ZUMANDIMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZUMANDIMINE (ZUMANDIMINE).

How it works

ZUMANDIMINE is a selective norepinephrine reuptake inhibitor that increases synaptic norepinephrine levels, enhancing adrenergic signaling in the CNS and peripheral nervous system.

What the body does with it

Metabolism	Primarily metabolized by CYP2D6 to its active metabolite, desmethylzumandimine; minor pathways involve CYP3A4.
Excretion	Renal excretion accounts for 65% of elimination (primarily as unchanged drug via glomerular filtration and tubular secretion), biliary/fecal excretion accounts for 30% (with enterohepatic recycling of metabolites), and 5% is metabolized via CYP3A4 with subsequent excretion. The cumulative urinary recovery of unchanged drug is 60-70% within 48 hours.
Half-life	Terminal elimination half-life is 12-15 hours in healthy adults (range 10-18 hours). In moderate renal impairment (CrCl 30-50 mL/min), half-life prolongs to 20-28 hours; in severe hepatic impairment (Child-Pugh C), half-life extends to 24-35 hours. This supports twice-daily dosing in normal renal function and requires dose adjustment in renal or hepatic impairment.
Protein binding	Highly bound (92-95%) primarily to albumin (80%) and alpha-1-acid glycoprotein (15%). Free fraction increases in hypoalbuminemia (e.g., cirrhosis, nephrotic syndrome), potentially enhancing pharmacodynamic effects.
Volume of Distribution	Volume of distribution is 0.8-1.2 L/kg (total Vd), indicating extensive tissue distribution. Mean Vd is 50-70 L in a 70 kg adult, suggesting binding to peripheral tissues and sequestration in erythrocytes (blood-to-plasma ratio 0.9).
Bioavailability	Oral bioavailability is 75-85% (with minimal first-pass metabolism). Subcutaneous bioavailability is 80% (relative to IV). Intravenous bioavailability is 100%. Food increases absorption (Cmax increased by 15-20%, AUC unchanged).
Onset of Action	Intravenous: 5-10 minutes (peak plasma concentration at end of infusion); Oral: 1-2 hours (median time to therapeutic effect, with clinical response noted within 2-4 hours after first dose); Subcutaneous: 30-45 minutes (bioavailability 80% versus IV).
Duration of Action	Duration of clinical effect is 12-24 hours depending on dose and route. At standard doses (e.g., 50 mg IV), effect duration is 12-16 hours; extended-release oral formulation provides 24-hour coverage. Tachyphylaxis may occur with continuous use beyond 7 days.

Classification & Brands

Dosing & administration

The typical adult dose of ZUMANDIMINE is 250 mg intravenously every 12 hours infused over 60 minutes.

Dosage form	TABLET
Renal impairment	For GFR 30-89 mL/min: no adjustment. For GFR 15-29 mL/min: 250 mg every 24 hours. For GFR <15 mL/min or on hemodialysis: 250 mg every 48 hours.
Liver impairment	Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose to 125 mg every 12 hours. Child-Pugh Class C: not recommended.
Pediatric use	For children ≥2 years: 5 mg/kg (max 250 mg) intravenously every 12 hours. For children <2 years: not established.
Geriatric use	Start at lower end of dosing range (250 mg every 12 hours) due to age-related renal function decline. Monitor renal function and adjust per renal dosing guidelines.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for ZUMANDIMINE (ZUMANDIMINE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Due to potential for serious adverse reactions in breastfed infants (hypotension, electrolyte disturbances), recommend discontinue breastfeeding or discontinue drug, considering importance to mother.
Teratogenic Risk	Data limited. First trimester: Possible increased risk of neural tube defects and cardiac malformations based on animal studies (doses 2x MRHD). Second and third trimester: Risk of fetal growth restriction and oligohydramnios due to potential uteroplacental hypoperfusion. Avoid use if alternative therapy available.

Warnings & precautions

■ FDA Black Box Warning

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS - ZUMANDIMINE increases the risk of suicidal thoughts and behaviors in children, adolescents, and young adults. Close monitoring is required during initial treatment.

Side Effect Profile

Serious Effects

Absolute Contraindications

Concurrent use or within 14 days of MAOIs. History of pheochromocytoma. Severe hepatic impairment (Child-Pugh Class C). Hypersensitivity to zumandimine or any excipients.

Clinical Precautions

Precautions

Risk of serotonin syndrome when used with other serotonergic drugs. May cause hypertension and tachycardia; monitor blood pressure and heart rate. Potential for activation of mania/hypomania in patients with bipolar disorder. Avoid abrupt discontinuation to prevent withdrawal symptoms.

Clinical Tips & Counseling

Drug interactions

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ZUMANDIMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ZUMANDIMINE (ZUMANDIMINE).

How it works

ZUMANDIMINE is a selective norepinephrine reuptake inhibitor that increases synaptic norepinephrine levels, enhancing adrenergic signaling in the CNS and peripheral nervous system.

What the body does with it

Metabolism	Primarily metabolized by CYP2D6 to its active metabolite, desmethylzumandimine; minor pathways involve CYP3A4.
Excretion	Renal excretion accounts for 65% of elimination (primarily as unchanged drug via glomerular filtration and tubular secretion), biliary/fecal excretion accounts for 30% (with enterohepatic recycling of metabolites), and 5% is metabolized via CYP3A4 with subsequent excretion. The cumulative urinary recovery of unchanged drug is 60-70% within 48 hours.
Half-life	Terminal elimination half-life is 12-15 hours in healthy adults (range 10-18 hours). In moderate renal impairment (CrCl 30-50 mL/min), half-life prolongs to 20-28 hours; in severe hepatic impairment (Child-Pugh C), half-life extends to 24-35 hours. This supports twice-daily dosing in normal renal function and requires dose adjustment in renal or hepatic impairment.
Protein binding	Highly bound (92-95%) primarily to albumin (80%) and alpha-1-acid glycoprotein (15%). Free fraction increases in hypoalbuminemia (e.g., cirrhosis, nephrotic syndrome), potentially enhancing pharmacodynamic effects.
Volume of Distribution	Volume of distribution is 0.8-1.2 L/kg (total Vd), indicating extensive tissue distribution. Mean Vd is 50-70 L in a 70 kg adult, suggesting binding to peripheral tissues and sequestration in erythrocytes (blood-to-plasma ratio 0.9).
Bioavailability	Oral bioavailability is 75-85% (with minimal first-pass metabolism). Subcutaneous bioavailability is 80% (relative to IV). Intravenous bioavailability is 100%. Food increases absorption (Cmax increased by 15-20%, AUC unchanged).
Onset of Action	Intravenous: 5-10 minutes (peak plasma concentration at end of infusion); Oral: 1-2 hours (median time to therapeutic effect, with clinical response noted within 2-4 hours after first dose); Subcutaneous: 30-45 minutes (bioavailability 80% versus IV).
Duration of Action	Duration of clinical effect is 12-24 hours depending on dose and route. At standard doses (e.g., 50 mg IV), effect duration is 12-16 hours; extended-release oral formulation provides 24-hour coverage. Tachyphylaxis may occur with continuous use beyond 7 days.

Classification & Brands

Dosing & administration

The typical adult dose of ZUMANDIMINE is 250 mg intravenously every 12 hours infused over 60 minutes.

Dosage form	TABLET
Renal impairment	For GFR 30-89 mL/min: no adjustment. For GFR 15-29 mL/min: 250 mg every 24 hours. For GFR <15 mL/min or on hemodialysis: 250 mg every 48 hours.
Liver impairment	Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose to 125 mg every 12 hours. Child-Pugh Class C: not recommended.
Pediatric use	For children ≥2 years: 5 mg/kg (max 250 mg) intravenously every 12 hours. For children <2 years: not established.
Geriatric use	Start at lower end of dosing range (250 mg every 12 hours) due to age-related renal function decline. Monitor renal function and adjust per renal dosing guidelines.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for ZUMANDIMINE (ZUMANDIMINE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Due to potential for serious adverse reactions in breastfed infants (hypotension, electrolyte disturbances), recommend discontinue breastfeeding or discontinue drug, considering importance to mother.
Teratogenic Risk	Data limited. First trimester: Possible increased risk of neural tube defects and cardiac malformations based on animal studies (doses 2x MRHD). Second and third trimester: Risk of fetal growth restriction and oligohydramnios due to potential uteroplacental hypoperfusion. Avoid use if alternative therapy available.

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

Concurrent use or within 14 days of MAOIs. History of pheochromocytoma. Severe hepatic impairment (Child-Pugh Class C). Hypersensitivity to zumandimine or any excipients.