AMBIEN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AMBIEN (AMBIEN).
Positive allosteric modulator of GABA-A receptors, enhancing the inhibitory effects of GABA. Binds selectively to the alpha-1 subunit, producing sedative, hypnotic, and anxiolytic effects.
| Metabolism | Primarily hepatic via CYP3A4 (major) and CYP2C9; also via oxidation and conjugation. Active metabolite (N-desalkyl-flurazepam) for flurazepam; for zolpidem, no active metabolites. |
| Excretion | Primarily renal excretion: approximately 56% of the dose is recovered in urine as metabolites (including 5% unchanged drug). Fecal excretion accounts for about 34% of the dose. Small amounts are excreted in bile. |
| Half-life | Terminal elimination half-life is approximately 2.6 hours (range 1.4–4.5 hours). In elderly patients, half-life may be prolonged to about 2.9 hours. In patients with hepatic cirrhosis, half-life is significantly increased (up to 9.8 hours). |
| Protein binding | Approximately 92–93% bound to plasma proteins, primarily albumin (major) and alpha-1-acid glycoprotein (minor). |
| Volume of Distribution | Volume of distribution is approximately 0.54 L/kg (range 0.4–0.7 L/kg), indicating moderate tissue distribution. Higher Vd in elderly may reflect increased body fat. |
| Bioavailability | Oral immediate-release: approximately 70% due to first-pass metabolism. Sublingual: bioavailability is about 75–80% (slightly higher than oral due to partial avoidance of first-pass). Extended-release oral: similar bioavailability to immediate-release. |
| Onset of Action | Oral immediate-release: 15–30 minutes. Sublingual formulation: approximately 8–10 minutes. Onset is rapid due to high lipophilicity and rapid absorption. |
| Duration of Action | Duration of hypnotic effect is approximately 3–4 hours for immediate-release formulations. Extended-release tablets provide prolonged sedation lasting 6–8 hours due to biphasic release. Clinical note: Duration is dose-dependent and shorter in patients with rapid clearance. |
5-10 mg orally once daily at bedtime, maximum 10 mg/day.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment; use caution in severe renal impairment (eGFR <30 mL/min) with maximum dose 5 mg. |
| Liver impairment | Child-Pugh A or B: 5 mg orally once daily at bedtime; Child-Pugh C: contraindicated. |
| Pediatric use | Not approved for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | Initial dose 5 mg orally once daily at bedtime due to increased sensitivity; maximum 5 mg/day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AMBIEN (AMBIEN).
| Breastfeeding | Zolpidem is excreted into breast milk with a milk-to-plasma ratio of approximately 0.13. The relative infant dose is estimated to be less than 2% of the maternal weight-adjusted dose. However, exposure may cause sedation and somnolence in the breastfeeding infant. Caution is recommended; avoid breastfeeding if maternal dose is high or infant is premature. |
| Teratogenic Risk | Pregnancy Category C. First trimester: Limited data, no well-controlled studies, potential risk of congenital anomalies cannot be excluded. Second/third trimesters: Use of zolpidem near term may cause respiratory depression, hypotonia, and withdrawal symptoms in neonates. Risk of preterm labor and low birth weight associated with continued use. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to zolpidem or any component","History of complex sleep behaviors after taking zolpidem","Severe hepatic impairment (use lower doses; contraindicated if Child-Pugh C)","Narrow-angle glaucoma (relative; caution with anticholinergic effects)","Myasthenia gravis (relative; caution due to muscle relaxant effects)","Concurrent use with alcohol or other CNS depressants (relative)"]
| Precautions | ["CNS depression: avoid alcohol and other CNS depressants","Complex sleep behaviors (e.g., sleep-driving, making phone calls, preparing and eating food)","Hypersensitivity reactions including anaphylaxis and angioedema","Respiratory depression risk in COPD or sleep apnea","Depression: monitor for suicidality","Dependence and withdrawal; risk of abuse","Elderly or debilitated: increased fall risk; use lower doses","Memory impairment (anterograde amnesia)","Paradoxical reactions (e.g., restlessness, agitation)"] |
| Food/Dietary | Avoid high-fat meals before taking Ambien, as they can delay absorption and decrease the drug's effect. Avoid grapefruit and grapefruit juice, as they may inhibit CYP3A4 metabolism, potentially increasing zolpidem levels and side effects. Alcohol must be avoided entirely, as it synergistically increases CNS depression and risk of complex sleep behaviors. There are no other significant food restrictions. |
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| Fetal Monitoring | Monitor maternal vital signs and level of sedation. Assess fetal heart rate and uterine activity if used for preterm labor. Neonates should be observed for signs of respiratory depression, hypotonia, poor feeding, and withdrawal symptoms (e.g., jitteriness, irritability). |
| Fertility Effects | In animal studies, zolpidem did not impair fertility at doses up to 20 times the human dose. No human data on effects on fertility; however, sedative-hypnotics may indirectly affect reproductive function via alteration of sleep patterns or hormonal disruption. |
| Clinical Pearls | Ambien (zolpidem) is a non-benzodiazepine hypnotic that acts as a positive allosteric modulator at GABA-A receptors, specifically the alpha-1 subunit. It has a rapid onset of action (15-30 minutes) and a short half-life (2-3 hours), making it suitable for sleep-onset insomnia. Avoid use with other CNS depressants due to risk of respiratory depression. Complex sleep behaviors (e.g., sleepwalking, sleep-driving) have been reported; discontinue if they occur. Tolerance and dependence can develop; limit use to short-term (4 weeks max). Elderly patients are more susceptible to falls and cognitive impairment; use lowest effective dose (5 mg). |
| Patient Advice | Take Ambien immediately before bedtime, only when you have at least 7-8 hours available for sleep. · Do not take with or immediately after a high-fat meal, as it can delay absorption and reduce effectiveness. · Do not consume alcohol while taking Ambien; it increases the risk of dangerous side effects. · Ambien may cause next-day drowsiness, dizziness, or impaired thinking; avoid driving or hazardous activities until you know how it affects you. · If you experience unusual behaviors such as sleepwalking, eating, or driving while not fully awake, stop the medication and contact your doctor immediately. · Do not take Ambien for longer than prescribed; it is intended for short-term use (usually 7-10 days) to avoid dependence. · If you miss a dose, skip it; do not double the dose to catch up. · Store Ambien at room temperature away from moisture and heat. · Keep Ambien in a secure place to prevent accidental ingestion by others. · Report any allergic reactions (rash, hives, swelling) or severe side effects like memory loss or depression to your healthcare provider. |