OTREXUP PFS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OTREXUP PFS (OTREXUP PFS).
Methotrexate is a folate analog that inhibits dihydrofolate reductase, thereby blocking the synthesis of purines and pyrimidines, leading to inhibition of DNA synthesis and cell proliferation. It also has immunosuppressive and anti-inflammatory effects through modulation of adenosine pathways and cytokine release.
| Metabolism | Primarily hepatic metabolism by aldehyde oxidase to 7-hydroxymethotrexate; also undergoes polyglutamation intracellularly. Elimination is mainly renal via tubular secretion and glomerular filtration. |
| Excretion | Renal excretion (80-90% unchanged) via glomerular filtration and tubular secretion; biliary/fecal elimination accounts for <10%. |
| Half-life | 5-8 hours (low-dose methotrexate); 8-15 hours (high-dose). Prolonged in renal impairment, third-space effusions, or concomitant NSAIDs. |
| Protein binding | ~50% bound to albumin, primarily at low concentrations; displacement interactions possible with salicylates, sulfonamides, phenytoin. |
| Volume of Distribution | 0.4-0.8 L/kg (total body water); distributes into third-space accumulations (e.g., ascites, pleural effusions) acting as drug reservoirs. |
| Bioavailability | Subcutaneous: ~100% (bioequivalent to IM). Oral: 60-70% (saturable absorption at doses >25 mg/m²). |
| Onset of Action | Subcutaneous: 0.5-2 hours for plasma concentration; clinical effect (anti-inflammatory) may take 3-6 weeks. |
| Duration of Action | Subcutaneous: Weekly dosing maintains effect; peak anti-inflammatory activity 24-48 hours post-dose. |
| Molecular Weight | 454.44 |
Methotrexate 7.5-15 mg subcutaneously once weekly. For rheumatoid arthritis, start at 7.5 mg weekly, titrate to 20-25 mg weekly as tolerated.
| Dosage form | SOLUTION |
| Renal impairment | GFR 30-60 mL/min: reduce dose by 50%. GFR <30 mL/min: contraindicated (use not recommended). Avoid in severe renal impairment. |
| Liver impairment | Child-Pugh A: no dose adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated. Avoid in active liver disease. |
| Pediatric use | For juvenile idiopathic arthritis: 10-15 mg/m² subcutaneously once weekly, or 0.3-0.6 mg/kg once weekly (max 20-25 mg/week). For acute lymphoblastic leukemia: higher doses used per protocol. |
| Geriatric use | Start at low end of dosing range (7.5 mg weekly) due to higher risk of toxicity. Monitor renal function and adjust per renal adjustment guidelines. Consider folic acid supplementation 1 mg daily. |
| 1st trimester | Methotrexate is contraindicated in the first trimester due to high risk of teratogenicity, including CNS anomalies, skeletal defects, and cardiac malformations. |
| 2nd trimester | Methotrexate is contraindicated in the second trimester as it continues to pose risk of fetal harm, including growth restriction and functional abnormalities. |
| 3rd trimester | Methotrexate is contraindicated in the third trimester due to risk of fetal toxicity, including neonatal myelosuppression and pulmonary hypertension. |
Clinical note
Comprehensive clinical and safety monograph for OTREXUP PFS (OTREXUP PFS).
| Placental transfer | Methotrexate actively crosses the placenta via folate transporters; fetal concentrations are comparable to maternal levels. |
| Breastfeeding | Methotrexate is excreted in breast milk in low concentrations, but due to potential for serious adverse reactions (e.g., immunosuppression, neutropenia, gastrointestinal toxicity) in the nursing infant, breastfeeding is not recommended during therapy. A decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
■ FDA Black Box Warning
Severe toxic reactions, including death, have been reported with methotrexate use. Caution is required: monitor for bone marrow suppression, hepatic toxicity, renal toxicity, pulmonary toxicity, gastrointestinal toxicity, and severe infections. Methotrexate should be used only by physicians with expertise in antimetabolite therapy. Patients should be informed of risks and required monitoring.
| Serious Effects |
PregnancyBreastfeedingSevere renal impairment (CrCl <10 mL/min)Severe hepatic impairmentPre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)Alcoholism or alcoholic liver diseaseImmunodeficiency syndromesHypersensitivity to methotrexate or any component of the formulation
| Precautions | Hepatotoxicity: monitor liver function tests; avoid in patients with preexisting liver disease or alcoholism, Pulmonary toxicity: acute or chronic interstitial pneumonitis; monitor for cough, fever, dyspnea, Bone marrow suppression: leukopenia, thrombocytopenia, anemia; monitor CBC regularly, Renal toxicity: maintain adequate hydration and urine output; adjust dose in renal impairment, Gastrointestinal toxicity: stomatitis, diarrhea, ulcerative stomatitis; may require dose interruption, Severe infections: risk of opportunistic infections including Pneumocystis jirovecii pneumonia, Tumor lysis syndrome: monitor patients with rapidly growing tumors, Fetal harm: pregnancy category X; women of childbearing potential must use contraception, Immunizations: avoid live vaccines during therapy, Methotrexate-induced lymphoma: reversible with discontinuation |
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| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | Pregnancy category X. First trimester: High risk of CNS, cardiac, and skeletal malformations (neural tube defects, cleft palate). Second and third trimesters: Fetal growth restriction, oligohydramnios, neonatal methotrexate syndrome (craniofacial anomalies, limb defects). Contraindicated in pregnancy due to dose-dependent teratogenicity. |
| Fetal Monitoring | Monthly pregnancy testing with beta-hCG in women of childbearing potential. Baseline and periodic liver function tests (AST, ALT), renal function (serum creatinine, BUN), and complete blood counts (CBC) with differential. For fetal exposure, ultrasound for growth and anatomy if accidental exposure occurs. Monitor for signs of bone marrow suppression, hepatotoxicity, and pulmonary toxicity. |
| Fertility Effects | Methotrexate can cause reversible oligospermia and menstrual dysfunction. In men, transient reduction in sperm count and motility; in women, ovulatory disturbances. Fertility may return after discontinuation, but long-term use may lead to premature ovarian insufficiency. |
| Food/Dietary | No specific food interactions, but alcohol consumption increases hepatotoxicity risk and should be avoided. Caffeine may reduce methotrexate efficacy; limit intake. Foods rich in folate (e.g., leafy greens) may theoretically interfere but concurrent folic acid supplementation is recommended. |
| Clinical Pearls | Methotrexate (OTREXUP PFS) is a folate analog antimetabolite used for rheumatoid arthritis, psoriasis, and juvenile idiopathic arthritis. Subcutaneous administration ensures reliable bioavailability; monitor for hepatotoxicity, myelosuppression, and pneumonitis. Always prescribe concurrent folic acid 1 mg daily to reduce toxicity. Avoid in pregnancy (teratogenic) and significant renal impairment. Weekly dosing only; accidental daily ingestion is dangerous. Check CBC, LFTs, creatinine, and chest X-ray baseline and periodically. |
| Patient Advice | Take OTREXUP PFS exactly once weekly on the same day; never take it daily as it can be fatal. · Swallow the folic acid tablet daily as prescribed to reduce side effects. · Store in refrigerator, protect from light. Allow to reach room temperature before injection. · Do not breastfeed while taking this medication. · Avoid alcohol completely due to increased risk of liver damage. · Report any signs of infection (fever, cough), easy bruising/bleeding, mouth ulcers, or shortness of breath. · Use effective contraception during treatment and for at least one menstrual cycle after stopping. · Do not receive live vaccines during therapy. |