What is the effect of azole (antifungal) drugs on the action of warfarin (Coumadin)?

From the Guidelines

Azole antifungal drugs significantly increase the anticoagulant effect of warfarin, potentially leading to dangerous bleeding complications. Medications such as fluconazole, itraconazole, voriconazole, and ketoconazole inhibit the cytochrome P450 enzyme system in the liver (particularly CYP2C9), which is responsible for metabolizing warfarin, as reported in a 2022 study published in Circulation: Arrhythmia and Electrophysiology 1. This inhibition causes warfarin to remain active in the bloodstream longer, intensifying its anticoagulant effects and raising the INR (International Normalized Ratio). Key points to consider include:

• The interaction is particularly strong with systemic azoles rather than topical formulations, with fluconazole and voriconazole being moderate inhibitors of CYP2C9 and CYP3A4, respectively 1.
• Patients taking both medications require close monitoring of their INR values, with warfarin dose reductions typically needed to maintain therapeutic anticoagulation while preventing bleeding complications.
• The interaction can begin within 24-48 hours of starting the azole and may persist for several days after discontinuation due to the medications' half-lives.
• Healthcare providers should consider alternative antifungal treatments when possible for patients on warfarin, such as nystatin oral solution, which does not appreciably affect the INR 1.
• More frequent INR monitoring with appropriate warfarin dose adjustments is necessary to maintain therapeutic anticoagulation while preventing bleeding complications, especially when initiating or discontinuing azole therapy.

From the FDA Drug Label

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 effect of azole drugs, such as fluconazole, on the action of warfarin is an increased risk of bleeding due to elevated prothrombin time. This is because azole drugs can inhibit the metabolism of warfarin, leading to increased warfarin levels. As a result, careful monitoring of prothrombin time and dose adjustment of warfarin may be necessary when coadministering azole drugs and warfarin 2. Key considerations include:

• Increased risk of bleeding events
• Elevated prothrombin time
• Potential need for warfarin dose adjustment
• Importance of careful monitoring of prothrombin time

From the Research

Effect of Azole Drugs on Warfarin Action

• The combination of azole antifungal agents and warfarin can enhance the anticoagulant effect of warfarin, increasing the risk of bleeding 3, 4.
• Studies have shown that fluconazole (FLCZ) and voriconazole (VRCZ) can significantly increase the international normalized ratio (INR) when coadministered with warfarin 3, 4.
• The warfarin sensitivity index (WSI) also increases when azole antifungal agents are coadministered with warfarin, indicating an increased sensitivity to warfarin 3, 4.
• The interaction between warfarin and azole antifungal agents can occur within 1 week of coadministration, highlighting the need for close monitoring of INR during this period 3, 4.
• Other studies have also reported an increased risk of bleeding with the concomitant use of warfarin and other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs) 5, 6.
• The mechanism of interaction between azole antifungal agents and warfarin is thought to involve the inhibition of cytochrome P450 enzymes, which can decrease the catabolism of warfarin and increase its anticoagulant effect 7.