7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on Methotrexate
Drugs that Increase Methotrexate Exposure
Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions.
Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with:
- Penicillin or sulfonamide antibiotics
- Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines)
- Proton pump inhibitors
- Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides)
- Aspirin and other nonsteroidal anti-inflammatory drugs
Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs)
- Hepatotoxic products
- Weak acids (e.g., salicylates)
- Nephrotoxic products
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. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.
Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.12)].