Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and
prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of
methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and
may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually
included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated,
however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in
psoriasis and that larger doses could lead to unexpected toxicity.
Ledertrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain
drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished
by probenecid; use of methotrexate with this drug should be carefully monitored.
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease
intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and
suppressing metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with
concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of
methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other
hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore,
patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine,
retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Ledertrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used
concurrently with methotrexate.
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered
methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered
leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and in humans, remain 1 - 3 orders of magnitude lower
than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin
may reduce the efficacy of intrathecally administered methotrexate.
Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported
rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate