AMBIEN CR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AMBIEN CR (AMBIEN CR).
AMBIEN CR's active ingredient is zolpidem, a non-benzodiazepine hypnotic that binds selectively to the benzodiazepine-1 (BZ1) receptor subtype on the GABA-A receptor complex, potentiating GABAergic inhibition and promoting sleep.
| Metabolism | Metabolized primarily by CYP3A4, with minor contributions from CYP2C9, CYP1A2, CYP2D6, and CYP2C19. |
| Excretion | Primarily renal (80% as metabolites, <5% unchanged), minor fecal (<10%) |
| Half-life | Zolpidem immediate-release: ~2.5 h (range 1.4–3.8 h); modified-release (Ambien CR): ~2.8 h (range 1.6–4.5 h). Clinical note: Half-life increased in hepatic impairment and elderly. |
| Protein binding | Approximately 92%, primarily to albumin |
| Volume of Distribution | 0.54 L/kg (range 0.3-0.7 L/kg), suggesting distribution into total body water with moderate tissue binding |
| Bioavailability | Oral immediate-release: ~70%; modified-release: ~70% due to first-pass metabolism |
| Onset of Action | Immediate-release: 15-30 min; modified-release: 30-60 min |
| Duration of Action | Immediate-release: 6-8 h; modified-release: 7-9 h. Clinical note: Modified-release provides middle-of-the-night sleep maintenance. |
12.5 mg orally once daily immediately before bedtime; lower dose of 6.25 mg may be considered. Not to exceed 12.5 mg per day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended for severe renal impairment (CrCl < 30 mL/min) due to lack of data. |
| Liver impairment | For Child-Pugh Class A or B: 6.25 mg orally once daily immediately before bedtime. Not recommended for Child-Pugh Class C. |
| Pediatric use | Not recommended for pediatric patients (safety and efficacy not established). |
| Geriatric use | Elderly or debilitated patients: 6.25 mg orally once daily immediately before bedtime. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AMBIEN CR (AMBIEN CR).
| Breastfeeding | Excreted into breast milk; M/P ratio not available. Caution advised; monitor infant for sedation, feeding difficulties, and respiratory depression. Avoid or use lowest effective dose. |
| Teratogenic Risk | First trimester: Limited data; no consistent evidence of major malformations. Second/third trimesters: May cause fetal respiratory depression, hypotonia, and withdrawal symptoms in neonates after prolonged use. Risk of floppy infant syndrome if used near term. |
| Fetal Monitoring |
■ FDA Black Box Warning
Complex sleep behaviors including sleep-driving, making phone calls, preparing and eating food, and other activities while not fully awake, which may result in injury or death. Discontinue immediately if such behaviors occur.
| Serious Effects |
["History of complex sleep behaviors after taking zolpidem","Hypersensitivity to zolpidem or any component of the formulation"]
| Precautions | ["Complex sleep behaviors","CNS depressant effects and daytime impairment","Need to evaluate for co-morbid diagnoses","Severe anaphylactic/anaphylactoid reactions","Abnormal thinking and behavioral changes","Suicide risk","Respiratory depression","Withdrawal effects","Use in patients with compromised respiratory function","Use in patients with hepatic impairment"] |
| Food/Dietary | Avoid high-fat or heavy meals before taking AMBIEN CR, as food, especially high-fat meals, delays absorption and reduces peak concentration. Grapefruit juice may theoretically affect metabolism via CYP3A4 inhibition, though not well documented; avoid concomitant intake. Caffeine consumption should be minimized in the evening as it may antagonize the hypnotic effect. |
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| Monitor maternal sedation, respiratory rate, and blood pressure. Fetal monitoring for heart rate patterns in third trimester if used regularly. Neonatal monitoring for withdrawal symptoms (e.g., irritability, tremors) post-delivery. |
| Fertility Effects | No specific human data on fertility impairment. Animal studies show no significant effects on fertility. |
| Clinical Pearls | For AMBIEN CR (zolpidem tartrate extended-release), the recommended dose in women is 6.25 mg and in men is 6.25 or 12.5 mg immediately before bedtime with at least 7-8 hours remaining before planned awakening. Avoid co-administration with CNS depressants, including alcohol. Use with caution in patients with hepatic impairment due to reduced clearance. Do not administer with or immediately after a meal as it may slow absorption and reduce efficacy. Monitor for complex sleep behaviors (e.g., sleep-driving) and discontinue if they occur. |
| Patient Advice | Take AMBIEN CR exactly as prescribed: one dose per night immediately before bedtime with at least 7-8 hours until planned awakening. · Do not take this medication with or right after a meal, as high-fat or heavy meals can reduce the drug's effectiveness. · Avoid drinking alcohol while taking AMBIEN CR; serious side effects like extreme drowsiness, difficulty breathing, or loss of consciousness may occur. · Do not engage in activities requiring full mental alertness (e.g., driving, operating machinery) the next day until you know how this drug affects you. · Seek immediate medical attention if you experience unusual behaviors such as sleep-driving, sleep-eating, or making phone calls while not fully awake. |