Summary

Enzalutamide significantly reduces warfarin effectiveness by inducing liver enzymes that metabolize warfarin, potentially leading to decreased anticoagulation and increased risk of blood clots. This interaction requires careful monitoring and likely warfarin dose adjustments.

Introduction

Enzalutamide (Xtandi) is an androgen receptor inhibitor primarily used to treat metastatic castration-resistant prostate cancer. It belongs to a class of medications called antiandrogens and works by blocking testosterone's effects on cancer cells. Warfarin (Coumadin) is an oral anticoagulant medication used to prevent and treat blood clots, including deep vein thrombosis, pulmonary embolism, and stroke prevention in atrial fibrillation. It belongs to the vitamin K antagonist class of blood thinners and works by inhibiting vitamin K-dependent clotting factors.

Mechanism of Interaction

Enzalutamide is a strong inducer of cytochrome P450 enzymes, particularly CYP2C9 and CYP3A4, which are responsible for metabolizing warfarin. When enzalutamide induces these enzymes, it increases the metabolism and clearance of warfarin from the body, leading to reduced warfarin plasma concentrations and decreased anticoagulant effect. This enzyme induction effect typically develops over several days to weeks after starting enzalutamide and can persist for weeks after discontinuation due to the long half-life of enzalutamide and its active metabolite.

Risks and Symptoms

The primary risk of this interaction is reduced anticoagulation effectiveness, which can lead to treatment failure and increased risk of thromboembolic events such as stroke, deep vein thrombosis, or pulmonary embolism. Patients may experience subtherapeutic INR (International Normalized Ratio) values despite previously stable warfarin dosing. The clinical significance is considered major, as inadequate anticoagulation can result in serious, potentially life-threatening complications. The interaction may be particularly concerning in patients with high thromboembolic risk, such as those with atrial fibrillation, mechanical heart valves, or history of venous thromboembolism.

Management and Precautions

Close monitoring of INR is essential when initiating, adjusting, or discontinuing enzalutamide in patients taking warfarin. INR should be checked more frequently than usual, potentially weekly initially, then every 2-4 weeks once stable. Warfarin dose increases are often necessary to maintain therapeutic anticoagulation, sometimes requiring 50-100% dose increases. Consider alternative anticoagulants such as direct oral anticoagulants (DOACs) like apixaban or rivaroxaban, which may be less affected by enzyme induction. If warfarin must be continued, establish new target INR ranges and dosing with careful titration. When discontinuing enzalutamide, warfarin doses may need to be reduced to prevent bleeding as enzyme induction effects gradually resolve over several weeks.

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.