Known brand names include Trexall.
A pill, usually taken once a week, for rheumatoid arthritis, severe psoriasis, and juvenile arthritis, and part of chemotherapy for some blood cancers. It blocks an enzyme cells need to use folate, and taking a weekly dose every day by mistake has caused deaths.
First-line. Adults with rheumatoid arthritis; the usual first disease-modifying drug.
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Labeled use. Mycosis fungoides (cutaneous T-cell lymphoma), and relapsed or refractory non-Hodgkin lymphoma in a metronomic combination regimen, in adults.
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Labeled use. Polyarticular juvenile idiopathic arthritis in children.
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Labeled use. Adults and children, as part of a combination chemotherapy maintenance regimen.
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The anchor disease-modifying drug for rheumatoid arthritis, usually started first and kept as the base when biologics or other agents are added. Also a standard systemic option for severe psoriasis and for polyarticular juvenile arthritis. Avoid it in pregnancy or when pregnancy is planned, with significant liver disease or heavy alcohol use, and with poor kidney function; alternatives such as hydroxychloroquine, sulfasalazine, or leflunomide (which is also teratogenic) are then weighed. Daily folic acid is commonly given to reduce side effects.
A folic acid antagonist that inhibits dihydrofolate reductase, so dihydrofolates are not reduced to the tetrahydrofolates needed to make purine nucleotides and thymidylate. DNA synthesis, repair, and cell replication fall, and rapidly dividing tissues (malignant cells, marrow, fetal cells, oral and intestinal mucosa, bladder) are most sensitive. Its mechanism in rheumatoid arthritis and psoriasis is unknown. Oral bioavailability is about 60% at doses of 30 mg/m² or less, the half-life is about 3 to 10 hours, and elimination is mainly renal; polyglutamate metabolites persist in tissues.
The label does not describe a narrow therapeutic index or direct dosing by measured blood levels of the drug. Methotrexate levels guide leucovorin and glucarpidase after overdose, not routine dosing.
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Doses come from the FDA label. Study tool, not for clinical decisions.
Elimination falls and toxicity risk rises with renal impairment. Monitor closely for adverse reactions when CrCl is below 90 mL/min (Cockcroft-Gault), and reduce the dose or stop as appropriate. Check renal function at baseline and periodically. For toxic levels with delayed clearance from renal impairment, give glucarpidase.
Pharmacokinetics and safety in hepatic impairment are unknown; monitor closely and reduce the dose or stop as appropriate. It can cause fibrosis, cirrhosis, and fatal liver failure. In psoriasis, fibrosis can develop without symptoms or abnormal liver tests, usually after a cumulative dose of 1.5 g or more, and heavy alcohol use raises the risk.
Embryo-fetal toxicity, hypersensitivity, severe adverse reactions, and medication errors. It can cause fetal death and is contraindicated in pregnancy for non-neoplastic diseases; patients treated for cancer need effective contraception. It is contraindicated after severe hypersensitivity, including anaphylaxis. Serious and fatal toxicity of the marrow, GI tract, liver, lungs, skin, and kidneys calls for close monitoring and withholding or stopping as appropriate. Taking it once daily by mistake has caused deaths.
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Leucovorin or levoleucovorin, started as soon as possible after an overdose, lessens methotrexate toxicity; serum creatinine and methotrexate levels guide their dosing. Glucarpidase treats toxic plasma levels (above 1 micromole per liter) with delayed clearance from impaired kidney function. Give hydration and urinary alkalinization. Standard hemodialysis and peritoneal dialysis have not been shown to help, though high-flux hemodialysis has cleared it.
Contraindicated in pregnancy for non-neoplastic diseases. It can cause embryo-fetal toxicity and fetal death; first-trimester exposure is linked to miscarriage and skull, facial, limb, and central nervous system defects. Verify pregnancy status before starting. Females need effective contraception during treatment and for 6 months after the last dose, and males with partners who could become pregnant for 3 months. With cancer, advise pregnant patients of the risk to the fetus.
Present in human milk in low amounts. Because of the risk of serious adverse reactions in the infant, avoid breastfeeding while taking it and until 1 week after the final dose.
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Established only for ALL maintenance and pJIA. For pJIA, start 10 mg/m² orally once weekly and adjust to response; doses above 30 mg/m² weekly raise the risk of serious adverse reactions, including myelosuppression. Give folic or folinic acid. Oral absorption in children with leukemia varies widely (23% to 95%).