Summary

Leflunomide can significantly increase warfarin's anticoagulant effects, leading to elevated INR levels and increased bleeding risk. This interaction requires careful monitoring and potential dose adjustments of warfarin when used concurrently with leflunomide.

Introduction

Leflunomide is an immunosuppressive disease-modifying antirheumatic drug (DMARD) primarily used to treat rheumatoid arthritis and psoriatic arthritis by inhibiting pyrimidine synthesis. Warfarin is an oral anticoagulant (vitamin K antagonist) commonly prescribed to prevent blood clots in conditions such as atrial fibrillation, deep vein thrombosis, and pulmonary embolism. Both medications are frequently prescribed in clinical practice, making their potential interaction clinically significant.

Mechanism of Interaction

The interaction between leflunomide and warfarin occurs through multiple mechanisms. Leflunomide and its active metabolite A77 1726 can inhibit cytochrome P450 enzymes, particularly CYP2C9, which is responsible for warfarin metabolism. This inhibition leads to decreased warfarin clearance and increased plasma concentrations. Additionally, leflunomide may displace warfarin from protein binding sites, further increasing the free (active) fraction of warfarin. These combined effects result in enhanced anticoagulant activity and prolonged prothrombin time/INR.

Risks and Symptoms

The primary risk of this drug interaction is significantly increased bleeding potential due to enhanced anticoagulation. Patients may experience major bleeding events including gastrointestinal hemorrhage, intracranial bleeding, or excessive bleeding from minor injuries. The interaction can cause INR values to rise substantially above therapeutic ranges, sometimes requiring warfarin dose reductions of 25-50%. Additional risks include delayed wound healing and increased perioperative bleeding complications. The interaction may persist for several weeks after leflunomide discontinuation due to its long elimination half-life.

Management and Precautions

Close monitoring is essential when initiating leflunomide in patients taking warfarin. INR should be checked within 1-2 weeks of starting leflunomide and then weekly until stable. Warfarin dose reductions are often necessary, typically ranging from 25-50% of the original dose. Patients should be educated about bleeding signs and symptoms, including unusual bruising, prolonged bleeding from cuts, blood in urine or stool, and severe headaches. Consider more frequent INR monitoring during dose adjustments and illness. Healthcare providers should evaluate the risk-benefit ratio and consider alternative therapies when appropriate. If leflunomide is discontinued, gradual warfarin dose increases may be needed as the interaction effect wanes.

Leflunomide interactions with food and lifestyle

Alcohol consumption should be avoided or limited while taking leflunomide due to increased risk of liver toxicity. Both leflunomide and alcohol can cause liver damage, and their combination may significantly increase this risk. Patients should discuss alcohol use with their healthcare provider and follow recommendations for liver function monitoring. Additionally, live vaccines should be avoided during leflunomide treatment due to the drug's immunosuppressive effects, which may reduce vaccine effectiveness and increase infection risk.

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.