Amiodarone and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amiodarone
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 methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with hepatotoxic agents like amiodarone may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with amiodarone may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic products1.
Why it happens (mechanism)
Additive hepatotoxicity; reduced methotrexate absorption
Literature reports
1 report — tap to read
a) A 79-year-old female maintained on methotrexate for severe psoriasis developed ulcerated skin lesions shortly after the initiation of amiodarone for atrial fibrillation. At the time of hospitalization, she was taking methotrexate 17.5 mg weekly, furosemide 120 mg daily, aMILoride 15 mg daily, isosorbide mononitrate 20 mg daily, digoxin 0.25 mg daily, and dothiepin 75 mg daily. Loading doses of amiodarone 200 mg three times daily were given for one week, followed by amiodarone 200 mg twice daily for another week, and then amiodarone was maintained at 200 mg daily. Furosemide and aMILoride were increased to 160 mg daily and 20 mg daily, respectively. Two weeks after the start of amiodarone, many of the patient's psoriatic plaques became tender, red, and eroded together. Methotrexate was discontinued, and the erosions rapidly healed. While it is possible that the increases in the diuretic doses may have contributed to methotrexate toxicity, the timing of the events in relation to amiodarone therapy suggests that amiodarone may have caused the methotrexate toxicity 2.
Common questions
Can I take Amiodarone and Methotrexate together?
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amiodarone 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 Amiodarone 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)
Keep reading about Amiodarone
Keep reading about Methotrexate
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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