METHOTREXATE, VIALS (methotrexate, vials) Drug Interactions

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Serious Drug Interactions

The use of nitrous oxide anesthesia with methotrexate is contraindicated (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS - Renal and DRUG INTERACTIONS - Drug-Drug Interactions)


Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that undergo tubular secretion, can markedly increase methotrexate serum levels. Laboratory studies demonstrate that methotrexate may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol and phenytoin.

Drug-Drug Interactions

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate. 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. These drugs have been reported to reduce the tubular secretion of methotrexate, in an animal model, and may enhance its toxicity by increasing methotrexate levels.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of Methotrexate Injection USP.  In treating rheumatoid arthritis with methotrexate, the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. 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 toxicity.

Disease Modifying Antirheumatic drugs (DMARDs)

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, or sulfasalazine has not been studied and may increase the incidence of adverse effects.


Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.


The administration of L-asparaginase has been reported to antagonize the effect of methotrexate.


Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.


Methotrexate in combination with leflunomide may increase the risk of pancytopenia.

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.

Packed Red Blood Cells

Care should be exercised whenever packed red blood cells and Methotrexate Injection USP are given concurrently. Patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum-Methotrexate concentrations.


Renal tubular transport is also diminished by probenecid; use of Methotrexate Injection USP with this drug should be carefully monitored.

Proton Pump Inhibitors

Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Concomitant use of PPIs and high-dose methotrexate should be avoided especially in patients with renal impairment. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydromethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

Psoralen Plus Ultraviolet Light (PUVA) Therapy

Skin cancer has been reported in patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy.

Nephrotoxic Drugs

In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin). Methotrexate clearance is decreased by cisplatinum.

Although not documented, other nephrotoxic drugs such as aminoglycosides, Amphotericin B and Cyclosporin could theoretically increase methotrexate toxicity by decreasing its elimination.

Nitrous Oxide

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis, neurotoxicity (with intrathecal administration of methotrexate) and nephritis (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Renal).  In case of accidental co-administration, this effect can be reduced by the use of leucovorin rescue.

Penicillins and Sulfonamides

Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity have been observed in combination with methotrexate. Use of Methotrexate Injection USP with penicillins should be carefully monitored.


Renal tubular transport is diminished by ciprofloxacin; use of Methotrexate Injection USP with this drug should be carefully monitored.

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 the drug by bacteria. For example: Neomycin, Polymyxin B, Nystatin, and Vancomycin decrease methotrexate absorption, whereas Kanamycin increases methotrexate absorption.

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive antifolate effect.


Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with Methotrexate Injection USP.


Methotrexate increases the plasma levels of mercaptopurine. Combination of Methotrexate Injection USP and mercaptopurine may therefore require dose adjustment.


Vitamin preparations containing folic acid or its derivatives may decrease responses to methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the cerebrospinal fluid primarily as 5-methyl tetrahydrofolate and, in humans, remain 1 to 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.

In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes.

Before taking a folate supplement, it is advisable to check B12 levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B12 deficiency.

Folate deficiency states may increase methotrexate toxicity.


Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.


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 Injection USP and other potential hepatotoxic agents (e.g., leflunomide, azathioprine, sulfasalazine, retinoids) should be closely monitored for possible increased risk of hepatotoxicity.

Cytarabine and other cytotoxic agents

Methotrexate given concomitantly with IV cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke-like episodes (see WARNINGS AND PRECAUTIONS: Neurologic).

Combined use of methotrexate with other cytotoxic agents has not been studied and may increase the incidence of adverse effects.

Drug-Herb Interactions

The effects of herbal products on the pharmacokinetics of methotrexate have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Use of alcohol with Methotrexate Injection USP is contraindicated (see CONTRAINDICATIONS). The effects of smoking, on the pharmacokinetics of methotrexate have not been specifically studied.

Some of the effects (e.g., dizziness and fatigue) may have an influence on the ability to drive or operate machinery.