ZALEPLON

Clinical safety rating: safe

Animal studies have demonstrated safety

How it works

Selective agonist of the benzodiazepine site on GABA-A receptors, enhancing GABA-mediated chloride conductance and neuronal inhibition. Binds preferentially to the α1 subunit-containing receptors.

What the body does with it

Metabolism	Primarily hepatic via aldehyde oxidase (major pathway) and CYP3A4 (minor pathway); undergoes first-pass metabolism. Active metabolite: 5-oxo-zaleplon (inactive).
Excretion	Approximately 70% of a dose is excreted as metabolites in urine (primarily as 5-oxo-zaleplon and other oxidative metabolites) and about 30% in feces. Less than 1% is excreted unchanged in urine.
Half-life	The terminal elimination half-life is approximately 1 hour (range 0.9–1.1 hours) in healthy adults. This short half-life minimizes next-day residual effects and is consistent with its use for sleep induction without significant morning sedation.
Protein binding	Plasma protein binding is approximately 60% (primarily to albumin).
Volume of Distribution	Volume of distribution is approximately 1.4 L/kg (range 1.0–1.8 L/kg) in adults, indicating extensive distribution into tissues.
Bioavailability	Oral bioavailability is approximately 30% due to extensive first-pass metabolism. Bioavailability is not significantly affected by food, but a high-fat meal may delay absorption and reduce peak concentrations.
Onset of Action	Oral: Onset of action occurs within 15–30 minutes following oral administration, with peak plasma concentrations at approximately 1 hour.
Duration of Action	Duration of action is approximately 3–4 hours based on clinical efficacy in sleep latency reduction. The short half-life limits duration, making it suitable for sleep initiation rather than maintenance.

Classification & Brands

Dosing & administration

10 mg orally once daily at bedtime; range 5-20 mg.

Dosage form	CAPSULE
Renal impairment	No dose adjustment required for mild to moderate renal impairment; not recommended in severe renal impairment (CrCl <30 mL/min) due to insufficient data.
Liver impairment	Child-Pugh A: 5 mg at bedtime; Child-Pugh B: 5 mg at bedtime (use with caution); Child-Pugh C: contraindicated.
Pediatric use	Not approved for pediatric use; safety and efficacy not established in patients <18 years.
Geriatric use	Initial dose 5 mg at bedtime; may increase to 10 mg if needed and tolerated; increased risk of falls and cognitive impairment.

Use during pregnancy

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

Clinical note

CNS depressants including alcohol increase sedation risk Can cause complex sleep behaviors like sleep-driving.

Breastfeeding	Excreted into breast milk in low amounts (M/P ratio ~0.5). Caution due to potential infant sedation and feeding difficulties. Use only if clearly needed; monitor infant for drowsiness and poor suckling.
Teratogenic Risk	Pregnancy Category C. First trimester: Limited human data; animal studies show increased fetal loss and skeletal variations at high doses. Second/third trimester: Risk of neonatal respiratory depression, hypotonia, and withdrawal if used near term. Avoid use, especially during first and third trimesters.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Common Effects	Dizziness
Serious Effects

Absolute Contraindications

["Hypersensitivity to zaleplon or any component of the formulation","Severe hepatic impairment (Child-Pugh class C)","Concurrent use with other CNS depressants (relative; requires dose adjustment)","Pregnancy (Category C; avoid use)","Lactation (use with caution)"]

Clinical Precautions

Precautions

["Risk of CNS depression and daytime sedation","Complex sleep behaviors (e.g., sleep-driving, preparing/eating food, making phone calls) while not fully awake","Worsening of depression or suicidal ideation","Anaphylaxis and angioedema (rare)","Tolerance, dependence, and withdrawal symptoms with prolonged use","Respiratory depression in patients with compromised respiratory function","Use with caution in elderly due to increased risk of falls and cognitive impairment","Not recommended for long-term use (beyond 7-10 days)"]

Clinical Tips & Counseling

Drug interactions

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