Leflunomide and Warfarin: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Leflunomide
Warfarin
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased risk of bleeding
Interaction Deep Dive
Concomitant administration of leflunomide and warfarin has resulted in elevation in international normalized ratio (INR) in 2 patients21. This interaction can be attributed to inhibition of the CYP2C9-mediated metabolism of warfarin by leflunomide may result in decreased clearance of warfarin, thereby enhancing warfarin's anticoagulant effect and increasing the risk of bleeding. Caution is advised if these agents are coadministered. Consider monitoring INR more frequently and adjust the warfarin dose accordingly to achieve desired level of anticoagulation 1.
Why it happens (mechanism)
Inhibition of CYP2C9-mediated metabolism of warfarin by leflunomide
Literature reports
2 reports — tap to read
a) Addition of leflunomide therapy in a 61-year-old Caucasian woman receiving warfarin resulted in an elevated international normalized ratio (INR). The woman, who had a history of recurrent thromboembolism and atrial fibrillation, was receiving warfarin (36 mg/week) for 4 months and had a stable INR (goal INR 2-3) prior to initiation of leflunomide. Concomitant medications also included ramipril, hydrochlorothiazide, propafenone, prednisone, sulindac, buspirone, folic acid, calcium and potassium supplementation. Leflunomide for rheumatoid arthritis was initiated at 100 mg/day for 3 days, followed by 20 mg/day thereafter. Subsequently, during a routine follow-up visit, the patient's INR had increased to 7.3 and this result was confirmed by using a separate laboratory testing method. Liver and renal function tests were normal and the patient had not experienced any recent illness or bleeding problems. Additionally, the patient reported to being compliant with warfarin and all other drug/disease-related contributors to INR elevation were ruled out. Subsequently, warfarin was withheld for 3 doses, followed by a decrease in warfarin dose from 36 to 32 mg/week. Repeat testing a week later resulted in an INR of 2 and over the next 10 weeks, with continual warfarin dosage reductions, the patient's INR (goal INR 2-3) stabilized at a warfarin dose of 28 mg/week. Inhibition of the CYP2C9-mediated metabolism of warfarin by leflunomide was proposed as the mechanism for this interaction 1.
b) A case report described an increase in a patient's international normalized ratio (INR) following concomitant use of leflunomide and warfarin. A 49-year-old man with resistant rheumatoid arthritis began taking leflunomide 100 mg daily for 3 days. His INR had been stable for a year while taking warfarin. Two days before treatment with leflunomide was initiated his INR was 3.4. He developed gross hematuria after taking two doses of leflunomide, requiring hospitalization. His INR rose to 11 and warfarin was discontinued. The hematuria resolved and his hemoglobin concentration was satisfactory. On the third day of hospital admission he was given vitamin K 1 mg intravenously. His ratio decreased to 1.9 which coincided with the change in leflunomide maintenance dose of 20 mg daily. Warfarin was prescribed at 1 mg daily, sufficient to maintain his INR within the recommended range. Leflunomide caused the increase in the patient's ratio and the subsequent lower warfarin doses required to maintain the ratio within the normal range 2.
Common questions
Can I take Leflunomide and Warfarin together?
Increased risk of bleeding Always confirm with your pharmacist or prescriber before making any change.
How serious is the Leflunomide and Warfarin interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Leflunomide or Warfarin need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
Keep reading about Leflunomide
Keep reading about Warfarin
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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