METHOTREXATE
Clinical safety rating: avoid
Contraindicated (not allowed)
Folate antimetabolite; inhibits dihydrofolate reductase (DHFR), blocking conversion of dihydrofolate (DHF) to tetrahydrofolate (THF), thereby inhibiting DNA synthesis, repair, and cellular replication. Also inhibits thymidylate synthetase and purine synthesis.
| Metabolism | Hepatic metabolism via aldehyde oxidase and xanthine oxidase to 7-hydroxymethotrexate; polyglutamation occurs intracellularly. Primarily excreted renally as unchanged drug (80-90%) via glomerular filtration and active tubular secretion. |
| Excretion | Renal: 80-90% unchanged via glomerular filtration and tubular secretion; biliary/fecal: <10% as metabolites (7-hydroxymethotrexate). |
| Half-life | Terminal half-life: 3-10 hours (low dose) to 8-15 hours (high dose); clinical context: prolonged to 24-48 hours in renal impairment, third-space effusions, or polyglutamation. Delayed elimination due to enterohepatic recirculation. |
| Protein binding | ~50% bound, primarily to albumin. Displaced by salicylates, sulfonamides, NSAIDs (increases free fraction). |
| Volume of Distribution | Vd: 0.4-0.8 L/kg (total body water). Higher (1-2 L/kg) with polyglutamation in tissues. Enters third-space fluids (pleural, peritoneal). |
| Bioavailability | Oral: 30-50% (saturable absorption, dose-dependent, 20 mg/m² max); IM/SC: ~100%; IV: 100%. |
| Onset of Action | Oral: 30-60 min (rheumatologic); IV: 15-30 min (antitumor); IM/SC: 30-60 min; IT: rapid (minutes) for CNS effects. |
| Duration of Action | Oral: 24-48 hours (clinical effect); IV: 24-72 hours (antitumor, dose-dependent). High-dose MTX: effect extends to 7-10 days due to polyglutamation. Note: folate rescue alters duration. |
7.5-25 mg orally once weekly; alternatively, 10-25 mg intramuscularly, intravenously, or subcutaneously once weekly.
| Dosage form | SOLUTION |
| Renal impairment | GFR 30-60 mL/min: reduce dose by 50%; GFR <30 mL/min: contraindicated; on hemodialysis: not recommended due to toxicity risk. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | For juvenile idiopathic arthritis: 10-15 mg/m² orally or subcutaneously once weekly (with folate support). |
| Geriatric use | Initiate at lower end of dosing range (e.g., 5-7.5 mg once weekly) with close monitoring for myelosuppression, hepatotoxicity, and renal function due to age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| Breastfeeding | Contraindicated during breastfeeding. Methotrexate is excreted in breast milk at low concentrations (M/P ratio ~0.08–0.15), but due to potential for accumulation in neonates (impaired renal excretion) and serious adverse effects (myelosuppression, mucosal damage), breastfeeding is not recommended. |
| Teratogenic Risk | Pregnancy category X. First trimester exposure causes methotrexate embryopathy (craniofacial anomalies, CNS defects, skeletal abnormalities) in up to 30% of cases; spontaneous abortion risk elevated. Second/third trimester: fetal growth restriction, preterm birth, neurodevelopmental delays. Avoid throughout pregnancy. |
■ FDA Black Box Warning
Severe toxicity including myelosuppression, hepatotoxicity, renal failure, pulmonary fibrosis, pneumonitis, gastrointestinal ulcerations, and severe infections. Can cause fetal death or congenital anomalies; not recommended for use in pregnancy. Methotrexate should be used only by physicians knowledgeable in antimetabolite therapy. Monitor closely for bone marrow, liver, lung, and kidney toxicity.
| Common Effects | certain cancers |
| Serious Effects |
["Pregnancy or breastfeeding","Severe renal impairment (creatinine clearance < 20 mL/min)","Severe hepatic impairment","Pre-existing severe bone marrow suppression (e.g., leukopenia, thrombocytopenia, anemia)","Alcoholism or alcoholic liver disease","Immunodeficiency syndromes","Hypersensitivity to methotrexate or any component"]
| Precautions | ["Bone marrow suppression: monitor CBC, avoid if severe anemia/neutropenia/thrombocytopenia","Hepatotoxicity: avoid alcohol, monitor LFTs, caution in pre-existing liver disease","Renal toxicity: ensure adequate hydration, avoid NSAIDs if possible","Pulmonary toxicity: acute or chronic interstitial pneumonitis, may occur at any dose","Gastrointestinal toxicity: mucositis, ulcerative stomatitis, diarrhea, intestinal perforation","Fetal toxicity: effective contraception required in men and women","Neurotoxicity: leucoencephalopathy (especially with high-dose or cranial RT), arachnoiditis","Serious infections: including Pneumocystis jirovecii, tuberculosis, opportunistic infections","Dermatologic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis","Immunizations: avoid live vaccines during therapy","Carcinogenesis: potential malignancy (e.g., lymphoma)","Interaction with other drugs: trimethoprim/sulfamethoxazole, NSAIDs, probenecid, phenytoin"] |
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| Fetal Monitoring | Preconception: rule out pregnancy, folic acid supplementation. During pregnancy if accidental exposure: serial fetal ultrasound for anomalies, echocardiography, growth scans. Maternal monitoring: CBC, liver function, renal function every 2–4 weeks; drug levels if toxicity suspected. |
| Fertility Effects | Reversible oligospermia and menstrual dysfunction may occur, but no permanent infertility usually. High doses may cause ovarian failure; case reports of reversible azoospermia. Advise contraception during therapy and for at least 3 months after discontinuation in both sexes. |