Eszopiclone

Pronunciation

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
Brands: Lunesta

Introduction

Sedative and hypnotic; pyrrolopyrazine derivative; structurally unrelated to benzodiazepines.1 1 2 3 5 10 11

Uses for Eszopiclone

Insomnia

Management of transient and chronic insomnia.1 2 3 11

Decreases sleep latency, improves sleep maintenance, and prolongs total sleep time in patients with chronic or transient insomnia;1 2 3 reportedly effective with repeated (i.e., nightly) use for periods up to 6 months in duration.1 2 3

Slideshow: 10 Common Sleep Disorders: Treatments and Truths

Sleep architecture (i.e., the percentage of time spent in each sleep stage) generally is preserved at usual dosages.5

Evidence is lacking to suggest that sleep improvement is maintained following discontinuance;13 some clinicians suggest that use of hypnotic agents in the management of chronic insomnia should be reserved for patients nonresponsive to psychotherapy/behavioral therapies (e.g., relaxation techniques, sleep hygiene education, sleep curtailment, stimulus control therapy).6 7 8

Eszopiclone Dosage and Administration

Administration

Oral Administration

Administer only immediately before retiring (when ready to sleep).1

Avoid administration with or immediately after a heavy, high-fat meal; may decrease rate of absorption and effect on sleep latency.1

Use only when able to get 7–8 hours of sleep before it is necessary to be active again.1

Dosage

Individualize dosage;1 use smallest effective dosage to minimize adverse effects.1

If used concomitantly with a potent CYP3A4 inhibitor, adjustment of eszopiclone dosage is recommended.1 (See Interactions.)

Adults

Insomnia
Oral

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

Dosage range of 2–3 mg shown to decrease sleep latency and improve measures of sleep maintenance in adults <65 years of age.1 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.1 (See CNS Depressant Effects and Next-day Impairment under Cautions.)

Prescribing Limits

Adults

Insomnia
Oral

Maximum 3 mg once daily immediately before bedtime.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment.1

In patients with severe hepatic impairment, do not exceed 2 mg once daily immediately before bedtime.1

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

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

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

Do not exceed 2 mg once daily immediately before bedtime in adults ≥65 years of age.1

Debilitated Patients

Do not exceed 2 mg once daily immediately before bedtime.1 13

Cautions for Eszopiclone

Contraindications

  • Known hypersensitivity (e.g., anaphylaxis, angioedema) to eszopiclone or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity 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.1 Other symptoms suggestive of anaphylaxis (e.g., dyspnea, throat closing, nausea, vomiting) also reported.1 Medical therapy in emergency department was required in some patients.1

Do not rechallenge with the drug if angioedema occurs.1

CNS Depressant Effects and Next-day Impairment

CNS depressant effects (i.e., memory impairment, confusion) reported following use of higher doses.1

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.1 Next-day impairment most severe at 7.5 hours postdose but still present and potentially clinically meaningful at 11.5 hours postdose.1 Patients often unaware of these impairments.1 15

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.1

To reduce risk of next-day impairment, manufacturer and FDA lowered recommended initial dosage from 2 mg to 1 mg immediately before bedtime (see Dosage under Dosage and Administration); lower initial dosage will result in less drug in the blood the next day.1 15 Patients currently receiving eszopiclone should continue therapy at the prescribed dosage and should contact their clinician to determine the most appropriate dosage.15 FDA is continuing to evaluate the risk of impaired mental alertness associated with other sedatives and hypnotics, including OTC preparations.15 OTC sedative and hypnotic drugs not considered safer than prescription drugs.15

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).1 (See Advice to Patients.)

Concomitant use with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) results in additive CNS depression.1 (See Specific Drugs under Interactions.)

Concomitant use with other sedatives and hypnotics at bedtime or in the middle of the night is not recommended.1

Adequate Patient Evaluation

Insomnia may be a manifestation of an underlying physical and/or psychiatric disorder; carefully evaluate patient before providing symptomatic treatment.1

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.1 Reevaluate patient if insomnia persists after 7–10 days of therapy.1

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.1 Amnesia and other neuropsychiatric symptoms may occur unpredictably.1 Worsening of depression and suicidal thoughts and actions (including completed suicides) reported in primarily depressed patients receiving sedative and hypnotic drugs.1

Complex behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative and hypnotic drug, with no memory of the event) and preparing and eating food, making phone calls, or having sex while not fully awake after taking a sedative and hypnotic drug (and usually with no memory of the event) reported.1

Complex behaviors may occur in sedative and hypnotic drug-naive or drug-experienced patients.1

Increased risk of complex behaviors with concomitant use of alcohol and other CNS depressants or use of the drug at doses exceeding the maximum recommended dose; however, may occur with the drug alone at therapeutic doses.1

Strongly consider discontinuing drug in patients who report a sleep-driving episode because of the risk to the patient and community.1

Carefully and immediately evaluate any new concerning behavioral sign or symptom.1

Withdrawal Effects

Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs and symptoms of withdrawal.1 3

No evidence of a serious withdrawal syndrome associated with eszopiclone;1 3 however, anxiety, abnormal dreams, nausea, upset stomach, hyperesthesia, and neurosis reported within 48 hours following discontinuance.1

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

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).1

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.1

Tolerance

Pharmacodynamic tolerance and adaptation to the hypnotic effect of eszopiclone not observed during studies of up to 6 months’ duration.1 2 3

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.1 (See Administration under Dosage and Administration.)

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.1 Reduce maximum dosage.1 (See Special Populations under Dosage and Administration.)

Concomitant Disease

Limited experience in patients with concomitant systemic disease.1 Use with caution in patients with diseases affecting metabolism and/or hemodynamic response.1

Respiratory depression was not reported in clinical studies to date in healthy individuals receiving doses 2.5-fold higher than the recommended dose;1 however, caution is advised in patients with impaired respiratory function.1

Use in Patients with Depression

Use with caution in patients with depression.1 Potential for suicidal tendencies; intentional overdosage more frequent in such patients.1 Prescribe and dispense drug in the smallest feasible quantity to avoid intentional overdosage.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into human milk;1 however, racemic zopiclone is distributed into milk.4

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Not effective in the management of insomnia associated with attention deficit hyperactivity disorder (ADHD).1

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.1

Pharmacokinetic changes in geriatric patients compared with younger adults.1 (See Absorption and also Elimination, under Pharmacokinetics.)

Reduce maximum dosage because of impaired motor and cognitive performance as well as increased sensitivity to sedatives and hypnotics.1 (See Geriatric Patients under Dosage and Administration.)1

Hepatic Impairment

Use with caution.1 Systemic exposure increased twofold in patients with severe hepatic impairment compared with healthy individuals.1 Reduce maximum dosage for severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Headache,1 3 dry mouth,1 3 dizziness,1 3 somnolence,1 nervousness,1 dyspepsia,1 nausea,1 3 infection,1 unpleasant taste.1 3

Interactions for Eszopiclone

Metabolized principally by CYP3A4 and CYP2E1.1

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

Not expected to alter clearance of drugs metabolized by common CYP isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Possible increased exposure to eszopiclone.1 If used concomitantly, do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime.1

Inducers of CYP3A4: Possible decreased systemic exposure to and efficacy of eszopiclone.1

Protein-bound Drugs

Pharmacokinetic interaction unlikely; not highly bound to plasma proteins.1

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (itraconazole, ketoconazole)

Increased plasma eszopiclone concentrations; 2.2-, 1.4-, and 1.3 fold increases in eszopiclone exposure, peak plasma concentrations, and half-life, respectively, reported following concomitant use of eszopiclone 3 mg and ketoconazole 400 mg1

Do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime1

CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants)

Possible additive CNS-depressant effects1

Alcohol: Additive psychomotor impairment1

Alcohol: Avoid concomitant use1

Other CNS depressants: Dosage reduction of eszopiclone and the CNS depressant may be necessary1

Digoxin

Pharmacokinetic interaction unlikely1

HIV protease inhibitors (nelfinavir, ritonavir)

Possible increased exposure to eszopiclone1

Do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime1

Lorazepam

No clinically important pharmacokinetic or pharmacodynamic interactions observed following single-dose administration of eszopiclone 3 mg with lorazepam 2 mg; however, possibility of pharmacodynamic interaction following long-term concomitant use cannot be ruled out1 13 16

Macrolide antibiotics (clarithromycin, troleandomycin)

Possible increased exposure to eszopiclone1

Do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime1

Nefazodone

Possible increased exposure to eszopiclone1

Do not exceed eszopiclone dosage of 2 mg once daily immediately before bedtime1

Olanzapine

Decreased psychomotor performance noted following concomitant administration of eszopiclone 3 mg with olanzapine 10 mg;1 pharmacokinetic interaction not observed1

Paroxetine

Pharmacokinetic or pharmacodynamic interactions not observed following administration of single eszopiclone dose (3 mg) with paroxetine (20 mg daily for 7 days); however, possibility of pharmacodynamic interaction following long-term concomitant use cannot be ruled out1 16

Rifampin

Decreased systemic exposure to and efficacy of eszopiclone1

Warfarin

Pharmacokinetic or pharmacodynamic (PT) interactions unlikely1 13

Eszopiclone Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration attained in about 1 hour.1 2 3 4

Food

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

Special Populations

In geriatric patients, AUC is increased by 41% compared with younger adults.1

In patients with severe hepatic impairment, systemic exposure is 2 times higher than in healthy individuals.1

Distribution

Plasma Protein Binding

Approximately 52–59%.1

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.1 2

Elimination Route

Racemic zopiclone excreted principally in urine (75%), mainly as metabolites.1 Similar excretion profile expected for eszopiclone, the S-isomer of racemic zopiclone;1 <10% of eszopiclone dose excreted unchanged in urine.1

Half-life

Approximately 6 hours.1

Special Populations

In geriatric patients, half-life is approximately 9 hours.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Interacts with the CNS GABAA-receptor complex at binding domains located close to or allosterically coupled to benzodiazepine receptors.1 2 10 11

  • Pharmacologically similar to zaleplon and zolpidem.1 2 10 11

  • 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).1 2 3 5 10

  • S-enantiomer of zopiclone (a hypnotic agent not commercially available in the US).1

  • Binding affinity (in vitro) for benzodiazepine receptors is about 50 times that of the R-enantiomer of racemic zopiclone.2 10

Advice to Patients

  • Provide patient with a copy of manufacturer’s patient information.1 Importance of advising patients to read the manufacturer's medication guide and instructions for use carefully prior to initiating therapy and each time the prescription is refilled.1

  • Importance of administering immediately before retiring.1

  • Importance of taking only when able to get a full night’s sleep (i.e., 7–8 hours) before being active again.1

  • Importance of taking only as prescribed (e.g., not with or immediately after a high-fat meal); do not increase dosage or duration of therapy unless otherwise instructed by a clinician.1

  • Importance of not taking eszopiclone if alcohol has been consumed in the evening or before bedtime.1

  • Risk of next-day impairment, even when used as prescribed; impairment may be present despite feeling fully awake.1 15 In patients receiving the 3-mg dose, importance of avoiding driving or engaging in other activities that require complete mental alertness the day after use.1 15

  • Risk of severe anaphylactic and anaphylactoid reactions; importance of immediately seeking medical attention if hypersensitivity reactions occur.1

  • Risk of abnormal thinking, behavioral changes, and complex behaviors (e.g., sleep-driving).1 Importance of contacting a clinician immediately if these changes occur.1

  • Importance of immediately reporting any suicidal thoughts.1

  • Importance of informing 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).1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

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

Eszopiclone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1 mg*

Eszopiclone Tablets (C-IV)

Lunesta ( C-IV)

Sunovion

2 mg*

Eszopiclone Tablets (C-IV)

Lunesta ( C-IV)

Sunovion

3 mg*

Eszopiclone Tablets (C-IV)

Lunesta ( C-IV)

Sunovion

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 01/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Lunesta 1MG Tablets (SUNOVION PHARMACEUTICALS): 30/$228.99 or 90/$653.98

Lunesta 2MG Tablets (SUNOVION PHARMACEUTICALS): 30/$226.00 or 90/$661.96

Lunesta 3MG Tablets (SUNOVION PHARMACEUTICALS): 30/$230.99 or 90/$662.95

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions January 1, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sunovion Pharmaceuticals Inc. Lunesta (eszopiclone) tablets prescribing information. Marlborough, MA; 2014 May.

2. Mack A, Salazar JO. Eszopiclone: a novel cyclopyrrolone with potential benefit in both transient and chronic insomnia. Formulary. 2003; 38:582-93.

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; 26:793-9. [IDIS 527792] [PubMed 14655910]

4. Fernandez C, Martin C, Gimenez F et al. Clinical pharmacokinetics of zopiclone. Clin Pharmacokinet. 1995; 29:431-41. [PubMed 8787948]

5. Rosenberg R, Caron J, Roth T et al. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med. 2005; 6:15-22. [IDIS 528997] [PubMed 15680290]

6. Schenck CH, Mahowald MW, Sack RL. Assessment and management of insomnia. JAMA. 2003; 289:2475-9. [IDIS 499774] [PubMed 12759306]

7. Jacobs GD, Pace-Schott EF, Stickgold R et al. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med. 2004; 164:1888-96. [IDIS 524535] [PubMed 15451764]

8. Morin CM, Colecchi C, Stone J et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999; 281:991-9. [IDIS 421436] [PubMed 10086433]

9. Walsh JK. Pharmacologic management of insomnia. J Clin Psychiatry. 2004; 65(suppl 16):41-5. [IDIS 526373] [PubMed 15575804]

10. Georgiev V. (S)-Zopiclone Sepracor. Curr Opin Investig Drugs. 2001; 2:271-3. [PubMed 11816843]

11. Anon. Eszopiclone (Lunesta), a new hypnotic. Med Lett Drugs Ther. 2005; 47:17-9. [PubMed 15767972]

12. Zammit GK, McNabb LJ, Caron J et al. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin. 2004; 20:1979-91. [IDIS 528996] [PubMed 15701215]

13. Sepracor, Marlborough, MA: Personal communication.

14. Food and Drug Administration. Lunesta (eszopiclone) tablets. [March 14, 2007: Sepracor] MedWatch drug labeling changes. Rockville, MD; April 2007. From FDA websites and

15. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose. Rockville, MD; 2014 May 15. From FDA website.

16. Sepracor Inc. Lunesta (eszopiclone) tablets prescribing information. Marlborough, MA; 2005 Feb.

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