What the FDA labels say about taking them together
Methotrexate and phenytoin
Methotrexate's FDA label of May 27, 2026 names phenytoin in its drug interactions section, and phenytoin's label names methotrexate too. The methotrexate label: “Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides.”
Check it at the source: the methotrexate FDA label on DailyMed (effective May 27, 2026, Accord Healthcare Inc.); the phenytoin FDA label on DailyMed (effective October 15, 2024, Mylan Pharmaceuticals Inc.).
What does the methotrexate label say about phenytoin?
Methotrexate label, drug interactionsOral 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 Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Hepatotoxic products Proton pump inhibitors Weak acids (e.g., salicylates) Nephrotoxic products Probenecid Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions.
Rasuvo label (Medexus Pharma Inc., December 15, 2025), drug interactionsMethotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides.
Methotrexate label (Hospira, Inc., August 22, 2025), drug interactionsHighly protein bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines)
Source: FDA drug label (Rasuvo, NDA205776), Medexus Pharma Inc., effective December 15, 2025 (SPL set d0075461-0e7e-4967-9c9b-d6440e912c0e), via openFDA
Source: FDA drug label (Methotrexate, NDA011719), Hospira, Inc., effective August 22, 2025 (SPL set 0e30eaef-5a09-4104-8a11-c32933eadeab), via openFDA
Source: FDA drug label (Methotrexate), Accord Healthcare Inc., effective May 27, 2026 (SPL set 874c7f43-a3be-4236-89cc-24c44e3c5813), via openFDA; the full label on DailyMed
What does the phenytoin label say about methotrexate?
Phenytoin label, drug interactionsInteracting Agent: Antineoplastic agents usually in combination; Examples: Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Source: FDA drug label (Phenytek), Mylan Pharmaceuticals Inc., effective October 15, 2024 (SPL set 0f94c791-8b07-4b41-927e-c9f28bec5f60), via openFDA; the full label on DailyMed
These are the labels' own sentences. PlainMeds does not grade interactions; a pharmacist or prescriber can say what they mean for one person's medicines.
Both medicines on the record
| Methotrexate | Phenytoin | |
|---|---|---|
| Labeled for | Rheumatoid arthritis, Psoriasis, Leukemia, lymphoma and myeloma, Breast cancer | Seizures and epilepsy |
| Boxed warning | Yes | No |
| Pharmacy cost (NADAC) | $0.158 per tablet 2.5 mg tablet | $0.145 per capsule 100 mg capsule |
| Shortage now | In shortage | No current entry |
Source: FDA NDC Directory, CMS NADAC of October 7, 2026 and the FDA Drug Shortage Database (FDA files October 8, 2026)
What next?
- Check more medicines together
- up to five at once