Methotrexate and Phenytoin Interaction
Drug interaction information between Methotrexate and Phenytoin.
Methotrexate and Phenytoin have a documented minor interaction in FDA labeling.
FDA drug labeling documents a minor-severity interaction between Methotrexate and Phenytoin. This page displays the available source-record category and label text. The category is not an individual risk estimate or medication-combination direction.
How They Interact
Phenytoin can push methotrexate off the proteins in your blood, which increases the amount of active methotrexate in your system.
FDA Label Information
If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Oral antibiotics (including neomycin) Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Oral or intravenous penicillin or sulfonamide antibiotics Aspirin and other nonsteroidal anti- inflammatory drugs Hepatotoxic products Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Weak acids (e.g., salicylates) Nephrotoxic products Probenecid Nitrous Oxide...
Methotrexate Also Interacts With
- Celecoxib moderate
- Diflunisal moderate
- Indomethacin moderate
- Mefenamic Acid moderate
- Meloxicam moderate
Phenytoin Also Interacts With
- Nirmatrelvir/Ritonavir major
- Posaconazole major
- Ranolazine major
- Voriconazole major
- Apixaban moderate
Frequently Asked Questions
What SPL severity band is on file for Methotrexate + Phenytoin?
Compiled FDA labeling labels this pair minor. That is a source-record field, not an individual medication-combination decision.
Which drug in this pair has the larger labeled-interaction portfolio?
Phenytoin has 147 labeled pairs on file vs Methotrexate's 38. In the minor band specifically: Methotrexate has 26 (also Aspirin, Folic Acid, Probenecid, Adalimumab); Phenytoin has 120 (also Atorvastatin, Omeprazole, Simvastatin, Methylphenidate).
What mechanism field is on file for Methotrexate and Phenytoin?
Phenytoin can push methotrexate off the proteins in your blood, which increases the amount of active methotrexate in your system.
Phenytoin carries more major-labeled pairs than Methotrexate
SPL source-record counts only. This page's band is minor · classes on file: Methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)); Phenytoin (Anticonvulsant (Hydantoin)).
Phenytoin has 4 major-labeled pairs vs Methotrexate's 0. This page itself is in the minor band, not the major band.
0 major · 12 moderate · 26 minor · 38 total
- Other minor peers for Methotrexate
- Aspirin
- Folic Acid
- Probenecid
- Adalimumab
4 major · 23 moderate · 120 minor · 147 total
- Other minor peers for Phenytoin
- Atorvastatin
- Omeprazole
- Simvastatin
- Methylphenidate
Sources: FDA Drug Labels (SPL) via openFDA (2026). This is for informational purposes only and is not medical advice. This registry does not provide individual medication-combination directions.
Read our methodology - how this data is sourced, computed, and verified.