Summary

Fluconazole significantly increases warfarin's anticoagulant effect by inhibiting its metabolism, leading to elevated INR levels and increased bleeding risk. This major drug interaction requires careful monitoring and potential warfarin dose reduction when both medications are used together.

Introduction

Warfarin is an oral anticoagulant (blood thinner) belonging to the vitamin K antagonist class, commonly prescribed to prevent blood clots in conditions such as atrial fibrillation, deep vein thrombosis, and pulmonary embolism. Fluconazole is a triazole antifungal medication used to treat various fungal infections including candidiasis, cryptococcal meningitis, and other systemic fungal infections. Both medications are frequently prescribed, making their potential interaction clinically significant.

Mechanism of Interaction

Fluconazole inhibits cytochrome P450 enzymes, particularly CYP2C9 and CYP3A4, which are responsible for metabolizing warfarin. The S-enantiomer of warfarin, which is more potent, is primarily metabolized by CYP2C9. When fluconazole blocks this enzyme, warfarin clearance decreases significantly, leading to higher plasma concentrations and prolonged anticoagulant effects. This pharmacokinetic interaction can increase warfarin's effect by 50-100% or more, depending on the fluconazole dose and duration of treatment.

Risks and Symptoms

The primary risk of this interaction is significantly increased bleeding, ranging from minor bruising to life-threatening hemorrhage. Patients may experience elevated INR (International Normalized Ratio) values, often exceeding therapeutic ranges within 2-3 days of starting fluconazole. Clinical manifestations can include excessive bruising, nosebleeds, gastrointestinal bleeding, intracranial hemorrhage, and prolonged bleeding from minor cuts. The interaction is dose-dependent, with higher fluconazole doses (≥200mg daily) posing greater risk. Elderly patients and those with multiple comorbidities face particularly high bleeding risks.

Management and Precautions

Close monitoring is essential when these drugs are used concurrently. INR should be checked within 2-3 days of starting fluconazole and then every 2-3 days until stable. Warfarin dose reduction of 25-50% may be necessary, depending on baseline INR and fluconazole dose. Consider using alternative antifungal agents with less CYP450 inhibition when possible, such as terbinafine for appropriate indications. If fluconazole is discontinued, warfarin doses may need to be increased back to previous levels with continued INR monitoring. Patients should be educated about bleeding signs and symptoms and advised to seek immediate medical attention for any concerning bleeding episodes.

Warfarin interactions with food and lifestyle

Warfarin has significant interactions with vitamin K-rich foods (such as leafy green vegetables like spinach, kale, broccoli, and Brussels sprouts) that can reduce its effectiveness. Patients should maintain consistent vitamin K intake rather than avoiding these foods entirely. Alcohol consumption can increase bleeding risk and should be limited or avoided. Cranberry juice and cranberry products may enhance warfarin's effects and increase bleeding risk. Large amounts of green tea may also interfere with warfarin effectiveness. Patients should avoid major dietary changes and consult their healthcare provider before making significant modifications to their diet or alcohol consumption patterns.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.