What is the interaction between Diflucan (fluconazole) and Warfarin?

From the Guidelines

Diflucan (fluconazole) can significantly increase the effects of warfarin, potentially leading to dangerous bleeding complications, and therefore, its use with warfarin requires careful monitoring and potential dose adjustments of warfarin. Patients taking warfarin who are prescribed Diflucan should have their INR (International Normalized Ratio) monitored more frequently, especially during the first week of combined therapy, as the interaction typically begins within 3-5 days of starting Diflucan and may persist for several days after discontinuation 1. The mechanism behind this interaction is fluconazole's inhibition of the CYP2C9 enzyme in the liver that metabolizes warfarin, resulting in higher warfarin blood levels and enhanced anticoagulant effects 1. Key considerations include:

• Monitoring for signs of excessive anticoagulation such as unusual bruising, nosebleeds, bleeding gums, or blood in urine or stool.
• Potential dose adjustments of warfarin, with reductions of 20-50% sometimes required depending on the Diflucan dose and individual patient factors.
• Considering alternative antifungal medications with less interaction potential if appropriate for the patient's condition, such as nystatin oral solution which does not appreciably affect the INR 1.
• If the combination cannot be avoided, careful monitoring and proactive warfarin dose adjustment are essential to maintain safe anticoagulation and prevent serious bleeding events.

From the FDA Drug Label

Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral fluconazole 200 mg administered daily for 14 days as compared to the administration of warfarin alone There was a mean ± SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2 to 13%). Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary.

The concomitant use of Diflucan (fluconazole) and warfarin may increase the risk of bleeding due to an increase in prothrombin time. Careful monitoring of prothrombin time is recommended, and dose adjustment of warfarin may be necessary 2, 2.

From the Research

Interaction between Diflucan and Warfarin

• The interaction between Diflucan (fluconazole) and warfarin has been studied in several research papers 3, 4, 5, 6, 7.
• These studies suggest that the combination of fluconazole and warfarin can enhance the anticoagulant effect of warfarin, increasing the risk of bleeding 3, 4, 5.
• The mechanism of this interaction is thought to be due to the inhibition of warfarin metabolism by fluconazole, which can be more pronounced in patients with decreased renal clearance of fluconazole 4.
• A systematic review and meta-analysis found that the combination of warfarin and fluconazole was associated with an increased risk of clinically relevant bleeding 6.
• Another study found that the co-prescription of warfarin and fluconazole was associated with an increased risk of serious bleeding events, particularly in patients who did not have their international normalized ratio (INR) monitored within 3-14 days of co-prescription 7.

Monitoring and Management

• It is recommended to closely monitor INR values in patients taking warfarin and fluconazole, particularly within 1 week of starting or stopping fluconazole therapy 3, 7.
• The dose of warfarin may need to be adjusted to minimize the risk of bleeding in patients taking fluconazole 3, 5.
• Patients with decreased renal clearance of fluconazole may be at higher risk of bleeding and should be monitored more closely 4.

Clinical Implications

• The interaction between fluconazole and warfarin has important clinical implications, particularly in patients at high risk of bleeding 6, 7.
• Healthcare providers should be aware of this potential interaction and take steps to minimize the risk of bleeding in patients taking both medications 3, 4, 5, 6, 7.