 3
- Serious bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, melena) have been reported with this combination 1
Monitoring Recommendations
Before starting fluconazole:
- Check baseline INR
- Consider alternative antifungal agents if appropriate for the infection
During concurrent therapy:
- Monitor INR more frequently (2-3 times weekly initially)
- Continue monitoring for 4-5 days after fluconazole discontinuation due to prolonged enzyme inhibition 1
Warfarin dose adjustment:
- Reduce warfarin dose preemptively by 20-40% when starting fluconazole
- Make further adjustments based on INR results
- Be prepared to increase warfarin dose when fluconazole is discontinued
Administration Timing
- Consider separating administration times of warfarin and fluconazole 4
- Evidence suggests administering warfarin in the evening and fluconazole in the morning may help minimize interaction severity 4
Alternative Antifungal Options
For patients requiring antifungal therapy while on warfarin:
- For oral candidiasis: Nystatin oral solution appears to be the safest alternative with no significant effect on INR 3
- For systemic infections: Caspofungin may be a safer alternative as it does not significantly affect INR 5
Special Precautions
- Patients with renal insufficiency may experience more pronounced interactions due to decreased fluconazole clearance 6
- Elderly patients are at higher risk for bleeding complications 7
- Additional risk factors (liver disease, recent surgery, concomitant antiplatelet therapy) further increase bleeding risk
Case Example
A case report described a patient with stable INR (2.0-2.7) on warfarin who experienced an INR increase to 5.2 just four days after starting fluconazole 50mg daily, despite warfarin dose reduction 6. This highlights the rapid and significant impact of this interaction.
Remember that this interaction is well-documented and potentially dangerous. Careful monitoring and proactive dose adjustment are essential to prevent serious bleeding complications when these medications must be used together.