Zaleplon

Indications

• FDA-approved for the short-term treatment of insomnia in adults, with demonstrated shortening of time to sleep onset.
• The one-hour half-life allows dosing after a middle-of-the-night awakening provided at least 4 hours of bed time remain.
• It is the preferred Z-drug when next-morning impairment must be minimized, such as for on-call staff or early-shift workers.
• It does not reliably improve sleep maintenance or total sleep time, so it is a poor choice for early morning awakening.
• Cognitive behavioral therapy for insomnia is first line per American Academy of Sleep Medicine and American College of Physicians guidance.
• Off-label use for jet lag or transient situational insomnia is common in practice but is not a labeled indication.

Mechanism of action

• Pyrazolopyrimidine that binds the benzodiazepine site of the GABA-A receptor and enhances chloride conductance in the presence of GABA.
• Selective for alpha-1 subunit-containing receptors, producing sedation with minimal anxiolytic, anticonvulsant or muscle relaxant effect.
• Very rapid receptor occupancy and equally rapid washout give a sharp hypnotic pulse with little pharmacodynamic tail by morning.
• Sleep architecture is essentially preserved, with no consistent suppression of slow wave sleep or REM at labeled doses.
• Brief action limits daytime carryover but also limits maintenance benefit, and rebound insomnia can occur in the second half of the night.

Pharmacokinetics

• Rapidly absorbed with peak levels at about 1 hour, but absolute bioavailability is only 30 percent because of extensive first-pass metabolism.
• Elimination half-life is roughly 1 hour, the shortest of any oral hypnotic in current US use, and the basis for middle-of-night dosing.
• Metabolized mainly by aldehyde oxidase to 5-oxo-zaleplon, with a minor CYP3A4 pathway; all metabolites are pharmacologically inactive.
• A high-fat or heavy meal delays the peak by about 2 hours and reduces it by roughly 35 percent, largely defeating the sleep-onset effect.
• Clearance falls sharply in cirrhosis, with exposure up to seven-fold higher in severe hepatic impairment, where it should not be used.

Dosing

• Adults: 10 mg PO immediately before bedtime or after a middle-of-the-night awakening, with at least 4 hours of bed time remaining.
• The labeled range is 5-20 mg; the 20 mg dose has been evaluated but offers little added benefit and increases adverse effects.
• Older adults, low-weight patients and mild to moderate hepatic impairment: start at 5 mg and do not exceed 10 mg per night.
• Not recommended in severe hepatic impairment; no dose adjustment is needed for mild to moderate renal impairment.
• Take on an empty stomach at least 2 hours after a heavy meal, and take only one dose per night by any route.
• Intended for 7-10 nights of use; taper after prolonged nightly dosing rather than stopping abruptly to limit rebound insomnia.

Adverse effects

• Headache in about 30 percent, drowsiness 6 percent, dizziness 7 percent, nausea 6 percent and abdominal pain at 20 mg doses.
• Complex sleep behaviors including sleepwalking, sleep-driving and sleep-eating without recall, which require immediate permanent discontinuation.
• Anterograde amnesia for the period after dosing, and confusion or hallucinations, particularly at the 20 mg dose.
• Rebound insomnia in the latter half of the night for some patients, a direct consequence of the very short duration of action.
• Falls, fractures and delirium in older adults, and impaired coordination if the patient gets up during the hour after dosing.
• Angioedema and anaphylaxis after the first or later doses, and additive respiratory depression with opioids and alcohol.

Monitoring

• Ask specifically about sleepwalking, sleep-driving, nocturnal eating and amnesia for nighttime events at every follow-up.
• Evaluate for sleep apnea, restless legs, alcohol use, pain and untreated mood disorder before or alongside hypnotic therapy.
• Reassess response and continued need within 7-10 days, since persistence beyond that suggests an untreated comorbid condition.
• Confirm the patient can commit to at least 4 hours in bed after any dose, including middle-of-the-night dosing.
• Check the prescription monitoring program and screen for substance use disorder before prescribing this schedule IV hypnotic.

Interactions

• Contraindicated in patients who have experienced a complex sleep behavior on zaleplon and in known hypersensitivity or prior angioedema.
• Cimetidine inhibits both aldehyde oxidase and CYP3A4 and raises zaleplon exposure by about 85 percent; start at 5 mg.
• Rifampin and other strong CYP3A4 inducers reduce exposure roughly four-fold and can render standard doses ineffective.
• Additive sedation and respiratory depression with opioids, alcohol, benzodiazepines, gabapentinoids and sedating antihistamines.
• Thioridazine and imipramine produce additive psychomotor impairment when combined, and alcohol markedly amplifies impairment.

Special populations

• Pregnancy: human data are limited; late exposure raises theoretical risk of neonatal sedation, hypotonia and respiratory depression.
• Lactation: excreted into human milk in small amounts with a very short half-life, so timing after the last feed limits infant exposure.
• Pediatrics: safety and effectiveness under age 18 are not established and use is not recommended in this age group.
• Older adults: the AGS Beers Criteria advise avoiding Z-drugs given delirium, falls, fractures and crash risk; cap the dose at 5-10 mg.
• Hepatic impairment: reduce to 5 mg in mild to moderate disease and avoid entirely in severe disease; renal dosing needs no change.

Clinical pearls

• The only hypnotic short enough to dose at 3 a.m. with 4 hours of bed time left.
• Poor for sleep maintenance; total sleep time barely changes and rebound can occur before dawn.
• Cimetidine nearly doubles levels because it blocks aldehyde oxidase, not just CYP3A4.