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. |
| Molecular Weight | 454.44 |
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 | Contraindicated due to high risk of teratogenicity (neural tube defects, cardiac anomalies, craniofacial defects, limb defects). Considered an abortifacient at high doses. |
| 2nd trimester | Contraindicated; potential for fetal growth restriction, oligohydramnios, and neurodevelopmental issues. Use only if maternal benefit outweighs risks. |
| 3rd trimester | Contraindicated; risk of neonatal myelosuppression, pneumonitis, and growth retardation. Avoid near term. |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| Placental transfer | Active placental transport via folate receptors; achieves fetal concentrations comparable to maternal. Extensive transfer documented. |
| Breastfeeding | Secreted in breast milk in low concentrations; however, due to potential for accumulation and neonatal immunosuppression, nursing is not recommended. Use with caution only if essential and monitor infant for adverse effects. |
■ 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 |
PregnancyBreastfeedingSevere hepatic impairmentSevere renal impairment (CrCl <10 mL/min)Preexisting immunodeficiencyActive infections (e.g., tuberculosis)Alcoholism or chronic liver diseasePancytopenia or significant bone marrow suppression
| 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 |
Loading safety data…
| Lactation Rating | L5 - Contraindicated |
| 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. |
| 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. |
| Food/Dietary | 1. Avoid alcohol to reduce hepatotoxicity risk. 2. Limit caffeine intake as it may affect absorption. 3. Foods high in folate (e.g., leafy greens, fortified grains) do not significantly interact but may reduce efficacy; maintain consistent intake. 4. No specific grapefruit interaction reported. |
| Clinical Pearls | 1. Folinic acid (leucovorin) rescue is mandatory 24 hours after high-dose methotrexate to prevent severe toxicity. 2. Monitor renal function, liver enzymes, and complete blood count closely. 3. Avoid NSAIDs and nephrotoxic drugs which reduce methotrexate clearance. 4. Hydrate aggressively (≥3 L/m²/day) and alkalinize urine (pH ≥7) to prevent precipitation. 5. Intrathecal methotrexate requires preservative-free formulation. |
| Patient Advice | Take methotrexate exactly once weekly for rheumatoid arthritis or psoriasis; never take daily. · Avoid alcohol completely due to hepatotoxicity risk. · Use effective contraception during therapy and for at least 3 months after stopping (men and women). · Report any signs of infection (fever, sore throat), unusual bleeding/bruising, mouth sores, or shortness of breath. · Do not take ibuprofen, naproxen, or other NSAIDs without consulting your doctor. |