Levetiracetam and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate
Levetiracetam
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 methotrexate exposure and toxicity
Interaction Deep Dive
Concomitant use of methotrexate and levetiracetam may result in increased methotrexate exposure and toxicity, however current reports are conflicting. A patient coadministered both drugs developed increased time to methotrexate elimination from 90 hours to an average of 130 hours (range, 106 to 155 hours)1. In a retrospective review (N=81), there was no significant difference in the proportion of patients with delayed elimination of methotrexate at 24, 48, or 72 hours between patients that received concomitant levetiracetam and those that did not 2. If delayed methotrexate elimination occurs when coadministered levetiracetam, substitution of levetiracetam may be beneficial. When possible, consider temporarily switching from levetiracetam to another antiepileptic agent, especially in patients with a history of delayed methotrexate elimination with levetiracetam coadministration or in those at a greater risk for methotrexate toxicity 1.
Why it happens (mechanism)
Delay of methotrexate elimination
Literature reports
2 reports — tap to read
a) There was no significant difference in the proportion of patients with delayed elimination of methotrexate at 24, 48, or 72 hours between patients that received concomitant levetiracetam and those that did not, in a retrospective study of patients receiving methotrexate for an oncology diagnosis (N=81). Median methotrexate concentrations were significantly higher at 24 hours with those not receiving levetiracetam compared to those with concomitant levetiracetam (7.37 micromol/L vs 2.91 micromol/L); however, there were no significant differences in concentrations at 48 and 72 hours. Only baseline CrCl was found to be a predictor of delayed elimination. Patients received at least 1 dose of methotrexate 1000 mg/m(2) or greater IV over 3 to 4 hours or 800 mg/m(2) or greater IV over 22 to 24 hours with or without concomitant levetiracetam 500 to 1500 mg once or twice daily 2.
b) A patient treated with methotrexate (12 g/m(2)) for relapsed osteosarcoma developed increased time to methotrexate elimination from 90 hours to an average of 130 hours (range, 106 to 155 hours) when coadministered levetiracetam 2 g/day. Methotrexate elimination times decreased to 95 hours when lorazepam was substituted for levetiracetam 1.
Common questions
Can I take Levetiracetam and Methotrexate together?
Increased risk of methotrexate exposure and toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Levetiracetam and Methotrexate 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 Levetiracetam or Methotrexate 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)
- Bain E, Birhiray RE, & Reeves DJ: Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination. Ann Pharmacother 2014; 48(2):292-296. PubMed
- Reeves D, DiDominick S, Finn S, et al: Methotrexate elimination when coadministered with levetiracetam. Ann Pharmacother 2016; 50(12):1016-1022. DOI
Keep reading about Methotrexate
Keep reading about Levetiracetam
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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