TREXALL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TREXALL (TREXALL).
Methotrexate is a folate analog that inhibits dihydrofolate reductase, preventing the conversion of folic acid to tetrahydrofolate, thereby inhibiting DNA synthesis, repair, and cellular replication. It also has immunomodulatory and anti-inflammatory effects through inhibition of purine and pyrimidine synthesis and release of adenosine.
| Metabolism | Primarily hepatic and intracellular metabolism to polyglutamate forms. Undergoes minimal CYP450 metabolism. Excreted predominantly unchanged in urine via glomerular filtration and tubular secretion. Small amounts excreted in feces. |
| Excretion | Renal excretion of unchanged drug accounts for 80-90% of elimination; biliary/fecal elimination is minor (<10%) |
| Half-life | Terminal elimination half-life is 3-10 hours; for high-dose methotrexate, half-life is 8-15 hours. Clinically, monitoring at 24, 48, and 72 hours is standard to guide leucovorin rescue |
| Protein binding | Approximately 50% bound to albumin |
| Volume of Distribution | 0.4-0.8 L/kg; distributes into third-space fluids (pleural, peritoneal), which can prolong elimination |
| Bioavailability | Oral: 60-70% (dose-dependent, saturable absorption); IM: 100% |
| Onset of Action | Oral: 30-60 minutes; IM: 30-60 minutes; IV: immediate; intrathecal: immediate |
| Duration of Action | Duration of antineoplastic effect persists as long as intracellular polyglutamates remain; clinical effects last 1-2 weeks. Methotrexate is retained in tissues for weeks to months |
Oral: 7.5-15 mg once weekly; subcutaneous: 7.5-15 mg once weekly for rheumatoid arthritis; may be increased up to 25-30 mg weekly based on response and tolerability.
| Dosage form | TABLET |
| Renal impairment | GFR 30-60 mL/min: reduce dose by 50%; GFR <30 mL/min: contraindicated. |
| 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 (max 25 mg). |
| Geriatric use | Use lower initial doses (e.g., 5-7.5 mg weekly) and titrate slowly due to increased risk of toxicity, especially myelosuppression and hepatotoxicity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TREXALL (TREXALL).
| Breastfeeding | Methotrexate is excreted into breast milk in low concentrations (M/P ratio ~0.08). However, due to potential for accumulation and adverse effects (e.g., neutropenia, gastrointestinal toxicity) in the nursing infant, breastfeeding is contraindicated during methotrexate therapy. Discontinue breastfeeding for at least one week after last dose. |
| Teratogenic Risk | TREXALL (methotrexate) is contraindicated in pregnancy. First trimester exposure is associated with a high risk of spontaneous abortion, craniofacial defects, limb deformities, and central nervous system abnormalities (methotrexate embryopathy). Second and third trimester use may cause fetal growth restriction, oligohydramnios, and neonatal myelosuppression. Folinic acid rescue does not eliminate risk. |
■ FDA Black Box Warning
Severe toxicity, including death, has occurred with methotrexate use. Significant toxicities include: (1) Hepatotoxicity: fibrosis and cirrhosis, especially with prolonged use. (2) Pulmonary toxicity: acute or chronic interstitial pneumonitis, sometimes fatal. (3) Myelosuppression: leukopenia, thrombocytopenia, anemia, pancytopenia. (4) Renal toxicity: acute renal failure, especially at high doses. (5) Gastrointestinal toxicity: ulcerative stomatitis, hemorrhagic enteritis, intestinal perforation. (6) Infection: increased risk of opportunistic infections. (7) Malignancy: lymphoma and other neoplasms. (8) Fetal toxicity: contraindicated in pregnancy. (9) Death: due to hematologic, hepatic, renal, gastrointestinal, or pulmonary toxicity. Monitor closely and adjust dose or discontinue if toxicity occurs. Use only by physicians experienced in antimetabolite therapy and familiar with the risks and monitoring requirements.
| Serious Effects |
["Absolute: Pregnancy (Category X), breastfeeding, severe hepatic impairment (active hepatitis, cirrhosis, history of alcoholism related liver disease), severe renal impairment (eGFR < 30 mL/min/1.73 m²), pre-existing profound myelosuppression (WBC < 3000/mm³, platelets < 100,000/mm³), hypersensitivity to methotrexate.","Relative: Active infection, immunodeficiency syndromes, peptic ulcer disease, ulcerative colitis, advanced age, poor performance status, significant pleural or peritoneal effusions (may accumulate and cause toxicity)."]
| Precautions |
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| Fetal Monitoring | Monitor complete blood count, liver function tests, renal function, and serum methotrexate levels weekly during dose titration and monthly thereafter. In pregnant patients (if inadvertent exposure), perform high-resolution ultrasound and fetal echocardiography. Monitor for signs of myelosuppression, hepatotoxicity, and pulmonary toxicity in the mother. |
| Fertility Effects | Methotrexate can cause reversible oligospermia and menstrual dysfunction. Both male and female fertility may be impaired during therapy; effects are typically reversible after discontinuation. Cases of transient infertility have been reported. Preconception counseling is recommended. |
| ["Hepatic toxicity: monitor liver enzymes and albumin; avoid in active liver disease or alcoholism; perform liver biopsy as indicated.","Pulmonary toxicity: acute or chronic interstitial pneumonitis; monitor for cough, fever, dyspnea; discontinue if suspected.","Myelosuppression: monitor CBC; dose reduction or discontinuation for severe cytopenias.","Renal toxicity: risk increased with high doses and concurrent nephrotoxic drugs; ensure adequate hydration and alkalinization of urine for high-dose therapy.","Gastrointestinal toxicity: stomatitis, oral ulcers, diarrhea; may require dose reduction.","Infection: increased susceptibility; avoid live vaccines.","Malignancy: lymphoproliferative disease may regress after discontinuation.","Tumor lysis syndrome: risk in patients with rapidly growing tumors.","Fetal toxicity: teratogenic; contraindicated in pregnancy; women of childbearing potential should use effective contraception.","Concomitant drugs: increased toxicity with NSAIDs, probenecid, salicylates, sulfonamides, and other folate antagonists.","Immunization: avoid live vaccines.","Carcinogenicity: may increase risk of secondary malignancies.","Radiation therapy: may increase risk of soft tissue necrosis."] |