Brand name: Lunesta
Drug class: Anxiolytics, Sedatives, and Hypnotics; Miscellaneous
Chemical name: (5S-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolol[3,4-b]pyrazin-5-yl-ester-4-methyl-1-piperazinecarboxylic acid
Molecular formula: C₁₇H₁₇ClN₆O₃
CAS number: 138729-47-2

Medically reviewed by Drugs.com on Apr 23, 2023. Written by ASHP.

Introduction

Sedative and hypnotic; pyrrolopyrazine derivative; structurally unrelated to benzodiazepines.

Uses for Eszopiclone

Insomnia

Management of transient and chronic insomnia.

Decreases sleep latency, improves sleep maintenance, and prolongs total sleep time in patients with chronic or transient insomnia; reportedly effective with repeated (i.e., nightly) use for periods up to 6 months in duration.

Sleep architecture (i.e., the percentage of time spent in each sleep stage) generally is preserved at usual dosages.

Evidence is lacking to suggest that sleep improvement is maintained following discontinuance.

Psychological and behavioral interventions are recommended as initial treatment for insomnia according to the American Academy of Sleep Medicine (AASM) and American College of Physicians (ACP). When pharmacologic therapy is indicated, choice of agent should be directed by symptoms, treatment goals, past treatment response, patient preference, drug cost and availability, comorbid conditions/contraindications, concomitant drug therapy/interactions, and potential adverse effects.

Eszopiclone is among several agents recommended for treatment of sleep onset and sleep maintenance insomnia. The lowest effective dosage and short-term treatment (4–5 weeks) are recommended.

Related/similar drugs

Quviviq, lorazepam, zolpidem, melatonin, diphenhydramine, Ativan, Ambien

Eszopiclone Dosage and Administration

General

Pretreatment Screening

• Screen patients for diseases or conditions that may affect drug metabolism or hemodynamic responses.

• Consider the risk of respiratory depression prior to use of eszopiclone in patients with respiratory impairment.

• Screen patients for signs and symptoms of depression.

• Screen patients for a history of alcohol or drug abuse or psychiatric disorders.

Patient Monitoring

• Monitor for excess CNS depressant effects.

• Reevaluate patient if insomnia persists after 7–10 days of treatment.

• Carefully evaluate any new behavioral sign or symptom of concern.

• Closely monitor patients with a history of alcohol or drug abuse or psychiatric disorders.

Administration

Oral Administration

Administer only immediately before retiring (when ready to sleep).

Avoid administration with or immediately after a heavy, high-fat meal; may decrease rate of absorption and effect on sleep latency.

Use only when able to get 7–8 hours of sleep before it is necessary to be active again.

Dosage

Individualize dosage; use lowest effective dosage to minimize adverse effects.

If used concomitantly with a potent CYP3A4 inhibitor, adjustment of eszopiclone dosage is recommended.

Adults

Insomnia

Oral

Initially, 1 mg. May increase to 2 or 3 mg if clinically indicated.

Dosage range of 2–3 mg shown to decrease sleep latency and improve measures of sleep maintenance in adults <65 years of age. However, in some patients, 2- or 3-mg dose may produce higher morning blood concentrations of eszopiclone, resulting in an increased risk of next-day impairment of driving and other activities that require full alertness.

Prescribing Limits

Adults

Insomnia

Oral

Maximum 3 mg once daily immediately before bedtime.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment.

In patients with severe hepatic impairment, do not exceed 2 mg once daily immediately before bedtime.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

Initially, 1 mg immediately before bedtime. May increase to 2 mg if clinically indicated.

Dosage range of 1–2 mg shown to decrease sleep latency and improve measures of sleep maintenance in geriatric patients.

Do not exceed 2 mg once daily immediately before bedtime in adults ≥65 years of age.

Debilitated Patients

Do not exceed 2 mg once daily immediately before bedtime.

Cautions for Eszopiclone

Contraindications

• History of a complex sleep behavior while taking eszopiclone, zaleplon, or zolpidem.

• Known hypersensitivity (e.g., anaphylaxis, angioedema) to eszopiclone or any ingredient in the formulation.

Warnings/Precautions

Warnings

Complex Sleep Behaviors

Complex sleep behaviors in which patients engage in activities while they are not fully awake reported; can result in serious injuries and/or death. (See Boxed Warning.) Such behaviors may include sleepwalking, sleep driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), and engaging in other activities (e.g., making phone calls, preparing and eating food).

Falls with serious injuries reported.

Can occur when sedative-hypnotic agents are taken alone or with alcohol or other CNS depressants.

Discontinue eszopiclone immediately if complex sleep behavior occurs.

Other Warnings and Precautions

Hypersensitivity Reactions

Angioedema involving the tongue, glottis, or larynx reported rarely following initial or subsequent doses of sedative and hypnotic drugs, including eszopiclone; airway obstruction may occur and may be fatal. Other symptoms suggestive of anaphylaxis (e.g., dyspnea, throat closing, nausea, vomiting) also reported. Emergency treatment was required in some patients.

Do not rechallenge with the drug if angioedema occurs.

CNS Depressant Effects and Next-day Impairment

CNS depressant effects (i.e., memory impairment, confusion) reported following use of higher doses.

Drowsiness and decreased levels of consciousness may increase the risk of falls, particularly in geriatric patients.

Next-day impairment of psychomotor function (i.e., ability to maintain a motor vehicle in the driving lane, working memory, motor coordination) reported in patients receiving 3-mg dose. Next-day impairment most severe at 7.5 hours postdose but still present and potentially clinically meaningful at 11.5 hours postdose. Patients often unaware of these impairments.

Risk of next-day psychomotor impairment is increased if drug is administered with <7–8 hours of sleep time remaining, if higher than recommended dose is administered, or if used concomitantly with other CNS depressants or with drugs capable of increasing eszopiclone concentrations.

To reduce risk of next-day impairment, manufacturer and FDA lowered recommended initial dosage from 2 mg to 1 mg immediately before bedtime; lower initial dosage will result in less drug in the blood the next day. Patients currently receiving eszopiclone should continue therapy at the prescribed dosage and should contact their clinician to determine the most appropriate dosage. FDA is continuing to evaluate the risk of impaired mental alertness associated with other sedatives and hypnotics, including OTC preparations. OTC sedative and hypnotic drugs not considered safer than prescription drugs.

Monitor patients for excessive CNS depression; however, impairment may occur in the absence of symptoms and may not be reliably detected by ordinary clinical examination (i.e., formal psychomotor testing may be required).

Concomitant use with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) results in additive CNS depression.

Concomitant use with other sedatives and hypnotics, including OTC preparations used to treat insomnia (e.g., diphenhydramine, doxylamine succinate), at bedtime or in the middle of the night is not recommended.

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.

Failure of insomnia to remit after 7–10 days of treatment, worsening of insomnia, or emergence of new abnormal thinking or behavior may indicate the presence of an underlying psychiatric, physical, and/or medical condition that requires evaluation. Reevaluate patient if insomnia persists after 7–10 days of therapy.

Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavioral changes (e.g., decreased inhibition, uncharacteristic extroversion and aggressiveness, bizarre behavior, agitation, hallucinations, depersonalization) reported in patients receiving sedative and hypnotic drugs. Amnesia and other neuropsychiatric symptoms may occur unpredictably.

Carefully and immediately evaluate any new concerning behavioral sign or symptom.

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs and symptoms of withdrawal.

No evidence of a serious withdrawal syndrome associated with eszopiclone; however, anxiety, abnormal dreams, nausea, upset stomach, hyperesthesia, and neurosis reported within 48 hours following discontinuance.

Rebound insomnia of 1 day’s duration reported in clinical trials of eszopiclone.

Abuse Potential

Abuse potential of high doses (2–4 times maximum recommended hypnotic dose) in individuals with a history of benzodiazepine abuse appeared to be similar to that of benzodiazepines (e.g., diazepam 20 mg).

Patients with a history of drug or alcohol abuse or a history of psychiatric disorders are at risk of habituation or dependence; use only with careful surveillance in such patients.

Tolerance

Pharmacodynamic tolerance and adaptation to the hypnotic effect of eszopiclone not observed during studies of up to 6 months’ duration.

Timing of Drug Doses

Administer eszopiclone only immediately before retiring; administering drug while still up and about could result in adverse CNS effects such as short-term memory impairment, hallucinations, dizziness, and impaired coordination.

Geriatric and/or Debilitated Patients

Possible increased sensitivity to pharmacologic and adverse effects (e.g., impaired motor and/or cognitive performance) of sedatives and hypnotics. Reduce maximum dosage.

Concomitant Disease

Limited experience in patients with concomitant systemic disease. Use with caution in patients with diseases affecting metabolism and/or hemodynamic response.

Respiratory depression was not reported in clinical studies to date in healthy individuals receiving doses 2.5-fold higher than the recommended dose; however, caution is advised in patients with impaired respiratory function.

Use in Patients with Depression

Worsening of depression and suicidal thoughts and actions (including completed suicides) reported in primarily depressed patients receiving sedative and hypnotic drugs.

Use with caution in patients with depression. Potential for suicidal tendencies; intentional overdosage more frequent in such patients. Prescribe and dispense drug in the smallest feasible quantity to avoid intentional overdosage.

Specific Populations

Pregnancy

Data on use in pregnant women insufficient to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

No evidence of teratogenicity observed in pregnant rats and rabbits administered eszopiclone throughout organogenesis.

Offspring toxicities observed at all doses tested in rats administered drug throughout pregnancy and lactation; lowest dose tested approximately 200 times the maximum recommended human dose of 3 mg daily based on body surface area.

Lactation

Not known whether distributed into human milk, affects the breast-fed infant, or affects milk production.

Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for eszopiclone and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Not effective in the management of insomnia associated with attention deficit hyperactivity disorder (ADHD).

Geriatric Use

The adverse effect profile of the 2-mg dosage in geriatric patients (median age: 71 years) was similar to that observed in clinical trials of the drug in younger adults.

Pharmacokinetic changes (e.g., longer elimination half-life; higher total systemic exposure) in geriatric patients compared with younger adults.

Reduce maximum dosage because of impaired motor and cognitive performance as well as increased sensitivity to sedatives and hypnotics.

Hepatic Impairment

Use with caution. Systemic exposure increased twofold in patients with severe hepatic impairment compared with healthy individuals. Reduce maximum dosage for severe hepatic impairment.

Renal Impairment

No dosage adjustment necessary in patients with renal impairment; <10% excreted unchanged in urine.

Common Adverse Effects

Adverse effects (reported in ≥2% of patients): Unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, viral infection.

Drug Interactions

Metabolized principally by CYP3A4 and CYP2E1.

Does not appear to inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Not expected to alter clearance of drugs metabolized by common CYP isoenzymes.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Possible increased exposure to eszopiclone. If used concomitantly, do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime.

Inducers of CYP3A4: Possible decreased systemic exposure to and efficacy of eszopiclone.

Protein-bound Drugs

Pharmacokinetic interaction unlikely; not highly bound to plasma proteins.

Specific Drugs

Eszopiclone Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration attained in about 1 hour.

Food

High-fat meal decreases peak plasma concentration by 21% and prolongs the time to peak plasma concentration by about 1 hour; effect on sleep onset may be decreased.

Special Populations

In geriatric patients, AUC is increased by 41% compared with younger adults.

In patients with severe hepatic impairment, systemic exposure is 2 times higher than in healthy individuals.

Distribution

Plasma Protein Binding

Approximately 52–59%.

Elimination

Metabolism

Extensively metabolized via oxidation and demethylation, principally by CYP3A4 and CYP2E1, to 2 major metabolites; (S)-N-desmethyl zopiclone is considerably less active than the parent drug, and (S)-zopiclone-N-oxide is inactive.

Elimination Route

Racemic zopiclone excreted principally in urine (75%), mainly as metabolites. Similar excretion profile expected for eszopiclone, the S-isomer of racemic zopiclone; <10% of eszopiclone dose excreted unchanged in urine.

Half-life

Approximately 6 hours.

Special Populations

In geriatric patients, half-life is approximately 9 hours.

Stability

Storage

Oral

Tablets

25°C (excursions permitted to 15–30°C).

Actions

• Interacts with the CNS GABA_A-receptor complex at binding domains located close to or allosterically coupled to benzodiazepine receptors.

• Pharmacologically similar to zaleplon and zolpidem.

• Structurally unrelated to benzodiazepines and other sedative and hypnotic agents that are commercially available in the US, including barbiturates, imidazopyridines (e.g., zolpidem), and pyrazolopyrimidines (e.g., zaleplon).

• S-enantiomer of zopiclone (a hypnotic agent not commercially available in the US).

• Binding affinity (in vitro) for benzodiazepine receptors is about 50 times that of the R-enantiomer of racemic zopiclone.

Advice to Patients

• Provide patient with a copy of manufacturer’s patient information. Advise patients to read the manufacturer's medication guide carefully prior to initiating therapy and each time the prescription is refilled.

• Instruct patients to administer the drug immediately before retiring.

• Instruct patients to take eszopiclone only when able to get a full night’s sleep (i.e., 7–8 hours) before being active again.

• Advise patients to avoid taking eszopiclone with or immediately after a meal.

• Advise patients to take the drug only as prescribed; do not increase dosage or duration of therapy unless otherwise instructed by a clinician.

• Advise patients to contact their clinician if their insomnia worsens or does not improve within 7–10 days of treatment.

• Advise patients to avoid taking eszopiclone if alcohol has been consumed in the evening or before bedtime. Advise patients to avoid concurrent use of other sedative and hypnotic drugs used to treat insomnia (including OTC preparations such as diphenhydramine or doxylamine succinate) or CNS depressants during therapy, unless otherwise instructed by a clinician.

• Risk of serious injury and/or death resulting from complex sleep behaviors (e.g., sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake). Advise patients to discontinue eszopiclone and notify a clinician immediately if an episode of complex sleep behavior occurs during therapy, even if it did not result in a serious injury.

• Risk of next-day impairment, even when used as prescribed; impairment may be present despite feeling fully awake. Advise patients to exercise caution when operating machinery or performing hazardous tasks while using eszopiclone and to avoid these activities until they feel fully awake. Advise patients receiving the 3-mg dose to avoid driving or engaging in other activities that require complete mental alertness the day after use.

• Advise patients that drowsiness and decreased consciousness may increase the risk of falls in some patients.

• Risk of severe anaphylactic and anaphylactoid reactions; instruct patients to seek immediate medical attention if hypersensitivity reactions occur.

• Risk of abnormal thinking, behavioral changes, memory loss, and anxiety. Instruct patients to contact a clinician immediately if these adverse effects occur.

• Advise patients to immediately report any suicidal thoughts.

• Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as concomitant or past illnesses (e.g., depression, substance abuse).

• Instruct women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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