Section 10 · Monograph

Zolpidem

Reviewed Nov 2026FDA label

Ambien / Ambien CRNonbenzodiazepine hypnotic (Z-drug)

Black Box Warning

COMPLEX SLEEP BEHAVIORS: Complex sleep behaviors, including sleepwalking, sleep-driving, and engaging in other activities while not fully awake (preparing/eating food, making phone calls, having sex), have been reported with zolpidem across all approved formulations. These behaviors can occur after the first dose or at any time during treatment, with or without concomitant alcohol/CNS depressants; patients usually do not remember these events. Serious injuries and deaths — falls, burns, drowning, hypothermia, motor vehicle accidents, firearm-related injuries — have occurred. Zolpidem is contraindicated in patients who have experienced a complex sleep behavior after taking the drug. Discontinue immediately if it occurs. (Class-wide boxed warning mandated by FDA April 30, 2019, for zolpidem-, eszopiclone-, and zaleplon-containing products.)

Ambien (immediate-release) and generic zolpidem tartrate tablets: short-term treatment of insomnia characterized by difficulties with sleep onset.FDA-labeled
Ambien CR (extended-release): short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.FDA-labeled
Edluar (sublingual tablet): short-term treatment of insomnia characterized by difficulties with sleep initiation.FDA-labeled
Zolpimist (oral spray): short-term treatment of insomnia characterized by difficulties with sleep initiation.FDA-labeled
Intermezzo (low-dose sublingual tablet): as-needed treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep, and the patient has at least 4 hours of planned bedtime remaining. NOT indicated when fewer than 4 hours of bedtime remain.FDA-labeled

Zolpidem is a non-benzodiazepine hypnotic of the imidazopyridine class.
Acts as a positive allosteric modulator at the GABA-A receptor-chloride channel complex, with relative selectivity for GABA-A receptors containing the alpha-1 subunit (most associated with sedative/hypnotic effects, as opposed to alpha-2/alpha-3 subunits more associated with anxiolytic/muscle-relaxant effects of classic benzodiazepines).
This alpha-1 selectivity underlies zolpidem's relatively hypnotic-predominant profile with less anxiolytic/myorelaxant/anticonvulsant activity than nonselective benzodiazepines, though it still carries dependence/abuse potential (Schedule IV).
Increases the frequency of chloride channel opening in response to GABA, enhancing inhibitory neurotransmission.
Ambien CR uses a bilayer tablet (immediate-release outer layer plus extended-release inner layer) for initial rapid release plus sustained release to support sleep maintenance.

Sex-specific dosing (all formulations, per 2013 FDA label changes): women clear zolpidem more slowly and have higher morning blood levels increasing next-day driving/psychomotor impairment risk; lower starting doses recommended for women.
Ambien (IR): Women 5 mg; Men 5 or 10 mg, once nightly immediately before bedtime with at least 7-8 hours remaining; max 10 mg/day.
Ambien CR (ER): Women 6.25 mg; Men 6.25 or 12.5 mg, once nightly with at least 7-8 hours remaining; max 12.5 mg/day; swallow whole.
Edluar (sublingual): Women 5 mg; Men 5 or 10 mg, once nightly; max 10 mg/day.
Intermezzo (sublingual, middle-of-night use only): Women 1.75 mg; Men 3.5 mg — taken only upon middle-of-night awakening with at least 4 hours of bedtime remaining; limit one dose per night.
All formulations: avoid concomitant alcohol; avoid taking with or immediately after a meal.

Zolpimist (oral spray): standard adult dose 10 mg (2 sprays) once nightly; 5 mg (1 spray) for elderly, debilitated, or hepatic impairment.
Elderly (≥65) and hepatic impairment: use the lowest recommended dose for each formulation regardless of sex.

Prior episode of complex sleep behavior after taking zolpidem.
Known hypersensitivity to zolpidem (reactions have included anaphylaxis and angioedema).

CNS depressants (opioids, benzodiazepines, other sedative-hypnotics, TCAs, alcohol): additive CNS/respiratory depression, increased risk of severe sedation, coma, and death.
CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): increase zolpidem exposure and effect; consider dose reduction.
CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): decrease zolpidem efficacy.
Sertraline: increases zolpidem Cmax (~43%) and reduces Tmax; monitor for increased sedation.
Imipramine and chlorpromazine: additive decreases in alertness and psychomotor performance.

Complex sleep behaviors — boxed warning; can result in serious injury or death.
Most common (short-term use, ≤10 nights): drowsiness, dizziness, diarrhea, headache.
Most common (longer-term use, 28-35 nights): dizziness, drugged/hangover feeling, next-day somnolence.
Next-day psychomotor and driving impairment, including impaired driving ability that can persist even when the patient feels fully awake — increased with higher doses (especially Ambien CR 12.5 mg), in women, and with concomitant CNS depressants or alcohol.
CNS depression, abnormal thinking, and behavioral changes (bizarre behavior, agitation, hallucinations, depersonalization).
Worsening of depression, emergence or worsening of suicidal thoughts/actions.
Respiratory depression, particularly with compromised respiratory function.
Hepatic encephalopathy risk in severe hepatic disease.
Withdrawal symptoms (rebound insomnia, anxiety, tremor, rarely seizures) with abrupt discontinuation after prolonged use.
Anaphylaxis and angioedema (rare but serious).
Tolerance and physical/psychological dependence with prolonged use.

Assess for prior history of complex sleep behaviors before initiating and at follow-up visits; discontinue immediately if any occur.
Screen for and counsel against concomitant alcohol or other CNS depressant use.
Assess next-day alertness/driving safety, particularly in women and with Ambien CR or higher doses.
Monitor for mood changes, depression, or emerging suicidal ideation.
Monitor for signs of misuse, tolerance, or dependence; use lowest effective dose for shortest duration.
Reassess ongoing need for therapy periodically.
Hepatic function assessment in patients with liver disease.
Respiratory status in patients with compromised pulmonary function or sleep apnea.

Pregnancy: Use especially late in the third trimester may cause neonatal CNS depression (respiratory depression, sedation, hypotonia/'floppy infant' symptoms); monitor neonates exposed during pregnancy. Available data have not established a clear association with major birth defects or miscarriage.
Lactation: Zolpidem is present in human milk in low concentrations. Advise mothers to monitor infants for increased sleepiness, poor feeding, or limpness.