MEXATE-AQ
Clinical safety rating: caution
Comprehensive clinical and safety monograph for MEXATE-AQ (MEXATE-AQ).
Methotrexate is a folate analog that inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate, which is required for the synthesis of purines and pyrimidines. This leads to inhibition of DNA, RNA, and protein synthesis, particularly in rapidly dividing cells. It also has immunosuppressive effects via inhibition of T cell activation and reduction of inflammatory cytokines.
| Metabolism | Metabolized primarily in the liver to polyglutamates (which are active metabolites) via folylpolyglutamate synthetase. Partial metabolism via aldehyde oxidase and xanthine oxidase to 7-hydroxymethotrexate. Methotrexate is also partially metabolized by intestinal flora. Elimination is primarily renal via glomerular filtration and active tubular secretion. |
| Excretion | Renal excretion predominates (80-90% as unchanged drug) via glomerular filtration and active tubular secretion. Biliary/fecal elimination is minor (<10%). |
| Half-life | Terminal elimination half-life is approximately 3–10 hours for low doses (<30 mg/m²) and 8–15 hours for high doses (>80 mg/m²). Prolonged to 48–72 hours in patients with third-space effusions or renal impairment. |
| Protein binding | Approximately 50–60% bound primarily to albumin. Weakly bound and readily displaceable by other drugs. |
| Volume of Distribution | Vd: 0.4–0.8 L/kg (initial 0.18 L/kg, steady-state 0.4–0.8 L/kg). Distributes into third-space fluids (pleural, ascitic), leading to prolonged elimination. |
| Bioavailability | Oral: 30–60% (dose-dependent; saturable absorption at high doses). Intramuscular: 80–100%. Subcutaneous: approximately 90%. |
| Onset of Action | Oral: 30–60 minutes; Intramuscular: 30–60 minutes; Intravenous: 5–10 minutes; Intrathecal: 5–15 minutes. |
| Duration of Action | Duration of antimitotic effect: 1–3 days after a single dose. Weekly dosing schedule for rheumatoid arthritis due to prolonged suppression of inflammatory mediators. |
Methotrexate: 7.5-25 mg orally once weekly for rheumatoid arthritis; 30-40 mg/m2 IV weekly for mycosis fungoides; 50-75 mg/m2 IV over 4-6 hours weekly for osteosarcoma; 15-20 mg/m2 IM weekly for psoriasis.
| Dosage form | INJECTABLE |
| Renal impairment | For GFR 40-59 mL/min: reduce dose by 20%; GFR 20-39 mL/min: reduce dose by 40%; GFR <20 mL/min: contraindicated. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | For acute lymphoblastic leukemia (ALL): 15-20 mg/m2 IM once weekly as maintenance; for osteosarcoma: 12 g/m2 IV over 4 hours with leucovorin rescue. |
| Geriatric use | Start at lowest recommended dose (e.g., 5 mg orally once weekly) with careful monitoring for renal function, hepatic function, and folate levels; adjust based on tolerance. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for MEXATE-AQ (MEXATE-AQ).
| Breastfeeding | Contraindicated. Methotrexate is excreted in breast milk; accumulation may occur in nursing infants due to immature renal function. M/P ratio not established; theoretical risk of serious adverse effects. |
| Teratogenic Risk | FDA Pregnancy Category X. First trimester: High risk of miscarriage, CNS defects, craniofacial anomalies. Second trimester: IUGR, skeletal abnormalities. Third trimester: Neonatal bone marrow suppression, immunosuppression. |
| Fetal Monitoring |
■ FDA Black Box Warning
Boxed Warning: Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women. It is contraindicated in pregnant women with psoriasis or RA. It also has a boxed warning for severe toxicity and death due to inadvertent daily (as opposed to weekly) dosing; hepatic toxicity, including acute hepatitis and chronic hepatic fibrosis; myelosuppression, including severe bone marrow suppression; and pulmonary toxicity, including acute or chronic interstitial pneumonitis. Additionally, anaphylactic reactions can occur. For patients with psoriasis, methotrexate should be used only for severe, recalcitrant cases unresponsive to other therapy.
| Serious Effects |
["Hypersensitivity to methotrexate or any component of the formulation.","Pregnancy and breastfeeding (due to risk of fetal death/teratogenicity and excretion in breast milk).","Patients with psoriasis or RA who have alcoholism, alcoholic liver disease, chronic liver disease, or overt immunodeficiency.","Pre-existing blood dyscrasias (severe anemia, leukopenia, neutropenia, thrombocytopenia).","Concomitant use with live vaccines."]
| Precautions | ["Fatal toxicities (including hematologic, hepatic, pulmonary, renal, dermatologic, and GI) can occur with methotrexate; monitor closely.","Hepatic toxicity: Monitor liver function tests; avoid or use with caution in patients with active liver disease or alcohol abuse.","Pulmonary toxicity: Acute or chronic interstitial pneumonitis may occur; monitor for cough, fever, dyspnea, and hypoxia.","Myelosuppression: Monitor CBC and platelet counts regularly; severe pancytopenia can occur.","Renal toxicity: Adequate renal function is essential; avoid NSAIDs, salicylates, and other nephrotoxic drugs if possible.","Gastrointestinal toxicity: Mucositis, ulcerative stomatitis, diarrhea, and hemorrhagic enteritis may occur.","Dermatologic toxicity: Phototoxicity, radiation recall, and severe skin reactions (including Stevens-Johnson syndrome) can occur.","Immunosuppression: Increased risk of infections, including opportunistic infections; avoid live vaccines.","Carcinogenicity: Increased risk of lymphoproliferative disorders (may be reversible with discontinuation).","Concomitant use with proton pump inhibitors (PPIs) may increase methotrexate levels."] |
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| Monitor CBC with differential, LFTs, renal function, and serum methotrexate levels weekly. Fetal ultrasound for growth and anatomy; amniocentesis if needed for karyotyping. |
| Fertility Effects | May cause oligospermia or amenorrhea. Reversible upon discontinuation; however, pre-existing gonadal dysfunction may persist. Advise contraception during therapy and for 3 months after last dose. |