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 |
| Molecular Weight | 454.44 |
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 | Contraindicated. Teratogenic effects including neural tube defects, craniofacial anomalies, and cardiovascular malformations. Pregnancy must be excluded before initiation. |
| 2nd trimester | Contraindicated. Risk of fetal growth restriction and developmental toxicity. |
| 3rd trimester | Contraindicated. Risk of neonatal myelosuppression, infections, and pulmonary toxicity. |
Clinical note
Comprehensive clinical and safety monograph for TREXALL (TREXALL).
| Placental transfer | Active placental transport via reduced folate carrier. Cord blood concentrations approximately 10% of maternal levels; significant accumulation in fetal tissues. |
| Breastfeeding | Methotrexate is excreted into breast milk in low concentrations but may accumulate in infant tissues. Use during breastfeeding is contraindicated due to potential for serious adverse effects (e.g., immunosuppression, gastrointestinal toxicity, developmental delay). |
■ 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 |
PregnancyBreastfeedingSevere hepatic impairmentSevere renal impairment (CrCl < 30 mL/min)Pre-existing blood dyscrasias (e.g., significant anemia, leukopenia, thrombocytopenia)Active serious infectionsAlcoholism or alcoholic liver diseaseKnown hypersensitivity to methotrexate
| Precautions | 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. |
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| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| Food/Dietary | Avoid alcohol due to hepatotoxicity. Limit caffeine as it may interfere with absorption. Foods rich in folate (e.g., leafy greens, legumes) may theoretically reduce efficacy but should not be restricted; instead, folic acid supplementation is recommended. Avoid grapefruit juice as it may increase methotrexate levels. Maintain adequate hydration to prevent renal toxicity. |
| Clinical Pearls | TREXALL (methotrexate) is a folate analog antimetabolite. Use folic acid supplementation to reduce toxicity. Avoid concomitant use of NSAIDs, probenecid, and trimethoprim-sulfamethoxazole due to increased methotrexate levels. Monitor LFTs, renal function, and CBC regularly. Screen for hepatitis B and C before initiation. Hydrate aggressively and alkalinize urine to prevent precipitation of methotrexate and its metabolites in renal tubules. Administer once weekly for non-oncologic indications; serious toxicity can result from daily dosing. |
| Patient Advice | Take exactly as prescribed, usually once a week for conditions like rheumatoid arthritis or psoriasis. · Do not take daily; accidental daily dosing can be fatal. · Take folic acid as directed to reduce side effects like mouth sores and nausea. · Avoid alcohol completely due to risk of hepatotoxicity. · Report any signs of infection (fever, sore throat), unusual bruising or bleeding, or persistent cough. · Use effective contraception during therapy and for at least 3 months after discontinuation. · Avoid sun exposure and use sunscreen, as sun sensitivity may occur. · Notify all healthcare providers you are taking methotrexate, especially before procedures or vaccinations. · Do not take NSAIDs (ibuprofen, naproxen) without discussing with your doctor. · Store at room temperature, away from light and moisture. |