Methotrexate

What it is used for

• For susceptible neoplastic diseases (usually as part of a multi-drug protocol)
• For non-suppurative cholangitis/cholangiohepatitis (CCHC) syndrome with fibrosis
• As part of the LMP protocol for maintenance of canine lymphoma
• In combination with other antineoplastics (per protocol)

How it is given

Possible side effects

• Diarrhea
• Nausea
• Vomiting
• Inappetence (especially in cats)
• GI toxicity (ulcers, mucosal sloughing, stomatitis)
• Hematopoietic toxicity / Myelosuppression (nadir at 4-6 days)
• Hepatopathy
• Renal tubular necrosis
• Alopecia
• Depigmentation
• Pulmonary infiltrates and fibrosis
• CNS toxicity (encephalopathy) if given intrathecally
• Anaphylaxis (rare)
• Myelosuppression (neutropenia, thrombocytopenia, anemia)
• Gastrointestinal toxicity (anorexia, vomiting, diarrhea, stomatitis)
• Hepatotoxicity (elevated liver enzymes)
• Nephrotoxicity (especially at high doses due to tubular precipitation)
• Alopecia (rare in most animals, but possible in continuously growing coats)

Cautions & contraindications

• Preexisting bone marrow depression
• Severe hepatic insufficiency
• Severe renal insufficiency
• Hypersensitivity to the drug
• Pregnancy (Teratogenic/Embryotoxic - FDA Category X)
• Nursing mothers
• Pre-existing severe bone marrow suppression
• Severe renal impairment
• Severe hepatic impairment
• Pregnancy and lactation (teratogenic and embryotoxic)
• Patients with significant third-space fluid accumulations (e.g., ascites, pleural effusion)
• Use with extreme caution in patients susceptible to or with preexisting clinical signs of MTX adverse reactions. **Handling Precautions:** Wear gloves or immediately wash hands after handling. Gloves are particularly important if handling split, broken, or crushed tablets. Preparation of intravenous solutions should ideally be performed in a vertical laminar flow hood to avoid human exposure. Teratogenic and may affect spermatogenesis.

Drug interactions

• Amiodarone: Prolonged PO administration (>2 weeks) may inhibit MTX metabolism
• Asparaginase: Given concomitantly with MTX may decrease MTX efficacy
• Azathioprine: Potential for increased risk for hepatic toxicity
• Chloramphenicol: May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
• Cisplatin: May have synergistic action with MTX, but alter the renal elimination of MTX
• Cyclosporine: May increase MTX levels
• Folic Acid: May reduce MTX efficacy, but folate deficiency increases MTX toxicity
• Neomycin (oral): May decrease the absorption of oral methotrexate if given concomitantly
• NSAIDs / Salicylates: Severe hematologic and GI toxicity risk; use caution in dogs also on MTX
• Penicillins: May decrease MTX renal elimination
• Probenecid: May inhibit the tubular secretion of MTX and increase its half-life
• Pyrimethamine: A similar folic acid antagonist; may increase MTX toxicity and should not be given to patients receiving MTX
• Retinoids: Potential for increased risk for hepatic toxicity
• Sulfasalazine: Potential for increased risk for hepatic toxicity
• Sulfonamides: May displace MTX from plasma proteins increasing risk for toxicity
• Tetracyclines: May displace MTX from plasma proteins increasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation
• Theophyllines: MTX may reduce theophylline elimination
• Trimethoprim/Sulfa: Rarely, may increase myelosuppression of MTX
• Vaccines, Live: Live virus vaccines should be used with caution, if at all during therapy
• NSAIDs: Decreased renal clearance of methotrexate, leading to increased serum levels and severe toxicity.
• Trimethoprim-sulfamethoxazole: Additive antifolate effects, significantly increasing the risk of severe bone marrow suppression.
• Omeprazole: May delay the elimination of methotrexate.

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