METHOTREXATE SODIUM PRESERVATIVE FREE
Clinical safety rating: avoid
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
Methotrexate is a folate analog that inhibits dihydrofolate reductase (DHFR), preventing the conversion of dihydrofolate to tetrahydrofolate, thereby interfering with DNA synthesis, repair, and cellular replication. It also inhibits thymidylate synthase and purine biosynthesis, and has immunosuppressive and anti-inflammatory effects mediated by adenosine release.
| Metabolism | Primarily hepatic metabolism via aldehyde oxidase (AOX) and xanthine oxidase (XO) to 7-hydroxymethotrexate. Also undergoes hydrolysis to 4-amino-4-deoxy-N10-methylpteroic acid (DAMPA) by carboxypeptidase G2 in the gut. Polyglutamation in cells enhances retention and activity. Renal excretion is the primary route of elimination. |
| Excretion | Primarily renal (80-90% excreted unchanged via glomerular filtration and active tubular secretion). Biliary/fecal elimination accounts for <10%. |
| Half-life | Terminal elimination half-life is 8-15 hours at standard doses; with high-dose therapy (>1 g/m²), half-life extends to 12-24 hours due to saturation of excretion pathways and potential third-space accumulation. |
| Protein binding | Approximately 50-60% bound, primarily to albumin. |
| Volume of Distribution | 0.4-0.8 L/kg. Total body water distribution with higher concentrations in kidneys, liver, and third-space fluids (e.g., pleural effusions, ascites) which can act as reservoirs, prolonging half-life. |
| Bioavailability | Oral: 20-100% (dose-dependent; saturable absorption above 25 mg/m²). Subcutaneous/Intramuscular: ~90% (more consistent than oral). Intravenous: 100%. |
| Onset of Action | Oral: 30-60 minutes. Intramuscular/Subcutaneous: 30-60 minutes. Intravenous: Immediate. Intrathecal: Within 30 minutes. |
| Duration of Action | Antirheumatic effect: 1 week (weekly dosing). Antineoplastic effect: Dose-dependent; typically 24-72 hours. Leucovorin rescue for high-dose methotrexate continues until plasma levels <0.05 µmol/L (usually 72-96 hours post-infusion). |
| Molecular Weight | 454.44 |
15-25 mg once weekly orally or intramuscularly for rheumatoid arthritis; 50-75 mg/m2 once weekly intravenously for single-agent acute lymphoblastic leukemia maintenance; 50 mg/m2 intravenously every 2-4 weeks for ectopic pregnancy; 30-40 mg/m2 intravenously once weekly for psoriasis. Dosing varies by indication.
| Dosage form | INJECTABLE |
| Renal impairment | GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: contraindicated due to tubular precipitation risk. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50%; Class C: contraindicated. |
| Pediatric use | For acute lymphoblastic leukemia (ALL) maintenance: 15-30 mg/m2 orally or intramuscularly once weekly. For juvenile idiopathic arthritis: 10-15 mg/m2 once weekly orally or subcutaneously. Maximum single dose: 25 mg. |
| Geriatric use | Initiate at lowest adult dose (e.g., 7.5 mg weekly for rheumatoid arthritis), titrate slowly due to increased risk of renal impairment, myelosuppression, and mucositis. Monitor renal function and blood counts closely. |
| 1st trimester | Contraindicated due to teratogenicity (FDA Pregnancy Category X). Causes fetal death, craniofacial defects, limb abnormalities, and neural tube defects. |
| 2nd trimester | Contraindicated. Continued risk of fetal growth restriction, developmental delay, and oligohydramnios due to folate antagonism. |
| 3rd trimester | Contraindicated. Risk of neonatal myelosuppression, immunosuppression, and folate deficiency. Use alternative therapies if possible. |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| FDA category | Contraindicated |
| Placental transfer | Methotrexate actively crosses the placenta via folate transporters. Fetal concentrations can exceed maternal levels. Placental transfer is high, especially in early gestation. |
■ FDA Black Box Warning
Methotrexate can cause severe or fatal toxicities: 1) Severe bone marrow suppression, anemia, aplastic anemia, leukopenia, neutropenia, thrombocytopenia. 2) Hepatotoxicity including fibrosis and cirrhosis. 3) Pulmonary fibrosis, interstitial pneumonitis. 4) Renal failure. 5) Gastrointestinal ulceration and hemorrhage. 6) Intrathecal use can cause neurotoxicity, acute chemical arachnoiditis, chronic leukoencephalopathy. 7) Fetal death or congenital anomalies. 8) Severe mucositis and dermatologic reactions. 9) Immunosuppression leading to serious infections. 10) Tumor lysis syndrome. 11) Hypersensitivity reactions, including anaphylaxis.
| Common Effects | certain cancers |
| Serious Effects |
PregnancyBreastfeedingSevere renal impairment (CrCl <10 mL/min)Severe hepatic impairment (Child-Pugh C)Preexisting blood dyscrasias (e.g., pancytopenia, bone marrow aplasia)Active infection (especially tuberculosis, HIV, hepatitis)Hypersensitivity to methotrexate or any component
| Precautions | Monitor CBC, liver function, renal function, and chest X-ray. Avoid in pregnancy. Use leucovorin rescue with high-dose therapy. Avoid NSAIDs, salicylates, sulfonamides, and nephrotoxic drugs due to decreased clearance. Monitor for neurotoxicity with intrathecal use. Contraception required during and for 3 months after treatment for both men and women. Risk of progressive multifocal leukoencephalopathy (PML). Risk of opportunistic infections. Avoid live vaccines. |
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| Breastfeeding | Methotrexate is excreted into human milk in low concentrations but accumulates in neonatal tissues due to immature renal function. Theoretical risk of immunosuppression, neutropenia, and developmental toxicity. Manufacturers recommend discontinuing breastfeeding or the drug. The American Academy of Pediatrics considers it contraindicated during breastfeeding. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Methotrexate is contraindicated in pregnancy. It is a known teratogen with high risk of fetal death and major congenital malformations, including craniofacial, cardiac, and central nervous system defects, especially if exposed during the first trimester. Second and third trimester exposure may lead to growth restriction, developmental delay, and methotrexate-related fetal toxicity. |
| Fetal Monitoring | In cases where methotrexate is used in childbearing potential women, regular pregnancy testing is essential. Liver function tests, renal function tests, complete blood counts, and pulmonary function tests should be monitored. Fetal ultrasound and echocardiography if exposure occurs. Consider methotrexate levels if toxicity suspected. |
| Fertility Effects | Methotrexate may cause reversible oligospermia in men and menstrual dysfunction, ovarian failure, or premature menopause in women. Fertility may be reduced during therapy but often returns after discontinuation. No long-term permanent infertility is typical unless high cumulative doses are used. |
| Food/Dietary | Avoid alcohol; may increase hepatotoxicity. Limit caffeine intake; may reduce methotrexate efficacy. Avoid foods fortified with folic acid (e.g., cereals, bread) as they may interfere with methotrexate action. No significant food-drug interactions beyond alcohol and folate-rich foods. |
| Clinical Pearls | For high-dose MTX (>=500 mg/m2), mandatory leucovorin rescue begins 24-36 hours after start; monitor MTX levels daily until <0.1 µmol/L. Avoid concomitant NSAIDs, salicylates, sulfonamides, and probenecid due to reduced renal clearance. Pre-hydrate (3 L/m2/day) and alkalinize urine (pH >= 7.0) to prevent nephrotoxicity. Intrathecal MTX may cause neurotoxicity; consider leucovorin rescue for systemic toxicity only. Use folic acid supplementation (1 mg daily) to reduce GI and hematologic toxicity in low-dose regimens. |
| Patient Advice | Avoid alcohol, NSAIDs (ibuprofen, naproxen), and aspirin while on methotrexate. · Do not become pregnant; use reliable contraception during and for at least 3 months after therapy. · Report any signs of infection, unusual bleeding, or mouth ulcers immediately. · Take folic acid as prescribed on days not taking methotrexate. · Stay well hydrated; drink at least 8-10 glasses of water daily. |