Warfarin and Methotrexate Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Warfarin
Methotrexate Injection
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 for elevated INR and subsequent bleeding; 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 highly protein bound drugs like warfarin may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with warfarin 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 reactions1. Elevated prothrombin time was experienced within 8 days in a patient and within 15 days in 2 patients treated with a methotrexate-chemotherapy regimen and concomitant warfarin. Patients experienced 1 or more symptoms of gross hematuria, microscopic hematuria, epistaxis, and/or subconjunctival hemorrhage 2.
Why it happens (mechanism)
Unknown; reduced methotrexate absorption/clearance; protein binding displacement
Literature reports
3 reports — tap to read
a) After starting warfarin, a 70-year-old woman treated with cycloPHOSphamide, methotrexate, and fluorouracil for breast cancer experienced elevated prothrombin times (PT) by day 15 on 4 chemotherapy cycles; furthermore, she experienced gross hematuria on the first occasion and epistaxis on each occasion. Her PT ranged from 8.2 to 21 sec with a stable warfarin dose. The PT increased to 44.2, 39, 31, and 29 sec, respectively, by day 15 of each subsequent cycle of chemotherapy. The PT returned to pre-treatment levels within 48 to 72 hours. Epistaxis and hematuria responded to discontinuation and reduction of warfarin dosage 2.
b) After starting warfarin, a 57-year-old woman treated with cycloPHOSphamide, methotrexate, and fluorouracil for breast cancer experienced elevated prothrombin times (PT) and microscopic hematuria by day 15 of each cycle. She also experienced epistaxis on 1 occasion. Her PT ranged from 14.8 to 17.2 sec over 3 weeks. The PT increased to a range of 24.6 to 26 sec by day 15 of each subsequent cycle of chemotherapy. The PT returned to pre-treatment levels within 48 hrs 2.
c) After starting warfarin, a 62-year-old man treated with cycloPHOSphamide, DOXOrubicin, etoposide, mechlorethamine, vinCRIStine, procarbazine, methotrexate, and predniSONE for lymphoma experienced elevated prothrombin times (PT) after days 1 and 8 of each chemotherapy cycle and subconjunctival hemorrhage on the first cycle. His PT ranged from 18 to 20 sec with a stable warfarin dose. The PT increased to 45, 30, and 36 sec, respectively, on 3 subsequent cycles. The PT returned to normal within 1 week of discontinuation of warfarin 2.
Common questions
Can I take Warfarin and Methotrexate Injection together?
Increased risk for elevated INR and subsequent bleeding; 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 Warfarin and Methotrexate Injection 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 Warfarin 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 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
- Seifter EJ, Brooks BJ, & Urba WJ: Possible interactions between warfarin and antineoplastic drugs. Cancer Treat Rep 1985; 69(2):244-245.
Keep reading about Warfarin
Keep reading about Methotrexate Injection
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