SPRAVATO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for SPRAVATO (SPRAVATO).

How it works

Esketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It binds to the phencyclidine site on the NMDA receptor, inhibiting glutamate-mediated excitotoxicity and modulating synaptic plasticity. It also enhances AMPA receptor activity and increases brain-derived neurotrophic factor (BDNF) release.

What the body does with it

Metabolism	Primarily metabolized by CYP2B6 and CYP3A4; major metabolite is noresketamine, which has reduced NMDA receptor activity.
Excretion	Primarily renal elimination of metabolites; less than 1% of the dose excreted unchanged in urine. Approximately 78% of the dose is excreted in urine (as metabolites) and about 12% in feces.
Half-life	Esketamine: 7–12 hours. Noesketamine (active metabolite): 8–14 hours. Clinical context: Twice-weekly dosing maintains therapeutic levels.
Protein binding	Esketamine: 43–47% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). Noesketamine: 24–35% bound.
Volume of Distribution	Esketamine: Vd = 8.9 L/kg (high, indicating extensive tissue distribution).
Bioavailability	Intranasal: Absolute bioavailability of esketamine is approximately 48% (range 35–70%) due to partial absorption and first-pass metabolism.
Onset of Action	Intranasal: Antidepressant effect observed within 1–2 hours post-dose.
Duration of Action	Antidepressant effect persists for approximately 7 days after a single dose, with twice-weekly maintenance dosing.

Classification & Brands

Dosing & administration

56 mg intranasally on Day 1, then 56 or 84 mg intranasally twice weekly; all doses given as two or three 28 mg devices, one per nostril, with 5-minute rest between devices.

Dosage form	SPRAY
Renal impairment	No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²); use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to limited data, consider risk-benefit.
Liver impairment	No adjustment needed for Child-Pugh Class A (mild); Child-Pugh Class B (moderate): reduce initial dose to 28 mg intranasally, then may increase to 56 mg twice weekly; not recommended in Child-Pugh Class C (severe).
Pediatric use	Not approved for pediatric patients under 18 years of age; safety and efficacy not established.
Geriatric use	No specific dose adjustment based on age alone; start at low end of dosing range (56 mg) due to potential for reduced tolerability; monitor for adverse effects such as sedation and falls.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for SPRAVATO (SPRAVATO).

Breastfeeding	No data on presence in human milk; M/P ratio unknown. Due to potential for CNS effects in infant, breastfeeding is not recommended during treatment and for 5 days after last dose.
Teratogenic Risk	Insufficient human data; animal studies show fetal harm at exposures similar to human doses. Considered contraindicated in pregnancy due to potential for neural tube defects and developmental toxicity. No trimester-specific risk profile available; avoid use in all trimesters.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

WARNING: RISK OF SERIOUS ADVERSE OUTCOMES DUE TO SEDATION, DISSOCIATION, ABUSE, AND MISUSE. Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours after administration in a certified healthcare setting. Additionally, esketamine carries risks of abuse and misuse, similar to other CNS depressants.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial)","Arteriovenous malformation","History of intracerebral hemorrhage","Hypersensitivity to esketamine or ketamine"]

Clinical Precautions

Precautions

["Sedation and dissociation (monitor for 2 hours post-dose)","Risk of abuse and misuse (Schedule III controlled substance)","Increased risk of suicidal thoughts and behaviors","Hypertension (monitor blood pressure)","Cognitive impairment (may impair driving)","Urinary tract events (e.g., cystitis)"]

Clinical Tips & Counseling

Drug interactions

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SPRAVATO

Clinical safety rating: caution

Comprehensive clinical and safety monograph for SPRAVATO (SPRAVATO).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP2B6 and CYP3A4; major metabolite is noresketamine, which has reduced NMDA receptor activity.
Excretion	Primarily renal elimination of metabolites; less than 1% of the dose excreted unchanged in urine. Approximately 78% of the dose is excreted in urine (as metabolites) and about 12% in feces.
Half-life	Esketamine: 7–12 hours. Noesketamine (active metabolite): 8–14 hours. Clinical context: Twice-weekly dosing maintains therapeutic levels.
Protein binding	Esketamine: 43–47% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). Noesketamine: 24–35% bound.
Volume of Distribution	Esketamine: Vd = 8.9 L/kg (high, indicating extensive tissue distribution).
Bioavailability	Intranasal: Absolute bioavailability of esketamine is approximately 48% (range 35–70%) due to partial absorption and first-pass metabolism.
Onset of Action	Intranasal: Antidepressant effect observed within 1–2 hours post-dose.
Duration of Action	Antidepressant effect persists for approximately 7 days after a single dose, with twice-weekly maintenance dosing.

Classification & Brands

Dosing & administration

56 mg intranasally on Day 1, then 56 or 84 mg intranasally twice weekly; all doses given as two or three 28 mg devices, one per nostril, with 5-minute rest between devices.

Dosage form	SPRAY
Renal impairment	No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²); use with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to limited data, consider risk-benefit.
Liver impairment	No adjustment needed for Child-Pugh Class A (mild); Child-Pugh Class B (moderate): reduce initial dose to 28 mg intranasally, then may increase to 56 mg twice weekly; not recommended in Child-Pugh Class C (severe).
Pediatric use	Not approved for pediatric patients under 18 years of age; safety and efficacy not established.
Geriatric use	No specific dose adjustment based on age alone; start at low end of dosing range (56 mg) due to potential for reduced tolerability; monitor for adverse effects such as sedation and falls.

Use during pregnancy

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

Clinical note

Comprehensive clinical and safety monograph for SPRAVATO (SPRAVATO).

Breastfeeding	No data on presence in human milk; M/P ratio unknown. Due to potential for CNS effects in infant, breastfeeding is not recommended during treatment and for 5 days after last dose.
Teratogenic Risk	Insufficient human data; animal studies show fetal harm at exposures similar to human doses. Considered contraindicated in pregnancy due to potential for neural tube defects and developmental toxicity. No trimester-specific risk profile available; avoid use in all trimesters.
Fetal Monitoring