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. |
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 | 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.
| FDA category | Contraindicated |
| Breastfeeding | METHOTREXATE SODIUM is contraindicated during breastfeeding due to potential serious adverse reactions in nursing infants. M/P ratio: Not established; drug partitions into breast milk with milk levels averaging 0.9% of maternal dose (range 0.2-8.9%). Long half-life and active metabolites increase risk of accumulation in infants. |
| Teratogenic Risk |
■ 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 |
Pregnancy (Category X), severe renal impairment (CrCl <10 mL/min), severe hepatic impairment, alcoholism, pre-existing blood dyscrasias (such as leukopenia, thrombocytopenia, anemia), breastfeeding, known hypersensitivity 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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| 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. |