METHOTREXATE SODIUM
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), blocking the conversion of dihydrofolate to tetrahydrofolate, thereby interfering with purine and pyrimidine synthesis, leading to inhibition of DNA replication and cell proliferation. It also has immunomodulatory effects via adenosine release.
| Metabolism | Primarily hepatic metabolism to polyglutamated forms. Small amount undergoes oxidation to 7-hydroxymethotrexate. Eliminated primarily via renal excretion (active tubular secretion). |
| Excretion | Renal excretion accounts for 80-90% of elimination via glomerular filtration and active tubular secretion; biliary/fecal excretion accounts for 10-20%. |
| Half-life | Terminal elimination half-life is 3-10 hours for low doses (≤50 mg/m²) and 8-15 hours for high doses (>50 mg/m²); in chronic therapy for rheumatoid arthritis, the half-life is approximately 5-8 hours. |
| Protein binding | Approximately 50% bound to albumin, primarily to albumin; binding can be displaced by various drugs. |
| Volume of Distribution | Volume of distribution is 0.4-0.8 L/kg, indicating distribution into total body water with some extravascular binding; higher Vd in high-dose therapy (up to 1.5 L/kg) due to tissue accumulation. |
| Bioavailability | Oral bioavailability is dose-dependent: 60-70% for doses <15 mg/m², decreasing to 20-30% for doses >80 mg/m². IM/SC bioavailability is nearly 100%. |
| Onset of Action | Oral: 30-60 minutes for antirheumatic effect; IM/IV: immediate (within minutes) for chemotherapy; Intrathecal: variable, typically within 1-2 hours. |
| Duration of Action | Duration of therapeutic effect: 24-48 hours for low doses; for high-dose methotrexate, duration of cytotoxic effect extends to 72-96 hours. Clinical effects in rheumatoid arthritis may last 1-2 weeks after a single dose. |
| Molecular Weight | 454.44 |
10-25 mg orally, intramuscularly, intravenously, or subcutaneously once weekly for rheumatoid arthritis; 7.5-15 mg orally once weekly for psoriasis. For oncology regimens, dosing varies (e.g., 50 mg/m² IV once weekly, or 1-5 g/m² IV with leucovorin rescue).
| Dosage form | Injectable |
| Renal impairment | CrCl 61-80 mL/min: no adjustment; CrCl 51-60 mL/min: reduce dose by 25%; CrCl 10-50 mL/min: reduce dose by 50%; CrCl <10 mL/min: avoid use (or use with extreme caution with dose reduction >50%). |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use. |
| Pediatric use | Juvenile idiopathic arthritis: 10-15 mg/m² orally or subcutaneously once weekly; acute lymphoblastic leukemia: induction 3.3 mg/m² intramuscularly or intravenously daily for 4-6 weeks, then maintenance 20-40 mg/m² orally or intramuscularly weekly. |
| Geriatric use | Start at low end of dosing range (e.g., 5-7.5 mg once weekly), monitor renal function closely, consider folic acid 1 mg daily to reduce toxicity. |
| 1st trimester | Contraindicated; teratogenic (major malformations, spontaneous abortion). Use only for life-threatening conditions with strict contraception. |
| 2nd trimester | Avoid; risk of fetal growth restriction, skeletal abnormalities, and CNS effects. Use only if benefit outweighs risk. |
| 3rd trimester | Avoid; risk of neonatal myelosuppression, immunosuppression, and gastrointestinal toxicity. Discontinue before delivery if possible. |
Clinical note
NSAIDs and probenecid can decrease renal excretion and increase levels Can cause myelosuppression and hepatotoxicity.
| FDA category | Contraindicated |
| Placental transfer | Extensive; actively transported across placenta via folate receptors and reduced folate carrier. Fetal concentrations exceed maternal levels. |
■ FDA Black Box Warning
Methotrexate can cause severe or fatal toxicities (e.g., bone marrow suppression, hepatotoxicity, pulmonary fibrosis, renal failure, gastrointestinal ulceration). Should be prescribed only by physicians experienced in antimetabolite therapy. Fatal reactions have been reported with concurrent NSAIDs. Do not use in pregnant women (teratogenic). Patients must be monitored for toxicity.
| Common Effects | certain cancers |
| Serious Effects |
PregnancyBreastfeedingSevere renal impairment (CrCl <10 mL/min)Severe hepatic impairmentPre-existing blood dyscrasias (eg, severe anemia, leukopenia, thrombocytopenia)Active infectionAlcoholism or alcoholic liver diseaseHypersensitivity to methotrexate
| Precautions | Hepatotoxicity (monitor LFTs), pulmonary toxicity (acute or chronic interstitial pneumonitis), bone marrow suppression (monitor CBC), renal impairment (dose adjustment), GI toxicity, dermatologic reactions, immunosuppression with increased infection risk, tumor lysis syndrome (in hematologic malignancies). Avoid live vaccines. Use with caution in patients with ascites or pleural effusion. |
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| Breastfeeding |
| Methotrexate is excreted in breast milk in low concentrations; however, due to potential for serious adverse effects (eg, immunosuppression, neutropenia, gastrointestinal toxicity) in the nursing infant, breastfeeding is generally not recommended. The American Academy of Pediatrics considers it contraindicated during breastfeeding. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | METHOTREXATE SODIUM is contraindicated in pregnancy. First trimester: High risk of miscarriage, craniofacial defects, CNS abnormalities, and skeletal anomalies. Second and third trimesters: Fetal growth restriction, neurodevelopmental delay, and potential for neonatal myelosuppression. Fetal methotrexate syndrome described with characteristic anomalies. |
| Fetal Monitoring | Pre-treatment: Pregnancy test, complete blood count, liver function tests, renal function, chest X-ray. During therapy: Weekly CBC, LFTs, creatinine; monitor for stomatitis, mucositis, pulmonary toxicity, and infection. Fetal monitoring: Serial ultrasound for growth and anatomy if exposure occurs. Avoid use without effective contraception. |
| Fertility Effects | Methotrexate can cause reversible oligospermia, impaired spermatogenesis, menstrual dysfunction, and anovulation in females. High doses may lead to permanent ovarian failure. Effects on male fertility: Reduced sperm count and motility; usually reversible after 2 months post-therapy. |
| Food/Dietary | Caffeine may reduce methotrexate efficacy; limit intake. Alcohol increases hepatotoxicity risk; avoid entirely while on therapy. Folic acid-rich foods (leafy greens, beans) may interfere with absorption if taken concurrently; take folic acid supplement at a different time. Grapefruit juice may increase methotrexate levels; avoid excessive consumption. Maintain adequate hydration; avoid dehydration. |
| Clinical Pearls | Monitor liver function tests and creatinine at baseline and monthly; folate supplementation reduces toxicity without compromising efficacy; held in active infections; contraindicated in pregnancy (X category); use leukovorin rescue in high-dose regimens; reduce dose in renal impairment (CrCl <60 mL/min); avoid NSAIDs as they reduce methotrexate clearance; pulmonary toxicity (cough, fever, dyspnea) may occur even at low doses; intrathecal overdose requires immediate cerebrospinal fluid drainage and high-dose leucovorin. |
| Patient Advice | Take exactly as prescribed; do not adjust dose without consulting your doctor. · Avoid alcohol completely due to increased risk of liver damage. · Use effective contraception during treatment and for at least 3 months after stopping. · Notify your doctor immediately if you develop cough, fever, shortness of breath, or unusual bleeding/brusing. · Do not take NSAIDs (e.g., ibuprofen, naproxen) unless directed by your physician. · Take folic acid supplements as prescribed to reduce side effects. · Stay well hydrated; drink at least 2-3 liters of water daily unless fluid restricted. · Avoid live vaccines (e.g., MMR, varicella, nasal flu) during treatment. · Report any signs of infection (fever, sore throat, chills) promptly. · Do not become pregnant; methotrexate can cause severe birth defects. |