NEUTREXIN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NEUTREXIN (NEUTREXIN).

How it works

NEUTREXIN (trimetrexate glucuronate) is a dihydrofolate reductase (DHFR) inhibitor. It inhibits the enzyme DHFR, leading to depletion of tetrahydrofolate and subsequent inhibition of DNA synthesis.

What the body does with it

Metabolism	Trimetrexate is metabolized primarily by the liver via cytochrome P450 enzymes, likely CYP3A4. It undergoes O-demethylation and other oxidative pathways.
Excretion	Renal excretion of unchanged drug accounts for approximately 40-50% of the administered dose. Biliary/fecal elimination is minimal, with less than 5% recovered in feces.
Half-life	Terminal elimination half-life is approximately 12-15 hours in patients with normal renal function. This half-life supports a twice-daily dosing regimen.
Protein binding	Approximately 80-90% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is 0.5-0.7 L/kg, indicating distribution into total body water with some tissue penetration.
Bioavailability	Oral bioavailability is approximately 60-80%, with food reducing absorption by about 20%.
Onset of Action	Oral administration: clinical effect (e.g., reduction in serum folate levels) typically observed within 2-4 hours. Intravenous administration: onset within 30-60 minutes.
Duration of Action	Duration of pharmacodynamic effect (folate antagonism) persists for 24-36 hours after a single dose, aligning with the half-life. Continuous daily dosing maintains sustained antifolate activity.

Classification & Brands

Dosing & administration

5 mg/kg intravenously once daily for 21 days for Pneumocystis jirovecii pneumonia; alternatively, 5 mg/kg intravenously once daily for 14 days for toxoplasmosis.

Dosage form	INJECTABLE
Renal impairment	CrCl 50-80 mL/min: 4 mg/kg once daily; CrCl 10-49 mL/min: 3 mg/kg once daily; CrCl <10 mL/min: 2 mg/kg once daily; peritoneal dialysis: 2 mg/kg once daily; hemodialysis: administer after dialysis on dialysis days.
Liver impairment	Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 25%; Child-Pugh Class C: reduce dose by 50%.
Pediatric use	For Pneumocystis jirovecii pneumonia: 5 mg/kg intravenously once daily for 21 days; for toxoplasmosis: 5 mg/kg intravenously once daily for 14 days; same adult mg/kg dosing applies to children.
Geriatric use	Monitor renal function closely; use weight-based dosing (5 mg/kg) but adjust for renal impairment as per renal adjustment guidelines; elderly patients may have reduced renal function and require dose reduction.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for NEUTREXIN (NEUTREXIN).

Breastfeeding	Excreted in human milk; M/P ratio unknown. Contraindicated due to potential for severe adverse reactions in nursing infants, including myelosuppression and gastrointestinal toxicity.
Teratogenic Risk	Pregnancy Category D. First trimester: high risk of neural tube defects, craniofacial, and cardiovascular malformations. Second and third trimesters: risk of fetal myelosuppression, intrauterine growth restriction, and potential neurodevelopmental impairment.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

WARNING: NEUTREXIN must be used with concurrent leucovorin (folinic acid) to prevent potentially fatal bone marrow suppression and other toxicities. Patients should be monitored for hematologic, hepatic, and renal toxicities.

Side Effect Profile

Serious Effects

Absolute Contraindications

Absolute: Known hypersensitivity to trimetrexate or any component of the formulation. Concomitant use with other drugs that cause significant bone marrow suppression (unless leucovorin is given). Relative: Severe hepatic impairment, severe renal impairment, pregnancy (may cause fetal harm), and breastfeeding (discontinue nursing).

Clinical Precautions

Precautions

Hematologic toxicity (neutropenia, thrombocytopenia, anemia), hepatotoxicity (elevated liver enzymes, hepatic failure), renal toxicity, gastrointestinal toxicity (nausea, vomiting, mucositis), and hypersensitivity reactions. Concomitant leucovorin is required to reduce toxicity. Monitor complete blood counts, liver function tests, and renal function regularly. Use caution in patients with pre-existing bone marrow suppression, hepatic impairment, or renal impairment.

Clinical Tips & Counseling

Drug interactions

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NEUTREXIN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NEUTREXIN (NEUTREXIN).

How it works

NEUTREXIN (trimetrexate glucuronate) is a dihydrofolate reductase (DHFR) inhibitor. It inhibits the enzyme DHFR, leading to depletion of tetrahydrofolate and subsequent inhibition of DNA synthesis.

What the body does with it

Metabolism	Trimetrexate is metabolized primarily by the liver via cytochrome P450 enzymes, likely CYP3A4. It undergoes O-demethylation and other oxidative pathways.
Excretion	Renal excretion of unchanged drug accounts for approximately 40-50% of the administered dose. Biliary/fecal elimination is minimal, with less than 5% recovered in feces.
Half-life	Terminal elimination half-life is approximately 12-15 hours in patients with normal renal function. This half-life supports a twice-daily dosing regimen.
Protein binding	Approximately 80-90% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is 0.5-0.7 L/kg, indicating distribution into total body water with some tissue penetration.
Bioavailability	Oral bioavailability is approximately 60-80%, with food reducing absorption by about 20%.
Onset of Action	Oral administration: clinical effect (e.g., reduction in serum folate levels) typically observed within 2-4 hours. Intravenous administration: onset within 30-60 minutes.
Duration of Action	Duration of pharmacodynamic effect (folate antagonism) persists for 24-36 hours after a single dose, aligning with the half-life. Continuous daily dosing maintains sustained antifolate activity.

Classification & Brands

Dosing & administration

5 mg/kg intravenously once daily for 21 days for Pneumocystis jirovecii pneumonia; alternatively, 5 mg/kg intravenously once daily for 14 days for toxoplasmosis.

Dosage form	INJECTABLE
Renal impairment	CrCl 50-80 mL/min: 4 mg/kg once daily; CrCl 10-49 mL/min: 3 mg/kg once daily; CrCl <10 mL/min: 2 mg/kg once daily; peritoneal dialysis: 2 mg/kg once daily; hemodialysis: administer after dialysis on dialysis days.
Liver impairment	Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 25%; Child-Pugh Class C: reduce dose by 50%.
Pediatric use	For Pneumocystis jirovecii pneumonia: 5 mg/kg intravenously once daily for 21 days; for toxoplasmosis: 5 mg/kg intravenously once daily for 14 days; same adult mg/kg dosing applies to children.
Geriatric use	Monitor renal function closely; use weight-based dosing (5 mg/kg) but adjust for renal impairment as per renal adjustment guidelines; elderly patients may have reduced renal function and require dose reduction.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for NEUTREXIN (NEUTREXIN).

Breastfeeding	Excreted in human milk; M/P ratio unknown. Contraindicated due to potential for severe adverse reactions in nursing infants, including myelosuppression and gastrointestinal toxicity.
Teratogenic Risk	Pregnancy Category D. First trimester: high risk of neural tube defects, craniofacial, and cardiovascular malformations. Second and third trimesters: risk of fetal myelosuppression, intrauterine growth restriction, and potential neurodevelopmental impairment.
Fetal Monitoring