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
Licence data	US FDA:link
Pregnancy cat.	C (US)
Legal status	Schedule IV (US)
Dependence liability	High
Routes	Oral
Pharmacokinetic data
Protein binding	52-59%
Metabolism	Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated)
Half-life	6 hours
Excretion	Renal
Identifiers
CAS number	138729-47-2 Y
ATC code	N05CF04
PubChem	CID 969472
DrugBank	DB00402
ChemSpider	839530 Y
UNII	UZX80K71OE Y
KEGG	D02624 Y
ChEBI	CHEBI:53760 Y
ChEMBL	CHEMBL1522 Y
Chemical data
Formula	C17H17ClN6O3
Mol. mass	388.808 g/mol
SMILES O=C(O[C@H]3c1nccnc1C(=O)N3c2ncc(Cl)cc2)N4CCN(C)CC4
InChI InChI=1S/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3/t16-/m0/s1 Y Key:GBBSUAFBMRNDJC-INIZCTEOSA-N Y
Y (what is this?)  (verify)

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

Eszopiclone is a short acting nonbenzodiazepine sedative hypnotic. According to its manufacturer, it has been shown to be safe and effective for the short term treatment of primary insomnia in the elderly and safe in younger adults for 6–12 months. All clinical trials of eszopiclone published so far have been funded by the manufacturer of eszopiclone, Sepracor. There were 43 million prescriptions issued for insomnia medications during 2005 in the USA which generated a total of $2.7 billion for pharmaceutical companies. Eszopiclone (Lunesta) along with other "Z-drugs" including zolpidem (Ambien), zaleplon (Sonata) are the most commonly prescribed sedative hypnotics in the USA.

Eszopiclone is not marketed in the European Union following a 2009 decision by the EMA denying it new active substance status, in which it ruled that eszopiclone was too similar to zopiclone to be considered a new patentable product.

Medical uses

Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. The benefit over placebo is of questionable clinical significance. It is not recommended for chronic use in the elderly.

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.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 nonbenzodiazepinesedative-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.

Adverse effects

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

Common side effects can include:

• unpleasant bitter or metallic taste
• headaches
• chest pain
• cold-like symptoms
• pain
• dry mouth
• daytime drowsiness
• lightheadedness
• dizziness
• upset stomach
• decreased sexual desire
• painful menstruation (periods)
• heartburn
• Breast enlargement in males

Less common side effects can include:

• rashes
• itching
• incoordination
• swelling of the hands, feet, ankles, or lower legs
• painful or frequent urination
• back pain

neuropsychiatric adverse effects reported include;

• aggressive behavior
• confusion
• agitation
• auditory and visual hallucinations
• worsening of depression
• suicidal thoughts
• depersonalisation
• amnesia

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 or 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.

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 and hallucinations was observed for both eszopiclone (lunesta) as well as for diazepam (Valium).

Overdose

Eszopiclone is dangerous in overdose. Signs of eszopiclone overdose reported included dulled mental status, ST-elevation coronary vasospasm, troponemia, ventricular fibrillation arrest and prolonged coma (lasting up to 48 hours). 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.

If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage. In potentially fatal overdose cases where eszopiclone has been consumed more than one hour before treatment, overdose symptoms may be successfully reversed with the intravenous administration of flumazenil, although this is not recommended for mixed overdoses.

Pharmacology

Eszopiclone acts on benzodiazepine binding site situated on GABA_A neurons as an agonist. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours. 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. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.

Controversy

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications including eszopiclone. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. The author was concerned that there is no discussion of adverse effects of sedative hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in eszopiclone and other sedative hypnotic drugs and an overemphasis on the positive effects. The author concluded by stating that "major hypnotic trials are needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks."

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."

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. Sepracor was expected to receive approximately 155 million dollars if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union's equivalent to the US FDA) for authorization to market the drug in the EU, and initially received a favourable response. 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. 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. 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.

External links

• National Institute of Health – Medline Plus – (Eszopiclone)
• Eszopiclone labeling text (PDF)
• Sepracor.com
• Lunesta.com