Eszopiclone

Eszopiclone
Systematic (IUPAC) name
(S)-(+)-6-(5-Chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl-4-methyl-1-piperazinecarboxylate
Clinical data
Trade names Lunesta
AHFS/Drugs.com monograph
MedlinePlus a605009
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability		 Moderate
Routes of
administration		 Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Protein binding 52–59%
Metabolism Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated)
Biological half-life 6 hours
Excretion Renal
Identifiers
CAS Number 138729-47-2 YesY
ATC code N05CF04 (WHO) [1]
PubChem CID 969472
IUPHAR/BPS 7429
DrugBank DB00402 YesY
ChemSpider 839530 YesY
UNII UZX80K71OE YesY
KEGG D02624 YesY
ChEBI CHEBI:53760 YesY
ChEMBL CHEMBL1522 YesY
Chemical data
Formula C17H17ClN6O3
Molar mass 388.808 g/mol
  (verify)

Eszopiclone, marketed by Sunovion under the brand-name Lunesta, is a nonbenzodiazepine hypnotic which is slightly effective for insomnia.[2] Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.

Eszopiclone (Lunesta) along with other "Z-drugs" including zolpidem (Ambien), zaleplon (Sonata) are the most commonly prescribed sedative hypnotics in the United States. Eszopiclone is not marketed in the European Union following a 2009 decision by the EMA denying it new active substance status,[3] in which it ruled that eszopiclone was too similar to zopiclone to be considered a new patentable product.[4]

Eszopiclone is now available in a generic form in the United States as of May 2014. On May 15, 2014, the USFDA asked that the starting dose of Eszopiclone (Lunesta) be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some patients were not able to cope with their next-day activities like driving and other activities that require full alertness.[5]

Medical uses

Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint.[2] Kirsch et al. found the benefit over placebo to be of questionable clinical significance.[2] Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response.[2] It is not recommended for chronic use in the elderly.[6]

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.[7] An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[8]

Adverse effects

Eszopiclone has fewer anticholinergic side effects than racemic zopiclone.[9] The following side effects may occur from usage of eszopiclone (Lunesta):[10]

Common side effects can include:

Less common side effects can include:

neuropsychiatric adverse effects reported include:

If a person does not sleep immediately after taking eszopiclone or if they get up shortly after taking the medication they may experience dizziness, lightheadedness, hallucinations (seeing things or hearing voices that are not there), as well as problems with coordination and memory.

Dependence

In the United States Eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of usage and concomitant use of other psychoactive drugs. The risk is also greater in patients with a history of alcohol abuse or other drug abuse or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks. Eszopiclone was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor.[11]

Abuse

A study of abuse potential of eszopiclone found that in persons with a known history of benzodiazepine abuse, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).[10]

Overdose

According to the U.S. Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official U.S. Prescribing Information, fatalities have been reported only in cases in which eszopliclone was combined with other drugs or alcohol.[12]

Texas poison control centers reported that during 2005–2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.[13]

If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.[14]

Pharmacology

Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as an agonist.[15] Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours.[16] The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone.[17] In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.[18]

Controversy

In a 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning."[19]

Availability in Europe

On September 11, 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell Eszopiclone (under the name Lunivia rather than Lunesta) in Europe.[20] Sepracor was expected to receive approximately 155 million dollars if the deal went through.[20] In 2008 Sepracor submitted an application to the EMA (the European Union's equivalent to the U.S. FDA) for authorization to market the drug in the EU, and initially received a favourable response.[21] However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone 'new active substance' status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product.[22] Since zopiclone's patent has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market.[23] As of November 2012, Sepracor has not resubmitted its authorization application and Lunesta/Lunivia is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion's Almorexant sleeping tablet, which entered stage three medical trials before development was abandoned due to side effects.

References

  1. ↑ WHO International Working Group for Drug Statistics Methodology (August 27, 2008). "ATC/DDD Classification (FINAL): New ATC 5th level codes". WHO Collaborating Centre for Drug Statistics Methodology. Archived from the original on 2008-05-06. Retrieved 2008-09-05.
  2. 1 2 3 4 Huedo-Medina, TB; Kirsch, I; Middlemass, J; Klonizakis, M; Siriwardena, AN (Dec 17, 2012). "Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration.". BMJ (Clinical research ed.) 345: e8343. doi:10.1136/bmj.e8343. PMC 3544552. PMID 23248080.
  3. ↑ Sepracor Pharmaceuticals Ltd withdraws its marketing authorisation application for Lunivia (eszopiclone) – EMA, 15 May 2009
  4. ↑ End of Sepracor-GSK Deal Raises Question in Lunesta Patent Fight – CBS/BNet, 13 Jun 2009
  5. ↑ FDA requiring lower starting dose for drug Eszopiclone (Lunesta)
  6. ↑ American Geriatrics Society 2012 Beers Criteria Update Expert, Panel (April 2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults.". Journal of the American Geriatrics Society 60 (4): 616–31. doi:10.1111/j.1532-5415.2012.03923.x. PMC 3571677. PMID 22376048.
  7. ↑ Tariq SH, Pulisetty S (February 2008). "Pharmacotherapy for insomnia". Clin Geriatr Med 24 (1): 93–105, vii. doi:10.1016/j.cger.2007.08.009. PMID 18035234.
  8. ↑ Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
  9. ↑ Patil PA, Kothekar MA (October 2006). "Development of safer molecules through chirality". Indian J Med Sci 60 (10): 427–37. doi:10.4103/0019-5359.27676. PMID 17006031.
  10. 1 2 rxlist. "Lunesta". Retrieved 22 March 2008.
  11. ↑ Brielmaier BD (January 2006). "Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent". Proc (Bayl Univ Med Cent). 19 (1): 54–9. PMC 1325284. PMID 16424933.
  12. ↑ "Lunesta Prescribing Information at Drugs@FDA" (PDF). Retrieved 2014-05-22.
  13. ↑ Forrester MB (October 2007). "Eszopiclone ingestions reported to Texas poison control centers, 2005 2006". Hum Exp Toxicol 26 (10): 795–800. doi:10.1177/0960327107084045. PMID 18025051.
  14. ↑ (( cite web | url = http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Informationforlicenceapplicants/Guidance/OverdosesectionsofSPCs/Genericoverdosesections/Zopiclone/index.htm ))
  15. ↑ Jufe GS (July–August 2007). "[New hypnotics: perspectives from sleep physiology]". Vertex 18 (74): 294–9. PMID 18265473.
  16. ↑ Halas CJ (January 1, 2006). "Eszopiclone". Am J Health Syst Pharm 63 (1): 41–8. doi:10.2146/ajhp050357. PMID 16373464.
  17. ↑ Najib J (April 2006). "Eszopiclone, a non-benzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia". Clin Ther 28 (4): 491–516. doi:10.1016/j.clinthera.2006.04.014. PMID 16750462.
  18. ↑ Professor Ashton (April 2007). "BENZODIAZEPINE EQUIVALENCE TABLE". Retrieved 21 March 2008.
  19. ↑ Schwartz, Lisa M.; Steven Woloshin (October 2009). "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians" (Online). New England Journal of Medicine (NEJM.org) 361 (18): 1717–1720. doi:10.1056/NEJMp0907708. PMID 19846841. Retrieved 2010-12-06.
  20. 1 2 GlaxoSmithKline and Sepracor Inc. announce international alliance for commercialisation of Lunivia
  21. ↑ COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USEm SUMMARY OF POSITIVE OPINION for LUNIVIA – European Medicines Agency/Committee for Medicinal Products for Human Use, 23 Oct 2010
  22. ↑ Sepracor Pharmaceuticals Ltd withdraws its marketing authorisation application for Lunivia (eszopiclone) – European Medicines Agency, 15 May 2009
  23. ↑ Data exclusivity and definition of a new active substance: suspension of generic escitalopram-containing medicines by CHMP – Bird and Bird Commercial Law 23 Apr 2010

External links

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