Eszopiclone - Drug Monograph

Introduction

Eszopiclone is a non-benzodiazepine hypnotic agent belonging to the cyclopyrrolone class, marketed under the brand name Lunesta®. It is FDA-approved for the treatment of insomnia characterized by difficulty with sleep initiation and/or sleep maintenance. As a Schedule IV controlled substance, eszopiclone represents an important therapeutic option in sleep medicine with a distinct pharmacological profile from traditional benzodiazepines.

Mechanism of Action

Eszopiclone exerts its hypnotic effects through selective binding to the gamma-aminobutyric acid (GABA) type A receptor complex at binding sites located close to or allosterically coupled to benzodiazepine receptors. This binding enhances GABAergic neurotransmission by increasing the frequency of chloride channel opening, resulting in neuronal hyperpolarization and reduced central nervous system excitability. The drug demonstrates selectivity for α1, α2, α3, and α5 subunit-containing GABAA receptors, which contributes to its sedative-hypnotic effects while potentially offering a different side effect profile compared to non-selective agents.

Indications

• Treatment of insomnia characterized by difficulty with sleep onset
• Treatment of insomnia characterized by difficulty with sleep maintenance
• FDA-approved for both short-term and long-term use (non-habit-forming claims not established)

Dosage and Administration

• Initial dose: 1 mg immediately before bedtime
• May increase to 2-3 mg if clinically indicated
• Maximum recommended dose: 3 mg daily

• Severe hepatic impairment: Initial dose should not exceed 1 mg
• Elderly patients: Initial dose of 1 mg recommended due to increased sensitivity
• Debilitated patients: Initial dose of 1 mg recommended
• Renal impairment: No dosage adjustment required
• Taking potent CYP3A4 inhibitors: Initial dose should not exceed 1 mg

• Take immediately before bedtime
• Ensure at least 7-8 hours remain before planned awakening
• Do not take with or immediately after a high-fat meal

Pharmacokinetics

Contraindications

• Hypersensitivity to eszopiclone or any component of the formulation
• Concomitant use with potent CYP3A4 inhibitors in patients with hepatic impairment
• History of complex sleep behaviors with previous hypnotic use

Warnings and Precautions

• Complex Sleep Behaviors: Reports of complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake that may result in serious injuries or death

• CNS depressant effects: Additive effects with other CNS depressants
• Need to evaluate for comorbid diagnoses: Underlying physical and/or psychiatric disorders
• Abnormal thinking and behavior changes: Including agitation, hallucinations, depression, and suicidal ideation
• Withdrawal effects: Rapid dose reduction or discontinuation may cause withdrawal symptoms
• Tolerance: May develop with repeated use
• Pregnancy: Not recommended during pregnancy
• Lactation: Not recommended while breastfeeding

Drug Interactions

• CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir): Increase eszopiclone concentrations
• CNS depressants (alcohol, opioids, benzodiazepines): Additive CNS depression
• CYP3A4 inducers (rifampin, carbamazepine): Decrease eszopiclone concentrations

• Olanzapine: Increased orthostatic hypotension
• Theophylline: May decrease eszopiclone efficacy

Adverse Effects

• Unpleasant taste (dysgeusia) (34%)
• Headache (17%)
• Somnolence (10%)
• Dizziness (8%)
• Dry mouth (7%)
• Nervousness (5%)
• Nausea (5%)

• Complex sleep behaviors
• Anaphylaxis
• Angioedema
• Depression exacerbation
• Suicidal ideation
• Memory impairment
• Withdrawal seizures

Monitoring Parameters

• Sleep patterns and quality assessment
• Mental status changes
• Signs of misuse, abuse, or dependence
• Withdrawal symptoms upon discontinuation
• Daytime alertness and cognitive function
• Adverse effects, particularly CNS effects
• Renal and hepatic function in impaired patients

Patient Education

• Take immediately before bedtime with at least 7-8 hours for sleep
• Do not take with alcohol or other sedating medications
• Report any sleep behaviors you don't remember performing
• Be aware of possible next-day impairment; use caution when driving
• Unpleasant taste is common but usually diminishes with continued use
• Do not stop medication abruptly without medical supervision
• Inform healthcare providers of all medications being taken
• Notify provider if pregnancy is planned or occurs
• Store securely to prevent misuse by others

References

1. FDA Prescribing Information: Lunesta (eszopiclone) tablets. Revised 2014. 2. Zammit G, McNabb LJ, Caron J, et al. Efficacy and safety of eszopiclone across 6 weeks of treatment for primary insomnia. Curr Med Res Opin. 2004;20(12):1979-1991. 3. Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003;26(7):793-799. 4. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004;43(4):227-238. 5. American Academy of Sleep Medicine. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults. J Clin Sleep Med. 2017;13(2):307-349. 6. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.