MEXATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for MEXATE (MEXATE).
MEXATE is an antimetabolite that inhibits dihydrofolate reductase (DHFR), reducing tetrahydrofolate synthesis and interfering with DNA, RNA, and protein synthesis. It also inhibits thymidylate synthetase and has immunomodulatory and anti-inflammatory effects.
| Metabolism | Methotrexate is primarily metabolized by hepatic aldehyde oxidase to 7-hydroxymethotrexate. It undergoes polyglutamation intracellularly. Less than 10% is metabolized by cytochrome P450 enzymes. Excretion is primarily renal via glomerular filtration and active tubular secretion. |
| Excretion | Renal excretion of unchanged drug is the primary route of elimination, accounting for 80-90% of the dose. Biliary/fecal excretion is minor (<10%). |
| Half-life | Terminal elimination half-life is 3-10 hours for low-dose therapy (≤30 mg/m²). For high-dose therapy (>100 mg/m²), terminal half-life extends to 8-15 hours due to saturable elimination. A third, prolonged terminal phase (8-72 hours) is observed in some patients due to enterohepatic recirculation. |
| Protein binding | 50-60% bound, primarily to albumin. |
| Volume of Distribution | 0.4-0.8 L/kg (total body water). Vd increases with dose, indicating tissue distribution. |
| Bioavailability | Oral: 30-70% (dose-dependent, saturable absorption). Intramuscular: 80-100%. Subcutaneous: approximately 100%. |
| Onset of Action | Oral: 30-60 minutes to therapeutic effect. Intramuscular: 30-60 minutes. Intravenous: immediate (within minutes). Intrathecal: 15-30 minutes. |
| Duration of Action | Clinical effects persist for 1-3 days depending on dose and route. Weekly low-dose therapy (e.g., for rheumatoid arthritis) shows sustained suppression of inflammation up to 1 week. Antineoplastic effects persist over the dosing interval. |
| Action Class | Antimetabolite- Methotrexate |
| Brand Substitutes | MEXATE 25 MG INJECTION, Folitrax 25 Injection, Mexate 25mg Injection |
10-25 mg/m2 orally or intramuscularly once weekly for rheumatoid arthritis; 50 mg/m2 intravenously once weekly for psoriasis; 30-40 mg/m2 intravenously weekly for certain cancers (dose varies by protocol).
| Dosage form | INJECTABLE |
| Renal impairment | GFR >50 mL/min: no adjustment; GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: avoid use. |
| Liver impairment | Child-Pugh A: 75% of normal dose; Child-Pugh B: 50% of normal dose; Child-Pugh C: contraindicated. |
| Pediatric use | For leukemia: 20-40 mg/m2 orally or intravenously once weekly; for juvenile idiopathic arthritis: 10-15 mg/m2 orally once weekly (max 25 mg/week). |
| Geriatric use | Start at lowest effective dose (e.g., 5-7.5 mg/week) with close monitoring of renal function, hepatic function, and hematologic parameters due to increased toxicity risk. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for MEXATE (MEXATE).
| Breastfeeding | Contraindicated. Methotrexate is excreted in human milk; M/P ratio approximately 0.08. Potential for severe neonatal toxicity. |
| Teratogenic Risk | Category X. 1st trimester: High risk of CNS, craniofacial, and skeletal malformations. 2nd and 3rd trimesters: Fetal growth restriction, oligohydramnios, and neonatal pancytopenia. |
| Fetal Monitoring | Weekly CBC, liver and renal function tests. Fetal ultrasound for growth and amniotic fluid volume every 4 weeks. |
■ FDA Black Box Warning
Boxed Warning: Methotrexate (MEXATE) can cause severe or fatal toxicities including bone marrow suppression, hepatic fibrosis/cirrhosis, pulmonary fibrosis, renal failure, and ulcerative stomatitis. Fatalities have been reported with inadvertent daily dosing instead of weekly. For rheumatoid arthritis and psoriasis, use only in patients with severe disease. Monitor for toxicity closely. Advise patients about risks of fatal toxicity.
| Serious Effects |
Hypersensitivity to methotrexate, alcohol abuse, pre-existing liver disease (including hepatitis), renal impairment (creatinine clearance < 60 mL/min), pre-existing bone marrow suppression, immunodeficiency, active infections (e.g., tuberculosis), pregnancy, breastfeeding, lactation.
| Precautions | Severe hematologic toxicity (bone marrow suppression, pancytopenia), hepatotoxicity (fibrosis, cirrhosis, acute hepatitis), pulmonary toxicity (pneumonitis, fibrosis), renal toxicity, gastrointestinal toxicity (stomatitis, ulceration), neurotoxicity (leukoencephalopathy), opportunistic infections, tumor lysis syndrome, photosensitivity, and dermatologic reactions. Avoid concomitant NSAIDs, salicylates, and nephrotoxic drugs. Monitor CBC, LFTs, creatinine, and chest imaging. Use caution in elderly, debilitated, or patients with renal impairment, ascites, or pleural effusions. |
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| Fertility Effects | May cause reversible oligospermia or amenorrhea. Risk of gonadal suppression with prolonged use. |