Leflunomide and Warfarin: Drug Interaction Risk
When leflunomide and warfarin are used together, there is a documented risk of increased INR requiring warfarin dose reduction of approximately 20-30%, and close INR monitoring is mandatory. 1, 2
Mechanism of Interaction
The interaction between leflunomide and warfarin occurs through multiple pathways:
The FDA drug label for leflunomide explicitly warns that increased INR has been rarely reported when leflunomide and warfarin are co-administered. 1
Leflunomide's active metabolite (M1) can displace warfarin from protein binding sites, transiently increasing free warfarin concentrations and enhancing anticoagulant effects. 1
In vitro studies demonstrate that M1 increases the free fraction of various drugs by 13-50% at clinically relevant concentrations, suggesting a protein displacement mechanism. 1
Published case reports document INR elevations requiring 22% reductions in weekly warfarin dose after initiating leflunomide therapy in patients with previously stable anticoagulation. 2
Clinical Management Strategy
Monitoring Requirements
The FDA mandates specific monitoring when these drugs are combined:
Increase INR monitoring frequency immediately upon initiating leflunomide in warfarin-treated patients. 1, 2
Monitor INR at baseline, then weekly for the first month, then every 2 weeks for the second month, then monthly if stable. 3
Continue close monitoring even after apparent stabilization, as the interaction can evolve over time. 2
Dose Adjustment Approach
Proactive warfarin dose reduction is recommended:
Consider prophylactic warfarin dose reduction of 20-30% when initiating leflunomide, though this must be guided by INR response. 3
Clinical experience suggests an average 22% reduction in weekly warfarin dose may be required to maintain therapeutic INR. 2
Adjust warfarin dosage based on INR results to maintain therapeutic range of 2.0-3.0. 1, 2
Additional Bleeding Risk Factors
The bleeding risk extends beyond simple INR elevation:
Concurrent use of potentially interacting drugs with warfarin increases serious bleeding risk 3-4.5 fold compared to warfarin alone. 4
Polypharmacy (>4 drugs) further compounds bleeding risk in warfarin-treated patients. 4
CYP2C9 inhibitors carry the highest adjusted odds ratio for bleeding (OR 3.6), though leflunomide's primary mechanism differs. 5
Hepatotoxicity Considerations
Combined hepatotoxicity risk requires additional monitoring:
Leflunomide carries its own hepatotoxicity risk, with the FDA requiring ALT monitoring at baseline and monthly for six months, then every 6-8 weeks. 1
When leflunomide is combined with other hepatotoxic drugs (including warfarin in some contexts), increased side effects may occur. 1
Small combination studies show 2-3 fold liver enzyme elevations in approximately 17% of patients on leflunomide with other DMARDs. 1
Critical Pitfalls to Avoid
Never assume INR stability means the interaction won't occur - case reports document INR elevation even after months of stable anticoagulation. 2
Don't rely solely on INR values - bleeding can occur even within therapeutic INR range, particularly when multiple interacting drugs are present. 3, 4
Avoid dismissing minor INR elevations - small increases can herald larger problems and warrant immediate warfarin dose adjustment. 2
Don't forget the drug elimination procedure - if leflunomide must be discontinued, cholestyramine or activated charcoal rapidly decreases M1 concentrations and may affect warfarin requirements. 1
Alternative Considerations
In high-risk patients, consider alternative anticoagulation: