OTREXUP
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).
Methotrexate is a folate analog metabolic inhibitor. It inhibits dihydrofolate reductase (DHFR), leading to depletion of tetrahydrofolate and inhibition of thymidylate and purine synthesis, resulting in immunosuppression and anti-inflammatory effects.
| Metabolism | Hepatic metabolism to polyglutamated forms; minor metabolism via aldehyde oxidase to 7-hydroxymethotrexate. Primarily eliminated renally via tubular secretion and glomerular filtration. |
| Excretion | Renal: 80-90% as unchanged drug and active metabolite (7-hydroxymethotrexate), primarily via glomerular filtration and active tubular secretion. Fecal: <10% via bile. |
| Half-life | Terminal elimination half-life is 3-10 hours for low-dose methotrexate (as used in OTREXUP). At high doses, half-life may extend to 8-15 hours. Clinically, this supports weekly dosing for rheumatoid arthritis. |
| Protein binding | Approximately 50% bound to serum albumin, primarily at low concentrations. Binding is saturable; at higher doses, free fraction increases. |
| Volume of Distribution | 0.4-0.8 L/kg. Distributes into total body water; accumulates in third-space fluids (e.g., pleural effusions, ascites), which can prolong elimination and increase toxicity. |
| Bioavailability | Subcutaneous: 100% (complete absorption). Oral: variable, 30-90% (dose-dependent, saturable absorption; typically 70% at low doses). |
| Onset of Action | Subcutaneous: 0.5-1 hour for peak plasma levels; clinical improvement in rheumatoid arthritis may take 3-6 weeks. Oral: similar plasma onset, but clinical effect delayed up to 8-12 weeks. |
| Duration of Action | Weekly subcutaneous dosing: therapeutic effect persists for 1 week. For rheumatoid arthritis, continued weekly administration is required; interruption may lead to symptom recurrence within 2-4 weeks. |
| Molecular Weight | 454.44 |
Subcutaneous: 10 mg once weekly (may be titrated up to 25 mg once weekly as tolerated).
| Dosage form | SOLUTION |
| Renal impairment | GFR 30-60 mL/min: reduce dose by 50%. GFR <30 mL/min: avoid use. |
| Liver impairment | Child-Pugh A: no adjustment needed. Child-Pugh B: reduce dose by 50%. Child-Pugh C: avoid use. |
| Pediatric use | Weight-based dosing: 10-15 mg/m² subcutaneously once weekly (max 25 mg/week) for juvenile idiopathic arthritis. |
| Geriatric use | Start at the lower end of the dosing range (10 mg weekly) due to increased risk of hepatic and renal impairment; monitor closely for toxicity. |
| 1st trimester | Methotrexate is teratogenic; contraindicated in pregnancy. Exposure associated with severe fetal malformations, spontaneous abortion, and fetal death. |
| 2nd trimester | Contraindicated; exposure can cause fetal toxicity and teratogenicity. |
| 3rd trimester | Contraindicated; risk of fetal harm including growth restriction and neonatal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).
| Placental transfer | Methotrexate is known to cross the placenta extensively, achieving fetal concentrations similar to maternal levels. Active transport and passive diffusion contribute to transfer. |
| Breastfeeding | Methotrexate is excreted into breast milk in low concentrations, but due to potential for serious adverse effects (e.g., immunosuppression, neutropenia, developmental delay) in the nursing infant, breastfeeding is contraindicated during therapy and for at least one week after the last dose. |
■ FDA Black Box Warning
Methotrexate can cause fetal death or congenital anomalies. It should not be used by pregnant women or women planning pregnancy. It may cause severe toxicity including myelosuppression, hepatotoxicity, pulmonary fibrosis, and renal failure. Deaths have been reported with methotrexate use. Only physicians experienced in antimetabolite therapy should prescribe it.
| Serious Effects |
PregnancyBreastfeedingSevere renal impairment (eGFR <30 mL/min/1.73 m²)Severe hepatic impairmentPreexisting blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)Alcoholism or alcoholic liver diseaseKnown hypersensitivity to methotrexate
| Precautions | Hepatotoxicity (fibrosis, cirrhosis), pulmonary toxicity (pneumonitis, fibrosis), myelosuppression (anemia, leukopenia, thrombocytopenia), renal impairment, gastrointestinal toxicity (ulcerative stomatitis, diarrhea), opportunistic infections, tumor lysis syndrome, photosensitivity, and neurotoxicity. Monitor CBC, LFTs, renal function, and chest imaging regularly. |
| Food/Dietary |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | OTREXUP (methotrexate) is contraindicated in pregnancy. It is an FDA Pregnancy Category X drug. First trimester exposure is associated with high risk of spontaneous abortion and major congenital malformations (e.g., craniofacial, cardiac, and CNS defects). Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and neurodevelopmental impairment. |
| Fetal Monitoring | In cases of inadvertent pregnancy exposure, immediate discontinuation is indicated. Monitor for fetal viability, anomalies via ultrasound, and maternal liver function, renal function, and complete blood counts. Fetal echocardiography and detailed anatomic survey recommended. For women of childbearing potential, negative pregnancy test before initiation and use of effective contraception during therapy are required. |
| Fertility Effects | Methotrexate can cause reversible oligospermia and menstrual dysfunction. In males, it may reduce sperm count and motility; effects are usually reversible after discontinuation. In females, it may disrupt ovulation and cause amenorrhea, potentially delaying conception. |
| High-folate foods (e.g., leafy greens, beans) may reduce effectiveness; advise consistent folate intake from supplements. Avoid alcohol due to hepatotoxicity risk. Caffeine may reduce methotrexate absorption; separate intake by at least 2 hours. |
| Clinical Pearls | Monitor for myelosuppression, hepatotoxicity, and pulmonary toxicity. Folate supplementation reduces adverse effects without reducing efficacy. Administer methotrexate once weekly; accidental daily dosing can be fatal. Avoid NSAIDs in patients with renal impairment due to reduced methotrexate clearance. |
| Patient Advice | Take OTREXUP exactly once weekly, not daily. Use a calendar or reminder. · Folic acid supplements are important to reduce side effects like mouth sores, nausea, and low blood counts. · Avoid alcohol completely as it increases risk of liver damage. · Notify your doctor immediately if you develop cough, fever, shortness of breath, or yellowing of skin/eyes. · Do not take NSAIDs (e.g., ibuprofen, naproxen) without consulting your doctor. |