Section 07 · Monograph

Methotrexate

Reviewed Nov 2026FDA label

TrexallFolate antagonist

Black Box Warning

CRITICAL DOSING WARNING: methotrexate for non-oncologic uses (RA, psoriasis, and off-label myasthenia gravis) is dosed ONCE WEEKLY. Inadvertent daily dosing has resulted in FATAL toxicity — verify prescribed frequency at every fill and refill
Embryo-fetal toxicity: can cause fetal death and/or congenital anomalies; contraindicated in pregnancy for non-oncologic indications
Severe, potentially fatal toxicities can occur even at low non-oncologic doses, including bone marrow suppression, aplastic anemia, GI toxicity, hepatotoxicity (fibrosis/cirrhosis with chronic use), pulmonary toxicity (interstitial pneumonitis, may be fatal, at any dose), dermatologic toxicity (SJS/TEN), and nephrotoxicity
Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAIDs

Acute lymphoblastic leukemia (ALL) — maintenance therapy component, adults and pediatricsFDA-labeled
Mycosis fungoides (advanced cutaneous T-cell lymphoma), adultsFDA-labeled
Relapsed or refractory non-Hodgkin lymphoma, adultsFDA-labeled
Severe, active rheumatoid arthritis in adultsFDA-labeled
Polyarticular-course juvenile idiopathic arthritis, pediatricsFDA-labeled
Severe, recalcitrant, disabling psoriasis in adults not adequately responsive to other therapyFDA-labeled

Steroid-sparing immunosuppressant for myasthenia gravis (studied in a randomized controlled trial; used as an alternative to azathioprine/mycophenolate); dosing is ONCE WEEKLY, not daily — typical target range 7.5-25 mg PO once weeklyOff-label
Folic acid or folinic acid supplementation is typically co-prescribed to reduce GI and hepatic/hematologic toxicityOff-label

Folate analog (antimetabolite) that competitively and irreversibly inhibits dihydrofolate reductase (DHFR)
DHFR inhibition blocks conversion of dihydrofolate to tetrahydrofolate, depleting intracellular folate cofactors needed for one-carbon transfer reactions
Impairs synthesis of thymidylate and purines, inhibiting DNA, RNA, and protein synthesis, with greatest effect on rapidly dividing cells
At low weekly autoimmune-disease doses, anti-inflammatory effects are thought to involve increased extracellular adenosine release, which has anti-inflammatory effects on lymphocytes and other immune cells
Net effect in autoimmune disease is modulation of T-cell and cytokine-mediated inflammation rather than pure cytotoxic immunosuppression

IMPORTANT: for MG and other non-oncologic autoimmune indications, methotrexate is given ONCE WEEKLY on the same day each week — never once daily
Rheumatoid arthritis: initial 7.5 mg PO once weekly, titrated gradually; maximum weekly dose generally 20 mg
Psoriasis: 10-25 mg PO once weekly; maximum 30 mg/week
Polyarticular JIA: 10 mg/m² once weekly
MG off-label: commonly initiated at 7.5-10 mg once weekly, titrated up to typical target of 15-25 mg once weekly, often with folic acid supplementation
Oncologic dosing follows separate, disease-specific protocols under oncology supervision with leucovorin rescue — distinct from the weekly low-dose regimens above

Renal impairment: reduce dose or avoid, as methotrexate is primarily renally eliminated and toxicity risk rises sharply with reduced clearance

Pregnancy, in patients being treated for non-neoplastic diseases (RA, psoriasis, and off-label MG use)
History of severe hypersensitivity reaction to methotrexate
Breastfeeding
Pre-existing severely compromised bone marrow function, or significant hepatic/renal impairment (relative, requiring risk-benefit assessment)
Alcoholism, chronic liver disease, or immunodeficiency syndromes — relative contraindication in RA/psoriasis labeling

NSAIDs (including high-dose salicylates) can reduce renal clearance of methotrexate and increase toxicity risk
Trimethoprim-sulfamethoxazole and other antifolate/sulfonamide antibiotics increase risk of severe bone marrow suppression via additive antifolate effect
Penicillins may reduce renal clearance of methotrexate, increasing toxicity
Proton pump inhibitors can delay methotrexate elimination and increase serum levels, especially at higher doses
Probenecid decreases renal clearance of methotrexate
Folic acid/folinic acid supplementation reduces GI and hematologic toxicity without significantly reducing efficacy at low doses
Nitrous oxide potentiates methotrexate's effect on folate metabolism, increasing toxicity risk — avoid nitrous oxide anesthesia
Hepatotoxic drugs (including alcohol) increase risk of methotrexate-associated liver injury

Stomatitis and other mucosal ulceration — common, often an early sign of toxicity
Bone marrow suppression: leukopenia, thrombocytopenia, anemia, rarely pancytopenia/aplastic anemia
Nausea, abdominal discomfort, diarrhea
Hepatotoxicity, including risk of hepatic fibrosis/cirrhosis with long-term use
Pulmonary toxicity: interstitial pneumonitis (can be acute and life-threatening, dose-independent)
Renal toxicity, particularly with dehydration or higher doses
Dermatologic reactions, including photosensitivity and rarely SJS/TEN
Increased infection risk due to immunosuppression
Neurotoxicity (headache, fatigue, rarely leukoencephalopathy)

CBC with differential and platelet count at baseline, then periodically throughout therapy
Liver function tests at baseline and periodically; consider baseline hepatitis B/C screening in at-risk patients
Renal function (creatinine/eGFR) at baseline and periodically
Chest X-ray at baseline (per some protocols) and prompt evaluation of any new pulmonary symptoms given risk of pneumonitis
Reinforce and re-verify the ONCE-WEEKLY dosing schedule at every visit and refill to prevent fatal daily-dosing errors
Assess for mucosal ulceration/stomatitis as an early toxicity marker
Pregnancy testing before initiation in females of reproductive potential

Contraindicated in pregnancy for non-oncologic (autoimmune) indications, including off-label MG use — known human teratogen and abortifacient
Can cause fetal death or congenital anomalies ('methotrexate embryopathy') with first-trimester exposure
Females of reproductive potential should use effective contraception during therapy and for at least 6 months after the final dose
Males with female partners of reproductive potential should use effective contraception during therapy and for at least 3 months after the final dose
Contraindicated during breastfeeding — present in human milk with potential for serious adverse reactions in nursing infants