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 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
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) or after retiring when experiencing difficulty falling asleep.1
Swallow tablets intact; do not chew, crush, or divide.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 ≥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
Adults <65 years of age: Initially, 2 mg.1 May consider an initial dosage of 3 mg or an increase in dosage to 3 mg if clinically indicated; 3-mg dosage is more effective than 2-mg dosage for sleep maintenance.1
Special Populations
Hepatic Impairment
In patients with severe hepatic impairment, 1 mg initially;1 doses >2 mg not recommended.1
No dosage adjustment required in patients with mild to moderate hepatic impairment.1
Renal Impairment
No dosage adjustment required.1
Geriatric Patients
In adults ≥65 years of age experiencing difficulty falling asleep, 1 mg initially.1 May increase dosage to 2 mg if clinically indicated.1
In adults ≥65 years of age experiencing difficulty staying asleep, 2 mg.1
Do not exceed 2 mg daily in adults ≥65 years of age.1
Debilitated Patients
Do not exceed 1 mg.1 13
Cautions for Eszopiclone
Contraindications
None known.1
Warnings/Precautions
Warnings
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 and/or medical condition.1
Adverse Psychiatric Events
Abnormal thinking and behavioral changes (e.g., decreased inhibition, uncharacteristic extroversion and aggressiveness, bizarre behavior, agitation, hallucinations, depersonalization, amnesia) may occur unpredictably.1 Immediately evaluate any new behavioral sign or symptom.1
Complex Sleep-related Behaviors
Potential risk of complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), making phone calls, or preparing and eating food while asleep.14
Withdrawal Effects
Rapid dosage reduction or abrupt discontinuance of sedatives or hypnotics has resulted in signs and symptoms of withdrawal.1 3
Rebound insomnia of 1 day’s duration reported in clinical trials of eszopiclone.1
Abuse Potential
Abuse potential of high doses (2–4 times 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 dependence or abuse are at risk of habituation or dependence; use only with careful surveillance in such patients.1
CNS Effects
Rapid onset of CNS effects (short-term memory impairment, hallucinations, impaired coordination, dizziness, lightheadedness); administer only immediately before going to bed or after unsuccessfully attempting to sleep.1
Performance of activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) may be impaired the day after ingestion.1
Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.1 (See Specific Drugs under Interactions.)
Sensitivity Reactions
Potential risk of anaphylaxis and angioedema; may occur as early as with the first dose of drug.14
General Precautions
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
Debilitated Patients
Potential increased sensitivity to sedatives and hypnotics or impaired motor or cognitive performance after repeated exposure.1 Reduce dosage and monitor closely.1 (See Debilitated Patients under Dosage and Administration.)
Suicide
Use with caution in depressed patients.1 Potential for suicidal tendencies; overdosage more frequent in such patients.1 Prescribe and dispense drug in the smallest feasible quantity.1
Specific Populations
Pregnancy
Category C.1
Lactation
Not known whether distributed into human milk;1 however, racemic zopiclone is distributed into milk.4 Use not recommended.1 13
Pediatric Use
Safety and efficacy not established in children <18 years of age.1
Geriatric Use
Pharmacokinetic changes in geriatric patients compared with younger adults.1 (See Absorption and also Elimination, under Pharmacokinetics.)
Possibility exists of greater sensitivity to pharmacologic and adverse effects of sedatives and hypnotics in patients ≥65 years of age;1 reduce initial and maximum dosages.1 (See Geriatric Patients under Dosage and Administration.)1
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
Hepatic Impairment
Use with caution.1 Systemic exposure increased twofold in patients with severe hepatic impairment compared with healthy individuals.1 Reduce 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
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4: potential pharmacokinetic interaction (increased plasma eszopiclone concentrations).1 In patients receiving a potent CYP3A4 inhibitor, initial eszopiclone dosage should not exceed 1 mg; dosage may be increased to 2 mg if clinically indicated.1
Inducers of CYP3A4: potential pharmacokinetic interaction (decreased plasma eszopiclone concentrations).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-fold increase in eszopiclone exposure reported following concomitant use of eszopiclone 3 mg and ketoconazole 400 mg1 | Initial eszopiclone dosage should not exceed 1 mg; may increase dosage to 2 mg if clinically indicated1 |
CNS depressants (e.g., psychotropic drugs, anticonvulsants, antihistamines, alcohol) | Possible additive CNS-depressant effects1 | Do not use with alcohol; consider dosage reduction if eszopiclone is used concomitantly with other CNS depressants1 |
Digoxin | Pharmacokinetic or pharmacodynamic interactions unlikely1 | |
HIV protease inhibitors (nelfinavir, ritonavir) | Increased plasma eszopiclone concentrations1 | Initial eszopiclone dosage should not exceed 1 mg; may increase dosage to 2 mg if clinically indicated1 |
Lorazepam | No clinically important pharmacokinetic or pharmacodynamic interactions observed following single-dose administration of eszopiclone 3 mg with lorazepam 2 mg1 13 | |
Macrolide antibiotics (clarithromycin, troleandomycin) | Increased plasma eszopiclone concentrations1 | Initial eszopiclone dosage should not exceed 1 mg; may increase dosage to 2 mg if clinically indicated1 |
Nefazodone | Increased plasma eszopiclone concentrations1 | Initial eszopiclone dosage should not exceed 1 mg; may increase dosage to 2 mg if clinically indicated1 |
Olanzapine | Decreased psychomotor performance noted following single-dose administration of eszopiclone 3 mg with olanzapine 10 mg;1 pharmacokinetic interaction unlikely1 | |
Paroxetine | Pharmacokinetic or pharmacodynamic interactions unlikely; concomitant use (eszopiclone 3 mg and paroxetine 20 mg daily for 7 days) did not alter relevant parameters1 | |
Rifampin | Decreased plasma eszopiclone concentrations1 | |
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
ActionsActions
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 administering immediately before retiring or after attempting to fall asleep.1
Importance of taking only when able to get a full night’s sleep (i.e., ≥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
Potential for drug to cause somnolence, dizziness, and/or coordination difficulties; importance of exercising caution when operating machinery or performing hazardous tasks.1
Advise of the possibility of adverse effects such as unpleasant taste, headache, and cold-like symptoms.1
Importance of reporting to clinicians any unusual and/or disturbing thoughts or behavior, memory impairment, or dependence/withdrawal symptoms after multiple dosing.1
Advise of possible rebound insomnia for 1 or 2 nights after discontinuance.1
Importance of avoiding alcohol-containing beverages or products.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
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 1 mg | Lunesta (C-IV) | Sepracor |
2 mg | Lunesta (C-IV) | Sepracor | ||
3 mg | Lunesta (C-IV) | Sepracor |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. 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/$217.99 or 90/$621.99
Lunesta 2MG Tablets (SUNOVION PHARMACEUTICALS): 30/$220 or 90/$645.95
Lunesta 3MG Tablets (SUNOVION PHARMACEUTICALS): 30/$220 or 90/$630
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Sepracor Inc. Lunesta (eszopiclone) tablets prescribing information. Marlborough, MA; 2005 Feb.
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
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