Drug Interaction Report

L-Methylfolate and Methotrexate Injection: Interaction Details

A pharmacist-reviewed analysis of the L-Methylfolate and Methotrexate Injection interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Methotrexate Injection

Abitrexate® Folex® Jylamvo Mexate® Otrexup Otrexup® Rasuvo Rasuvo®
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L-Methylfolate

No brand names on record
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Moderate
Can be significant — usually manageable with monitoring.
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.

Of 30 documented L-Methylfolate interactions, 25 are rated moderate — including this one.
Onset
unspecified
Evidence
theoretical
Severity
Moderate

What happens

Decreased methotrexate and/or l-methylfolate efficacy

Interaction Deep Dive

L-methylfolate is the bioactive form of folic acid and is used as a medical food12. Although no studies have been conducted, coadministration of l-methylfolate with methotrexate may decrease folate plasma levels 2. Additionally, l-methylfolate may counteract the therapeutic efficacy of folic acid antagonists, such as methotrexate, if given concomitantly. Therefore, use caution when prescribing l-methylfolate to patients receiving methotrexate. Close monitoring for loss of methotrexate and/or l-methylfolate efficacy is recommended.

Why it happens (mechanism)

Pharmacologic antagonism

Common questions

Can I take L-Methylfolate and Methotrexate Injection together?

Decreased methotrexate and/or l-methylfolate efficacy Always confirm with your pharmacist or prescriber before making any change.

How serious is the L-Methylfolate and Methotrexate Injection 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 L-Methylfolate or Methotrexate Injection 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 (2)

  1. Product Information: DEPLIN(R) oral tablets, l-methylfolate oral tablets. Pamlab,LLC, Covington, LA, 2006. DailyMed
  2. Product Information: Zervalx(R) oral tablets, l-methylfolate oral tablets. Pamlab,LLC, Covington, LA, 2008. DailyMed
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L-Methylfolate

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