Chemotherapeutic agents: Enhancement of nephrotoxicity may be seen when high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin).
Cytarabine: Intrathecal methotrexate given concomitantly with IV cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke-like episodes.
L-asparaginase: The administration of L-asparaginase has been reported to antagonize the effect of MTX.
Mercaptopurine: Methotrexate increases the plasma levels of mercaptopurine. Combination of methotrexate and mercaptopurine may therefore require dose adjustment.
Disease-modifying antirheumatic drug (DMARD) and Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs should not be administered prior to or concomitantly with the high doses of methotrexate such as used in the treatment of osteosarcoma. Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic (including bone marrow suppression and aplastic anemia) and gastrointestinal toxicity. NSAIDs and salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity by increasing methotrexate levels. Therefore, caution should be used when they are administered concomitantly with lower doses of methotrexate.
In treating rheumatoid arthritis with methotrexate, aspirin, NSAIDs, and/or low dose steroids may be continued.
The possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosing regimens of NSAIDs, without difficulty. However, the methotrexate doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis, and larger doses could lead to unexpected toxicity. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, has not been studied and may increase the incidence of adverse effects.
Proton pump inhibitors: Co-administration of proton pump inhibitors (PPIs) with methotrexate may decrease the clearance of methotrexate causing elevated methotrexate plasma levels with clinical signs and symptoms of methotrexate toxicity. Concomitant use of PPIs and high dose methotrexate should therefore be avoided, especially in patients with renal impairment.
Antibiotics: Ciprofloxacin: Renal tubular transport is diminished by ciprofloxacin; use of methotrexate with this drug should be carefully monitored.
Penicillins and sulfonamides: Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity has been observed in combination with high- and low-dose methotrexate.
Oral antibiotics: 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 methotrexate by bacteria.
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or additive antifolate effect.
Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive antifolate effect.
Hepatotoxic agents: 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 hepatotoxic agents (e.g., leflunomide, azathioprine, sulfasalazine, retinoids) should be closely monitored for possible increased risk of hepatotoxicity.
Nitrous oxide anesthesia: The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression and stomatitis. This effect can be reduced by the use of folinic acid rescue (see Dosage & Administration).
Probenecid: Renal tubular transport is diminished by probenecid; use of methotrexate with this drug should be carefully monitored.
Vitamins: Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate, however, folate deficiency states may increase methotrexate toxicity.
Amiodarone: Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.
Drugs highly bound to plasma proteins: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by other highly bound drugs, such as sulfonylureas, aminobenzoic acid, salicylates, phenylbutazone, phenytoin, sulfonamides, some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid, and chloramphenicol.
Leflunomide: Methotrexate in combination with leflunomide may increase the risk of pancytopenia.
Psoralen plus ultraviolet light (PUVA) therapy: Skin cancer has been reported in few patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy (methoxsalen and ultraviolet light).
Theophylline: Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Diuretics: Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.