Drug Review

Brand name: Lunesta

Generic name: Eszopiclone

Manufacturer: Sepracor

Drug class (1,2,3):  nonbenzodiazepine hypnotic agent

Uses (1,2,3): Lunesta is used in the treatment of insomnia

Mechanism of action (3): It is not known exactly how eszopiclone works.  It is postulated that it has an effect on the GABA receptors somewhere near the site where benzodiazepines produce their effect.

Pharmacokinetics (1,2,3,4)

*the bioavailability of eszopiclone is not currently available; however, racemic zopiclone has a bioavailability of 75%.

Metabolism (2,3): Eszopiclone is metabolized by the CYP450 system, most notably 3A4 and 2E1.  The main metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethylzopiclone.  (S)-N-desmethylzopiclone does have some activity but not nearly the amount that the parent drug exhibits.  The other metabolite is inactive.

Elimination (1,3): Elimination information is not complete but is likely comparable to racemic zopiclone.  About 75% is excreted as metabolites and less than 10% is excreted unchanged as the parent drug in the urine.

Efficacy (3,4,5):

Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, 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 Nov 1; 26(7): 793-9. 

Study design:  Double blind, randomized, multicenter, placebo controlled.                Description of Study: Patients were randomized into one of two groups to participate in the study.  593 patients received eszopiclone 3 mg and 195 patients received placebo.  The study utilized an interactive voice response system which patients called in once a week to report sleeping patterns.  The patients called to report sleep latency, wake time after sleep onset, total sleep time, number of awakenings, number of nights they awakened, sleep quality, daytime ability to function, daytime alertness, and sense of physical well-being.  Monthly clinic visits were used to assess safety and compliance and also to provide refills for study medication.  The researchers determined there was a statistically significant difference in the areas that were measured.  At the 6 month point, sleep latency in the eszopiclone group was 30 minutes compared to 45 minutes in the placebo group (p<.0001).  The number of awakenings per night was 2.0 for patients in the placebo group and 1.6 in the eszopiclone group (p<.0001).  Also, the number of nights per week that patients awakened was 5.2 in the placebo group compared to 4.0 in the eszopiclone group (p=.0001).  Other measurements included sleep quality, ability to function during the day, and total sleep time.  These were all statistically significant and  favored the eszopiclone group.  As for safety, the authors concluded that the drug had a fairly safe overall profile. 

Limitations: The methods of the study did not seem as if they were clearly stated and could have been more detailed.  It seems as if the parameters being measured are difficult to quantify when trying to determine if values are significant.  The findings did support that the medication could be of benefit, but the values measured did not seem to be that overwhelming.  Also, a very high dropout rate of about 40% occurred in the study. 

Conclusion: The authors concluded that eszopiclone improved the problems involved with insomnia.  The authors also concluded that long-term therapy of insomnia with eszopiclone was effective.

     Other studies have been done and are in the drug’s prescribing information but were not available in their full form.  The first of these studies was done in adults with chronic insomnia who received eszopiclone 2-3 mg or placebo.  Eszopiclone proved superior to placebo on the endpoints analyzed. The second group studied was the elderly.  The dose used here was 1-2 mg for 2 weeks.  Eszopiclone proved superior to placebo in measuring sleep latency and sleep maintenance. 

     Two studies assessed single dose effects of eszopiclone.  These set out to determine the effect of the drug on a person’s cognitive function.  The 3 mg group performed more poorly than the placebo group in some of the areas measured.

Adverse Effects (1,3,4): Event listed with percentage in parentheses

Drug interactions (1,3):

Due to CYP450 involvement, drugs which induce or inhibit CYP2E1 and 3A4 may affect eszopiclone; 3A4 is the major pathway so drugs affecting that particular enzyme have a greater effect. 

CYP3A4 inducers could decrease the effect of eszopiclone.  Some examples include aminogluthimide, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, nafcillin, and nevirapine. 

CYP3A4 inhibitors increase the effect of eszopiclone.  Examples include azole antifungals, protease inhibitors, amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluoxamine, grapefruit juice, mibefradil, nefazadone, and verapamil.

Eszopiclone and olanzapine interact with each other and lead to a decrease in psychomotor function. 

When given with lorazepam, the Cmax of both drugs decreased by about 20%.

Dosing/Administration (1,2,3):

Usual dose: 2 mg; may increase to 3 mg if needed.

Geriatric: 1 mg for patients who have difficulty falling asleep; may be increased to 2 mg.  For elderly patients who have difficulty staying asleep, the dose is 2 mg.

Pediatric dosing is not available.

Renal impairment:  No dose modification is necessary. 

Hepatic impairment: For mild-moderate impairment-use with caution.  For severe impairment, start at 1 mg and use with caution.  Dose may be increased to 2 mg if needed.

Conclusion (1,2,3,4):  Eszopiclone appears as though it could be a useful therapy in insomnia.  However, comparisons with current available treatments for insomnia such as Ambien and benzodiazepines need to be completed in order to determine what the best available therapy is for people in that particular population.  Some of the disadvantages of eszopiclone include interactions with other drugs due to the P450 system and lack of comparison data with other commonly used agents.  Advantages include providing patients with another alternative in the treatment of insomnia and tolerance does not appear to occur with Lunesta.

References:

1)      http://www.lexi.com/web/content/newdrugs/chapter/mono/newdrugsdisp.jsp?id=hf051315

2)      http://www.micromedex.com/products/updates/drugdex_updates/de/eszopiclone.html

3)      http://www.lunesta.com/PostedApprovedLabelingText.pdf

4)      Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, 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 Nov 1; 26(7): 793-9.

5)      Jacobs GD.  Is Eszopiclone appropriate and effective for the long-term clinical management of chronic insomnia?  Sleep 2004 Mar 15;27(2):345.

Tim Miller, PharmD Candidate