What is the effect of Diflucan (fluconazole) on International Normalized Ratio (INR) in patients taking warfarin?

Fluconazole Significantly Increases INR in Patients Taking Warfarin

Fluconazole significantly increases the anticoagulant effect of warfarin, with INR elevations peaking approximately 7 days after co-administration, requiring close monitoring and potential warfarin dose reduction of 25-33%. 1, 2, 3

Mechanism of Interaction

Fluconazole (Diflucan) interacts with warfarin through several mechanisms:

• Inhibits CYP2C9 enzyme, which metabolizes the more potent S-enantiomer of warfarin 4
• Also inhibits CYP2C19 and CYP3A4, affecting metabolism of the R-enantiomer 1
• Results in decreased warfarin clearance and increased plasma concentrations
• Leads to significant increases in prothrombin time response 1

Magnitude of Effect on INR

The interaction between fluconazole and warfarin is substantial:

• INR increases by more than 20% in patients receiving both medications 2
• In studies with low-dose fluconazole (100mg daily), mean PT increased from 15.8 seconds to 21.9 seconds after 8 days 3
• Higher doses of fluconazole produce more pronounced effects
• Mathematical relationship has been established: with fluconazole, INR = 1.25(baseline INR) + 2.15 2

Time Course of Interaction

The effect of fluconazole on warfarin's anticoagulant activity follows a predictable pattern:

• INR begins rising within 2-3 days of co-administration 3
• Peak effect typically occurs around day 7 of combined therapy 2, 5
• The enzyme inhibiting effect persists 4-5 days after discontinuation of fluconazole due to its long half-life 1

Clinical Management Recommendations

When fluconazole must be administered to patients on warfarin:

1. Monitor INR closely within the first week of co-administration 4, 2, 3

   • Initial check at day 2-3
   • Follow-up check at day 5-7 when interaction peaks

2. Consider preemptive warfarin dose reduction 4

   • Reduce warfarin dose by 25-33% when initiating fluconazole
   • Similar to recommendations for other strong CYP2C9 inhibitors

3. Adjust timing of administration if necessary

   • Separating administration times may reduce interaction magnitude 5
   • Consider administering warfarin in evening and fluconazole in morning

4. Be vigilant for signs of bleeding

   • Bruising, epistaxis, gastrointestinal bleeding, hematuria, melena 1
   • Risk increases with higher INR values

Special Considerations

• Renal impairment: Patients with decreased renal function may experience more pronounced interactions due to reduced fluconazole clearance 6

• Genetic factors: CYP2C9 polymorphisms may intensify this interaction 2

• Other medications: Additional drug interactions may further compound anticoagulant effects 4

• Duration of therapy: Even short courses of fluconazole can significantly affect INR 3

Common Pitfalls to Avoid

1. Failure to monitor INR promptly - The interaction develops rapidly within days

2. Attributing INR changes solely to warfarin non-compliance - Consider medication interactions

3. Overlooking the persistent effect - Fluconazole's inhibitory effect continues 4-5 days after discontinuation 1

4. Neglecting dose adjustments - Proactive warfarin dose reduction may prevent excessive anticoagulation

5. Ignoring patient-specific factors - Renal function, age, and concomitant medications can amplify the interaction

This interaction is clinically significant and requires proactive management to prevent potentially serious bleeding complications while maintaining therapeutic anticoagulation.