Methotrexate and Leflunomide: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Leflunomide
Methotrexate
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 exposure of methotrexate and increased risk of hepatotoxicity and bone marrow toxicity
Interaction Deep Dive
The active metabolite of leflunomide is teriflunomide, which is an organic anion transporter 3 (OAT3) inhibitor. Concomitant administration of leflunomide or teriflunomide with methotrexate (an OAT3 substrate) may increase the plasma concentration of methotrexate via inhibition of OAT-mediated transport system. Consider reducing the dose of methotrexate when coadministered with teriflunomide1. The starting and maximum dosage of leflunomide is 20 mg once a day without a loading dose when coadministered with methotrexate. Monitor blood counts monthly during concurrent treatment. If evidence of bone marrow suppression occurs, stop leflunomide or teriflunomide and reduce the plasma concentration of the active metabolite with cholestyramine or charcoal. If leflunomide and methotrexate are given concomitantly, American College of Rheumatology (ACR) guidelines for monitoring methotrexate liver toxicity must be followed, with ALT, AST, and serum albumin testing monthly 2.
Why it happens (mechanism)
Inhibition of OAT-mediated transport of methotrexate by leflunomide or its active metabolite, teriflunomide
Literature reports
2 reports — tap to read
a) In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients. These effects were generally reversible. Pancytopenia, agranulocytosis, and thrombocytopenia have also been reported more frequently when leflunomide was given concomitantly with methotrexate 2.
b) The combination of leflunomide and methotrexate has been associated with increased risk of pancytopenia in 18 cases of leflunomide-associated pancytopenia in elderly patients. Of the 18 patients, 14 were receiving the combination of leflunomide and methotrexate. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in 9 cases. Eleven of the 14 patients were over 60 years old and 4 of these patients died. Time to onset of pancytopenia ranged from 11 days to 4 years. Acute renal failure associated with dehydration and nonsteroidal antiinflammatory drugs may have led to the decreased clearance of leflunomide and precipitated the onset of pancytopenia in 1 fatal case. This patient was treated with leflunomide 20 mg/day for 4 years and methotrexate 10 mg/week for 10 years. Her regimen had been stable for 6 months prior to admission. A cohort study of 3325 patients treated with leflunomide over 33 months had 5 cases of leukopenia but no cases of pancytopenia 3.
Common questions
Can I take Methotrexate and Leflunomide together?
Increased exposure of methotrexate and increased risk of hepatotoxicity and bone marrow toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Methotrexate and Leflunomide 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 "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Methotrexate or Leflunomide 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 (3)
- Product Information: AUBAGIO(R) oral tablets, teriflunomide oral tablets. Genzyme Corporation (per FDA), Cambridge, MA, 2014. DailyMed
- Product Information: ARAVA(R) oral tablets, leflunomide oral tablets. sanofi-aventis U.S. LLC (per FDA), Bridgewater, NJ, 2015. DailyMed
- Chan J, Sanders DC, Du L, et al: Leflunomide-associated pancytopenia with or without methotrexate. Ann Pharmacother 2004; 38:1206-1211. PubMed
Keep reading about Leflunomide
Keep reading about Methotrexate
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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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