therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
Like other cytotoxic drugs, methotrexate may induce "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.)
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
DESCRIPTION
Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Chemically methotrexate is L-(+)-N-[p-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl]glutamic acid. The structural formula is:
Methotrexate injection USP (Preservative Free) products are sterile and non-pyrogenic and may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. (See DOSAGE AND ADMINISTRATION.)
Methotrexate Injection, USP, isotonic liquid, preservative free, for single use only, is available in 25 mg/mL, 2 mL (50 mg), 10 mL (250 mg) and 40 mL (1g) vials.
Each 25 mg/mL, 2 mL, 10 mL and 40 mL vial contains methotrexate sodium equivalent to 50 mg, 250 mg and 1g methotrexate respectively, and the following inactive ingredients: sodium chloride 0.490% w/v and water for injection qs ad 100% v. Sodium hydroxide and, if necessary, hydrochloric acid are added to adjust the pH to approximately 8.5. The 2 mL, 10 mL and 40 mL solutions contain approximately 0.43 mEq, 2.15 mEq and 7 mEq of sodium per vial, respectively, and are isotonic solutions.
CLINICAL PHARMACOLOGY
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa and cells of the urinary bladder are in general more sensitive to this effec
