Leflunomide and Pioglitazone: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Leflunomide
Pioglitazone
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 pioglitazone exposure
Interaction Deep Dive
Mean Cmax and AUC of repaglinide, a CYP2C8 substrate, were increased by 1.7- and 2.4-fold, respectively, when repaglinide 0.25 mg was administered following repeated doses of teriflunomide (the active metabolite of leflunomide1), suggesting that teriflunomide is a CYP2C8 inhibitor 2. The AUC of pioglitazone, a CYP2C8 substrate, was increased 3.4-fold and the half-life increased from 6.5 to 15.1 hours when a 30-mg dose was coadministered with gemfibrozil, a strong CYP2C8 inhibitor, dosed at 600 mg twice daily for two days 3. Monitor patients taking pioglitazone and leflunomide or teriflunomide concomitantly 2; a pioglitazone dose adjustment may be necessary 3.
Why it happens (mechanism)
Inhibition of CYP2C8-mediated pioglitazone metabolism by teriflunomide, the active metabolite of leflunomide
Common questions
Can I take Leflunomide and Pioglitazone together?
Increased pioglitazone exposure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Leflunomide and Pioglitazone interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Leflunomide or Pioglitazone 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 anything you'd monitor while I'm on both?
References (3)
- Product Information: ARAVA(R) oral tablets, leflunomide oral tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2016. DailyMed
- Product Information: AUBAGIO(R) oral tablets, teriflunomide oral tablets. Genzyme Corporation, Cambridge, MA, 2012. DailyMed
- Product Information: ACTOS(R) oral tablets, pioglitazone HCl oral tablets. Takeda Pharmaceuticals America, Inc.(per FDA), Deerfield, IL, 2011. DailyMed
Keep reading about Leflunomide
Keep reading about Pioglitazone
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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