OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Eszopiclone	138729-47-2	C17-H17-Cl-N6-O3

ANNOTATED BIBLIOGRAPHY

References updated: 20 February 2018

• Zimmerman HJ. Anxiolytic agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 491-3.

  (Expert review of hepatotoxicity published in 1999 discusses benzodiazepines and minor tranquilizers; "In general, the hepatotoxic potential of this widely used group of compounds seems low").
• Larrey D, Ripault MP. Anxiolytic agents. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 455-6.

  (Review of hepatotoxicity of hypnotics and sedatives discusses benzodiazepines, buspirone and valerian, all of which have been linked to rare cases of liver injury; no discussion of eszopiclone).
• Mihic SJ, Harris RA. Hypnotics and sedatives. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 457-80.

  (Textbook of pharmacology and therapeutics).
• Roblin X, Boudemaghe T, Paris F, Pellissier L, Le Gall S. [Unexplained increase in aminotransferases and obstructive sleep apnea syndrome]. Gastroenterol Clin Biol 2002; 26: 416-7. French. [PubMed: 12070418]

  (45 year old woman found to have minor serum ALT elevations [1.5-3 times ULN] without jaundice or symptoms while taking zolpidem, which improved on stopping, but which were subsequently shown to be due to severe sleep apnea).
• Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003; 26: 261-82. [PubMed: 12608888]

  (Comparison of adverse events and tolerability of three new drugs for insomnia, focusing upon CNS symptoms such as headache, drowsiness and fatigue; mentions rare observations suggestive of hepatotoxicity of zolpidem [Karsenti 1999]).
• Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 2004; 43: 227-38. [PubMed: 15005637]

  (Review of mechanism of action, pharmacology, efficacy and adverse effects of 3 non-benzodiazepine hypnotic agents: zaleplon, zolpidem and zopiclone).
• Zammit GK, McNabb LJ, Caron J, Amato DA, Roth T. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin 2004; 20: 1979-91. [PubMed: 15701215]

  (Controlled trial of 44 days of two doses of eszopiclone vs placebo in 308 patients with insomnia; adverse events were uncommon, but included headache, dry mouth and drowsiness; "there was no evidence of drug-related effects on...laboratory...measures").
• Rosenberg R, Caron J, Roth T, Amato D. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med 2005; 6: 15-22. [PubMed: 15680290]

  (Controlled trial of 4 doses of eszopiclone vs placebo given for one night in 436 patients; most common side effect was unpleasant taste and changes in laboratory test results "were similar across all treatment groups, including placebo").
• Eszopiclone (Lunesta), a new hypnotic. Med Lett Drugs Ther 2005; 47 (1203): 17-9. [PubMed: 15767972]

  (Concise summary of mechanism of action, pharmacokinetics, efficacy and safety of eszopiclone for insomnia published shortly after its approval in the US; no mention of change in ALT levels or hepatotoxicity).
• Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med 2005; 6: 487-95. [PubMed: 16230048]

  (Results of open label extended use [12 months] study of eszopiclone in 382 patients who had participated in a placebo controlled trial; eszopiclone was well tolerated and there were "no systematic differences" in blood chemistry results during the open label period).
• Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 2006; 28: 491-516. [PubMed: 16750462]

  (Systematic review of efficacy and safety of eszopiclone for treatment of insomnia; in 6 large controlled trials involving ~1550 patients, adverse events were uncommon and mild and there were no laboratory test abnormalities identified or mention of clinically apparent liver injury).
• Morin AK, Willett K. The role of eszopiclone in the treatment of insomnia. Adv Ther 2009; 26: 500-18. [PubMed: 19513631]

  (Systematic review of efficacy and safety of eszopiclone in treatment of insomnia; side effects occurring more often than with placebo included unpleasant [bitter] taste, headache, somnolence, dizziness, and dry mouth; no mention of changes in ALT levels or hepatotoxicity).
• Ancoli-Israel S, Krystal AD, McCall WV, Schaefer K, Wilson A, Claus R, Rubens R, Roth T. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010; 33: 225-34. PubMed Citation. [PMC free article: PMC2817909] [PubMed: 20175406]

  (Controlled trial of 12 week course of eszopiclone vs placebo in 288 elderly patients with insomnia; the only adverse event that was more frequent with eszopiclone was unpleasant taste [12.4% vs 1.5%]; one treated patient developed cholecystitis which was considered unrelated to therapy).
• Owen RT. Eszopiclone: an update on its use in insomnia. Drugs Today (Barc) 2011; 47: 263-75. [PubMed: 21573250]

  (Review of mechanism of action, pharmacology, efficacy and safety of eszopiclone for insomnia; side effects [except unpleasant taste] are uncommon and no more common with eszopiclone than placebo; no mention of changes in ALT levels or hepatotoxicity).
• Drugs for insomnia. Treat Guidel Med Lett 2012; 10 (119): 57-60. [PubMed: 22777275]

  (Guidelines for therapy of insomnia; mentions that benzodiazepine receptor agonists such as eszopiclone, benzodiazepines, ramelteon and low doses of doxepin are effective and generally safe; in discussing adverse events, no mention is made of ALT elevations or hepatotoxicity of any of the recommended agents).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to a sleeping aid, despite the fact that zopiclone and zolpidem are among the 25 most commonly prescribed drugs in Iceland).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to eszopiclone or other sedatives or sleeping aids).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 82 [9%] were attributed to agents active in the central nervous system, but none were due to eszopliclone or other sedatives or sleeping aids).
• Drugs for insomnia. Med Lett Drugs Ther 2015; 57 (1472): 95-8. [PubMed: 26147892]

  (Concise review of the mechanism of action, efficacy, safety and costs of drugs for insomnia including benzodiazepine receptor agonists including eszopliclone as well as benzodiazepines, melatonin receptor agonists, orexin receptor antagonists and other agents including nonprescription and herbal products).