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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for OTREXUP PFS (OTREXUP PFS).
| Breastfeeding | Methotrexate is excreted in breast milk at low levels (M/P ratio approximately 0.08). However, due to potential accumulation in nursing infants (especially with weekly high-dose regimens) and risk of infantile methotrexate toxicity, breastfeeding is contraindicated during OTREXUP therapy. |
| 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. |
■ 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 |
["Hypersensitivity to methotrexate or any component of the formulation","Pregnancy and breastfeeding","Severe renal impairment (creatinine clearance less than 10 mL/min)","Severe hepatic impairment or active liver disease","Severe bone marrow depression (e.g., aplastic anemia, leukopenia, thrombocytopenia)","Alcoholism or alcoholic liver disease","Overt or laboratory evidence of immunodeficiency syndromes","Preexisting severe infections (e.g., active tuberculosis, HIV)"]
| 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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| 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. |