Methotrexate

Antifolate, DMARD, Antineoplastic, Immunosuppressant

Methotrexate

Trexall, Otrexup, Rasuvo, Xatmep, Rheumatrex (discontinued)

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Titration strategies

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Effects

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Pharmacy

Starting dose

Rheumatologic: 7.5-15 mg PO or SC once weekly (not daily — daily dosing is a recognized fatal error); folic acid 1 mg PO daily on non-MTX days; oncology dosing is far higher and indication-specific

Preparations

2.5 mg tablets; 10-50 mg/mL injection; pre-filled subcutaneous autoinjectors (Otrexup, Rasuvo); 2.5 mg/mL oral solution (Xatmep)

US FDA Max

Rheumatologic ~25 mg/week; oncology indication-specific

Common uses

Classification(s)

Classes

Antifolate, DMARD, Antineoplastic, Immunosuppressant

Pharmacology

Routes

Oral, subcutaneous, intramuscular, IV, intrathecal

Onset

Rheumatologic effect at 4-8 weeks; ectopic resolution over 2-3 weeks

Duration

Once-weekly dosing in rheumatology

Half-life

3-10 hours (low dose); 8-15 hours (high dose); much longer in third-space accumulation (pleural effusion, ascites)

Bioavailability

60-70% PO at low doses; saturable at high doses (parenteral routes preferred above 15-25 mg/week)

Pregnancy

Contraindicated in pregnancy (Category X); abortifacient and teratogenic. Discontinuation 3-6 months before conception is standard.^{[citation needed]}

Legal status

Rx-only in US

Purported mechanism

Methotrexate competitively inhibits dihydrofolate reductase, depleting tetrahydrofolate and blocking thymidylate, purine, and amino acid synthesis; in rheumatologic doses the immunomodulatory effect appears mediated less by DHFR inhibition and more by AICAR transformylase inhibition with subsequent adenosine accumulation and anti-inflammatory adenosine A2A signaling.▲0▼ Folic acid co-supplementation reduces stomatitis, GI, and hepatic toxicity without compromising efficacy. Bone marrow suppression, hepatotoxicity, pneumonitis, and nephrotoxicity (especially with high-dose oncology regimens) are the major adverse effects. Glucarpidase rescues high-dose methotrexate toxicity by cleaving extracellular drug.