Methotrexate and Tamoxifen: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate
Tamoxifen
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
An increased risk of thromboembolism, increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with hepatotoxic agents like tamoxifen may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with tamoxifen may also subsequently reduce active metabolite formation, which may reduce 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. The addition of a regimen of cycloPHOSphamide, methotrexate, and fluorouracil to tamoxifen has been shown to increase the risk of thromboembolic events in postmenopausal women being treated for breast cancer 2.
Why it happens (mechanism)
Unknown; additive hepatotoxicity; reduced methotrexate absorption
Literature reports
1 report — tap to read
a) In a multicenter randomized trial of 705 postmenopausal women undergoing treatment for breast cancer, the incidence of thromboembolism while undergoing therapy with tamoxifen for two years was compared to tamoxifen therapy for two years plus a six-month regimen of intravenous cycloPHOSphamide, methotrexate, and fluorouracil (CMF). Out of 353 women receiving tamoxifen plus CMF, 48 women (13.6%) experienced one or more thromboembolic events, compared to nine out of 352 women (2.6%) in the tamoxifen-only group. In addition, significantly more serious thromboembolic events (such as deep venous thromboses, pulmonary emboli, arterial events, or fatal events) were seen in the tamoxifen plus CMF group compared to the tamoxifen-only group 2.
Common questions
Can I take Methotrexate and Tamoxifen together?
An increased risk of thromboembolism, increased methotrexate exposure, an increased risk of 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 Methotrexate and Tamoxifen 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 Methotrexate or Tamoxifen 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)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Pritchard KI, Paterson AH, Paul NA, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996; 14:2731-2737.
Keep reading about Methotrexate
Keep reading about Tamoxifen
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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