MEXATE-AQ
Clinical safety rating
cautionComprehensive clinical and safety monograph for MEXATE-AQ (MEXATE-AQ).
Comprehensive clinical and safety monograph for MEXATE-AQ (MEXATE-AQ).
FDA-approved: Chemotherapy for gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphocytic leukemia, meningeal leukemia, breast cancer, head and neck cancer, cutaneous T-cell lymphoma, lung cancer, non-Hodgkin's lymphoma, osteosarcoma, and mycosis fungoides.FDA-approved: Severe, active rheumatoid arthritis (RA) in adults who have failed first-line therapy.FDA-approved: Pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) who have failed first-line therapy.FDA-approved: Psoriasis (severe, recalcitrant) in adults.Off-label: Prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation.Off-label: Crohn's disease (maintenance of remission in steroid-dependent patients).Off-label: Ectopic pregnancy (medical management).
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. |
| Molecular Weight | 454.44 |
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 | Contraindicated; teratogenic (neural tube defects, craniofacial anomalies). Use only for life-threatening conditions. |
| 2nd trimester | Contraindicated; risk of fetal growth restriction and neurodevelopmental impairment. |
| 3rd trimester | Contraindicated; risk of neonatal myelosuppression and immunosuppression. |
Clinical note
Comprehensive clinical and safety monograph for MEXATE-AQ (MEXATE-AQ).
| Placental transfer | Active transfer; methotrexate crosses the placenta via passive diffusion and active transport (folate carrier). Achieves fetal concentrations 2-3 times maternal levels. |
| Breastfeeding | Methotrexate is excreted into breast milk in low concentrations, but accumulates in neonatal tissues due to immature clearance. Breastfeeding is contraindicated due to potential toxicity (e.g., myelosuppression, gastrointestinal ulceration). Discontinue breastfeeding during therapy and for at least 1 week after last dose. |
| Lactation Rating | L5 (Contraindicated) |
| 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 | 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. |
■ 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 |
PregnancyBreastfeedingSevere renal impairment (CrCl <10 mL/min)Severe hepatic impairment (Child-Pugh C)Active alcoholismPre-existing immunodeficiency syndromesMucositis or oral ulcerationSignificant thrombocytopenia (platelets <50,000/μL) or neutropenia (ANC <1,000/μL)
| 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. |
| Food/Dietary | Avoid folic acid-rich foods (leafy greens, fortified grains) in large amounts during methotrexate therapy as they may reduce efficacy. No specific food-drug interactions; maintain a well-balanced diet. |
| Clinical Pearls | Mexate-AQ (methotrexate) requires folic acid supplementation to reduce gastrointestinal and hematologic toxicity. Administer leucovorin rescue after high-dose therapy. Avoid NSAIDs, salicylates, and sulfonamides due to increased methotrexate toxicity. Monitor renal function, liver enzymes, and blood counts regularly. Contraindicated in pregnancy, breastfeeding, and active infections. |
| Patient Advice | Take exactly as prescribed; do not change dose without consulting your doctor. · Avoid alcohol completely while on this medication. · Report any signs of infection (fever, sore throat), unusual bleeding, or mouth ulcers immediately. · Use effective contraception during treatment and for at least 3 months after stopping. · Do not take any over-the-counter medications, especially NSAIDs (ibuprofen, naproxen), without permission. · Drink plenty of fluids to prevent kidney damage. · Attend all scheduled blood tests and appointments. · Capsules should be swallowed whole; do not crush or chew. |
Loading safety data…