ABITREXATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ABITREXATE (ABITREXATE).
Methotrexate, the active ingredient, is a folate analog that inhibits dihydrofolate reductase (DHFR), thereby blocking the conversion of dihydrofolate to tetrahydrofolate, inhibiting DNA synthesis, repair, and cellular replication. It also has immunosuppressive and anti-inflammatory effects via modulation of adenosine and cytokine pathways.
| Metabolism | Methotrexate is metabolized intracellularly to active polyglutamated forms by folylpolyglutamate synthetase. It also undergoes minor oxidation by hepatic aldehyde oxidase to 7-hydroxymethotrexate. Phase II polyglutamation is significant. No CYP450 involvement. |
| Excretion | Primarily renal (80-90% as unchanged drug) via glomerular filtration and active tubular secretion; biliary/fecal excretion accounts for <10%. |
| Half-life | Terminal elimination half-life is 6-12 hours (mean 7.5 hours) in patients with normal renal function; prolonged in renal impairment. |
| Protein binding | Approximately 50% bound, primarily to albumin. |
| Volume of Distribution | 0.4-0.8 L/kg (total body water); distributes extensively into tissues, including third-space fluids (e.g., pleural effusions). |
| Bioavailability | Oral: 60-70% (dose-dependent, saturable absorption); Intramuscular: 100%; Subcutaneous: approximately 100%. |
| Onset of Action | Oral: 30-60 minutes; Intramuscular: 30-60 minutes; Intravenous: 5-10 minutes; Intrathecal: within 15 minutes. |
| Duration of Action | Antirheumatic and antineoplastic effects persist for 1-2 weeks after a single dose due to prolonged retention in cells; clinical effects may last until drug is cleared. |
| Molecular Weight | 454.45 |
7.5 mg orally once weekly; alternatively, 7.5 mg subcutaneously once weekly. Dose may be increased by 2.5 mg every 1-2 weeks up to 20 mg once weekly based on response and tolerability.
| Dosage form | INJECTABLE |
| Renal impairment | GFR 60-90 mL/min: no adjustment. GFR 30-59 mL/min: reduce dose by 50%. GFR 15-29 mL/min: use 25% of normal dose. GFR <15 mL/min: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose by 50%. Child-Pugh Class C: contraindicated. |
| Pediatric use | Weight-based dosing: 0.5-1 mg/kg orally or subcutaneously once weekly. Maximum single dose: 20 mg. Dosing based on pediatric rheumatology guidelines. |
| Geriatric use | Start at 5 mg orally once weekly. Increase dose cautiously in 2.5 mg increments every 2-4 weeks. Monitor renal function and folate levels closely. Increased risk of myelosuppression and hepatotoxicity. |
| 1st trimester | Contraindicated due to teratogenicity (neural tube defects, cardiac anomalies). |
| 2nd trimester | Contraindicated due to risk of fetal growth restriction and neurotoxicity. |
| 3rd trimester | Contraindicated due to risk of neonatal myelosuppression and immunosuppression. |
Clinical note
Comprehensive clinical and safety monograph for ABITREXATE (ABITREXATE).
| Placental transfer | Methotrexate crosses the placenta and accumulates in fetal tissues, with fetal concentrations reaching up to 2-3 times maternal plasma levels. |
| Breastfeeding | Methotrexate is excreted in human milk in small amounts; however, due to potential for serious adverse reactions (e.g., immunosuppression, neutropenia), breastfeeding is contraindicated during therapy and for at least 1 week after the last dose. |
■ FDA Black Box Warning
Boxed Warning: Methotrexate can cause severe or fatal toxicities including myelosuppression, hepatic fibrosis/cirrhosis, pulmonary fibrosis, renal failure, and severe infections. It is contraindicated in pregnancy (teratogenic). Severe adverse reactions may occur at any dose, especially with frequent or high doses. Deaths have been reported with inadvertent daily dosing of low-dose methotrexate. Patients must be closely monitored for bone marrow, liver, lung, and kidney toxicity.
| Serious Effects |
PregnancyBreastfeedingSevere renal impairment (CrCl < 20 mL/min)Severe hepatic impairmentPre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia)Active infectious disease (e.g., tuberculosis, hepatitis)Hypersensitivity to methotrexate or any component
| Precautions | Hepatotoxicity (monitor LFTs, avoid in preexisting liver disease), pulmonary toxicity (acute or chronic interstitial pneumonitis, may be fatal), myelosuppression (monitor CBCs), renal impairment (dose adjust, avoid NSAIDs), severe infections (including opportunistic), neurotoxicity (especially in high-dose regimens), gastrointestinal toxicity (stomatitis, ulcerations), dermatologic reactions (Stevens-Johnson syndrome), latent infections (hepatitis B reactivation), immunodeficiency (avoid live vaccines). Caution in ascites, pleural effusion (prolonged elimination), preexisting bone marrow aplasia, and concomitant hepatotoxic drugs. |
Loading safety data…
| Lactation Rating |
| L5 - Contraindicated |
| Teratogenic Risk | First trimester: High risk of congenital malformations (neural tube defects, craniofacial, skeletal). Second and third trimesters: Risk of fetal growth restriction, oligohydramnios, and neonatal myelosuppression. |
| Fetal Monitoring | Pre-treatment: CBC, liver function, renal function, pregnancy test. During therapy: Monthly CBC, liver/renal function; fetal ultrasound for anomalies and growth; amniotic fluid volume assessment. |
| Fertility Effects | Reversible oligospermia and amenorrhea. May cause ovarian failure; consult reproductive specialist before conception. |
| Food/Dietary | Avoid folic acid supplements unless prescribed, as they may interfere with methotrexate action. No specific food restrictions, but maintain adequate hydration. Avoid grapefruit juice? (not typically interacting, but caution with CYP3A4 substrates). |
| Clinical Pearls | ABITREXATE (high-dose methotrexate) requires aggressive hydration, urine alkalinization (target pH ≥7.0), and leucovorin rescue to prevent nephrotoxicity. Monitor methotrexate levels at 24, 48, and 72 hours; hold leucovorin if levels are elevated. Avoid NSAIDs and penicillins that can increase methotrexate toxicity. |
| Patient Advice | Avoid alcohol during treatment due to increased hepatotoxicity risk. · Report any signs of infection, unusual bleeding, or mouth sores immediately. · Use effective contraception during and for at least 3 months after therapy. · Avoid live vaccines while on this medication. · Stay well hydrated; drink plenty of fluids as directed. |