OTREXUP

Clinical safety rating: caution

Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).

Breastfeeding	Methotrexate is excreted into breast milk in low concentrations (M/P ratio approximately 0.08). However, due to potential for accumulation in the infant and risk of adverse effects (e.g., immunosuppression, neutropenia), breastfeeding is not recommended during OTREXUP therapy.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

Pregnancy, breastfeeding, severe renal impairment (CrCl <10 mL/min), severe hepatic impairment, alcoholism, alcoholic liver disease, immunodeficiency syndromes, pre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia), and hypersensitivity to methotrexate.

Clinical Precautions

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.

Clinical Tips & Counseling

Drug interactions

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OTREXUP

Clinical safety rating: caution

Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).

How it works

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for OTREXUP (OTREXUP).

Breastfeeding	Methotrexate is excreted into breast milk in low concentrations (M/P ratio approximately 0.08). However, due to potential for accumulation in the infant and risk of adverse effects (e.g., immunosuppression, neutropenia), breastfeeding is not recommended during OTREXUP therapy.
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.