Zolpidem - Drug Monograph

Introduction

Zolpidem is a non-benzodiazepine sedative-hypnotic medication primarily used for the short-term treatment of insomnia. Marketed under brand names including Ambien, Intermezzo, and Edluar, it belongs to the imidazopyridine class and acts as a GABA-A receptor agonist with selective affinity for the ω-1 receptor subtype.

Mechanism of Action

Zolpidem enhances the effects of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. It binds selectively to the benzodiazepine binding site on GABA-A receptors, particularly those containing α1 subunits. This binding increases chloride ion conductance through GABA-gated channels, resulting in neuronal hyperpolarization and CNS depression. Unlike traditional benzodiazepines, zolpidem demonstrates relative selectivity for ω1 receptors, which are associated with sedative effects rather than anxiolytic, muscle relaxant, or anticonvulsant properties.

Indications

• Short-term treatment of insomnia characterized by difficulties with sleep initiation
• Middle-of-the-night awakening (lower-dose sublingual formulation only)
• FDA-approved for use generally not exceeding 2-4 weeks duration

Dosage and Administration

• Immediate-release tablets: 5 mg (women) or 5-10 mg (men) orally before bedtime
• Extended-release tablets: 6.25 mg (women) or 12.5 mg (men) orally before bedtime
• Sublingual tablets: 1.75 mg (women) or 3.5 mg (men) once per night after awakening

• Hepatic impairment: Reduce dose to 5 mg immediately before bedtime
• Elderly: Initial dose of 5 mg immediately before bedtime
• Renal impairment: No specific dosage adjustment recommended

• Take immediately before bedtime with at least 7-8 hours remaining before planned awakening
• Do not take with or immediately after a meal
• Sublingual formulation: Place under tongue and allow to dissolve completely

Pharmacokinetics

Contraindications

• Hypersensitivity to zolpidem or any component of the formulation
• History of complex sleep behaviors while taking zolpidem
• Concurrent use with other CNS depressants in certain clinical situations
• Severe hepatic impairment
• Obstructive sleep apnea
• Myasthenia gravis
• Severe respiratory depression

Warnings and Precautions

• Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake

• CNS depressant effects: Additive effects with other CNS depressants
• Next-day impairment: Risk of impaired alertness and coordination
• Withdrawal symptoms: May occur with rapid discontinuation
• Tolerance: May develop with repeated use
• Abnormal thinking and behavior changes: Including agitation, hallucinations, depression
• Anaphylaxis and angioedema: Have been reported
• Respiratory depression: Use with caution in patients with respiratory compromise
• Depression: May worsen depression; evaluate for underlying psychiatric disorders
• Drug tolerance, dependence, and withdrawal: Potential for abuse and dependence

Drug Interactions

• CNS depressants (alcohol, opioids, benzodiazepines): Additive CNS depression
• CYP3A4 inhibitors (ketoconazole, ritonavir): Increased zolpidem levels
• CYP3A4 inducers (rifampin, carbamazepine): Decreased zolpidem levels
• Imipramine: Increased risk of next-day psychomotor impairment
• Chlorpromazine: Impaired psychomotor function

• SSRIs: Potential increased sedation
• Antipsychotics: Additive CNS effects
• Anticonvulsants: Possible altered seizure threshold

Adverse Effects

• Headache (19%)
• Drowsiness (8%)
• Dizziness (5%)
• Diarrhea (5%)
• Nausea (4%)

• Complex sleep behaviors (sleep-walking, sleep-driving)
• Anaphylaxis
• Angioedema
• Respiratory depression
• Depression, suicidal ideation
• Withdrawal symptoms
• Memory impairment
• Hallucinations
• Paradoxical reactions (agitation, aggression)

Monitoring Parameters

• Sleep patterns and quality
• Daytime alertness and cognitive function
• Signs of complex sleep behaviors
• Respiratory status in patients with pulmonary disease
• Hepatic function in patients with liver impairment
• Signs of tolerance, dependence, or withdrawal
• Psychiatric symptoms
• Fall risk in elderly patients
• Medication adherence and duration of use

Patient Education

• Take immediately before bedtime with at least 7-8 hours available for sleep
• Do not crush, break, or chew extended-release tablets
• Avoid alcohol and other CNS depressants
• Be aware of potential next-day impairment; use caution when driving or operating machinery
• Report any unusual sleep behaviors, memory problems, or mood changes
• Do not discontinue abruptly without medical supervision
• Inform healthcare providers of all medications being taken
• Store safely to prevent accidental ingestion or misuse
• Use only as prescribed and for the shortest duration necessary

References

1. FDA. (2022). Ambien (zolpidem tartrate) prescribing information. 2. Schlich, D., et al. (2021). "Zolpidem: Efficacy and Safety." Sleep Medicine Reviews, 55, 101405. 3. Greenblatt, D. J., & Zammit, G. K. (2022). "Pharmacokinetic evaluation of zolpidem." Clinical Pharmacokinetics, 61(3), 301-315. 4. American Academy of Sleep Medicine. (2021). Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults. 5. National Institutes of Health. (2022). MedlinePlus Drug Information: Zolpidem. 6. European Medicines Agency. (2021). Zolpidem-containing medicinal products. 7. Krystal, A. D., et al. (2020). "Long-term efficacy and safety of zolpidem extended-release 12.5 mg." Journal of Clinical Sleep Medicine, 16(3), 397-406. 8. Substance Abuse and Mental Health Services Administration. (2022). Clinical Guidance for Treating Sleep Disorders.