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Lunesta (Eszopiclone) - Description and Clinical Pharmacology




LUNESTA (eszopiclone) is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C H ClN O. Eszopiclone has a single chiral center with an ()-configuration. It has the following chemical structure: 17 17 6 3 S

Eszopiclone is a white to light-yellow crystalline solid. Eszopiclone is very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2).

Eszopiclone is formulated as film-coated tablets for oral administration. LUNESTA tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and triacetin. In addition, both the 1 mg and 3 mg tablets contain FD&C Blue #2.



The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. Eszopiclone is a nonbenzodiazepine hypnotic that is a pyrrolopyrazine derivative of the cyclopyrrolone class with a chemical structure unrelated to pyrazolopyrimidines, imidazopyridines, benzodiazepines, barbiturates, or other drugs with known hypnotic properties.


The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (t) of approximately 1 hour and a terminal-phase elimination half-life (t) of approximately 6 hours. In healthy adults, LUNESTA does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg. max 1/2

Absorption And Distribution

Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52-59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.


Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are ()-zopiclone-N-oxide and ()-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes. S S In vitro


After oral administration, eszopiclone is eliminated with a mean t of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug. 1/2

Effect Of Food

In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean C of 21%, and delayed t by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of LUNESTA on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal. max max

Special Populations


Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of eszopiclone (t approximately 9 hours). C was unchanged. Therefore, in elderly patients the starting dose of LUNESTA should be decreased to 1 mg and the dose should not exceed 2 mg. 1/2 max


The pharmacokinetics of eszopiclone in men and women are similar.


In an analysis of data on all subjects participating in Phase 1 studies of eszopiclone, the pharmacokinetics for all races studied appeared similar.

Hepatic Impairment

Pharmacokinetics of a 2 mg eszopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. C and t were unchanged. The dose of LUNESTA should not be increased above 2 mg in patients with severe hepatic impairment. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. LUNESTA should be used with caution in patients with hepatic impairment. (See) max max . DOSAGE AND ADMINISTRATION

Renal Impairment

The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and C were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug. max

Drug Interactions

Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine, digoxin, or warfarin. When eszopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of eszopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function. Eszopiclone and lorazepam decreased each other's C by 22%. Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole 400 mg, a potent inhibitor of CYP3A4, resulted in a 2.2-fold increase in exposure to eszopiclone. LUNESTA would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes. (See) max . PRECAUTIONS


The effect of LUNESTA on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18-86) with chronic and transient insomnia in six placebo-controlled trials of up to 6 months' duration. Two of these trials were in elderly patients (n=523). Overall, at the recommended adult dose (2-3 mg) and elderly dose (1-2 mg), LUNESTA significantly decreased sleep latency and improved measures of sleep maintenance (objectively measured as wake time after sleep onset [WASO] and subjectively measured as total sleep time).

Transient Insomnia

Healthy adults were evaluated in a model of transient insomnia (n=436) in a sleep laboratory in a double-blind, parallel-group, single-night trial comparing two doses of eszopiclone and placebo. LUNESTA 3 mg was superior to placebo on measures of sleep latency and sleep maintenance, including polysomnographic (PSG) parameters of latency to persistent sleep (LPS) and WASO.

Chronic Insomnia (Adults And Elderly)

The effectiveness of LUNESTA was established in five controlled studies in chronic insomnia. Three controlled studies were in adult subjects, and two controlled studies were in elderly subjects with chronic insomnia.


In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks' duration comparing LUNESTA 2 mg and 3 mg with placebo. Objective endpoints were measured for 4 weeks. Both 2 mg and 3 mg were superior to placebo on LPS at 4 weeks. The 3 mg dose was superior to placebo on WASO.

In the second study, adults with chronic insomnia (n=788) were evaluated using subjective measures in a double-blind, parallel-group trial comparing the safety and efficacy of LUNESTA 3 mg with placebo administered nightly for 6 months. LUNESTA was superior to placebo on subjective measures of sleep latency, total sleep time, and WASO.

In addition, a 6-period cross-over PSG study evaluating eszopiclone doses of 1 to 3 mg, each given over a 2-day period, demonstrated effectiveness of all doses on LPS, and of 3 mg on WASO. In this trial, the response was dose-related.


Elderly subjects (ages 65-86) with chronic insomnia were evaluated in two double-blind, parallel-group trials of 2 weeks' duration. One study (n=231) compared the effects of LUNESTA with placebo on subjective outcome measures, and the other (n=292) on objective and subjective outcome measures. The first study compared 1 mg and 2 mg of LUNESTA with placebo, while the second study compared 2 mg of LUNESTA with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of LUNESTA was superior to placebo on measures of sleep maintenance.

Studies Pertinent To Safety Concerns For Sedative/Hypnotic Drugs

Cognitive, Memory, Sedative, and Psychomotor Effects

In two double-blind, placebo-controlled, single-dose cross-over studies of 12 patients each (one study in patients with insomnia; one in normal volunteers), the effects of LUNESTA 2 and 3 mg were assessed on 20 measures of cognitive function and memory at 9.5 and 12 hours after a nighttime dose. Although results suggested that patients receiving LUNESTA 3 mg performed more poorly than patients receiving placebo on a very small number of these measures at 9.5 hours post-dose, no consistent pattern of abnormalities was seen.

In a 6-month double-blind, placebo-controlled trial of nightly administered LUNESTA 3 mg, 8/593 subjects treated with LUNESTA 3 mg (1.3%) and 0/195 subjects treated with placebo (0%) spontaneously reported memory impairment. The majority of these events were mild in nature (5/8), and none were reported as severe. Four of these events occurred within the first 7 days of treatment and did not recur. The incidence of spontaneously reported confusion in this 6-month study was 0.5% in both treatment arms. In a 6-week adult study of nightly administered LUNESTA 2 mg or 3 mg or placebo, the spontaneous reporting rates for confusion were 0%, 3.0%, and 0%, respectively, and for memory impairment were 1%, 1%, and 0%, respectively.

In a 2-week study of 264 elderly insomniacs randomized to either nightly LUNESTA 2 mg or placebo, spontaneous reporting rates of confusion and memory impairment were 0% vs. 0.8% and 1.5% vs. 0%, respectively. In another 2-week study of 231 elderly insomniacs, the spontaneous reporting rates for the 1 mg, 2 mg, and placebo groups for confusion were 0%, 2.5%, and 0%, respectively, and for memory impairment were 1.4%, 0%, and 0%, respectively.

A study of normal subjects exposed to single fixed doses of LUNESTA from 1 to 7.5 mg using the DSST to assess sedation and psychomotor function at fixed times after dosing (hourly up to 16 hours) found the expected sedation and reduction in psychomotor function. This was maximal at 1 hour and present up to 4 hours, but was no longer present by 5 hours.

In another study, patients with insomnia were given 2 or 3 mg doses of LUNESTA nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and LUNESTA 3 mg groups showed an improvement in DSST scores relative to baseline the following morning (presumably due to a learning effect), the improvement in the placebo group was greater and reached statistical significance on night 1, although not on nights 15 and 29. For the LUNESTA 2 mg group, DSST change scores were not significantly different from placebo at any time point.

Withdrawal-Emergent Anxiety And Insomnia

During nightly use for an extended period, pharmacodynamic tolerance or adaptation has been observed with other hypnotics. If a drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night's use. This is believed to be responsible for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics: increased wakefulness during the last quarter of the night and the appearance of increased signs of daytime anxiety.

In a 6-month double-blind, placebo-controlled study of nightly administration of LUNESTA 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the LUNESTA arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1.0% of the placebo, 2 mg, and 3 mg treatment arms, respectively. In this study, single-blind placebo was administered on nights 45 and 46, the first and second days of withdrawal from study drug. New adverse events were recorded during the withdrawal period, beginning with day 45, up to 14 days after discontinuation. During this withdrawal period, 105 subjects previously taking nightly LUNESTA 3 mg for 44 nights spontaneously reported anxiety (1%), abnormal dreams (1.9%), hyperesthesia (1%), and neurosis (1%), while none of 99 subjects previously taking placebo reported any of these adverse events during the withdrawal period.

Rebound insomnia, defined as a dose-dependent temporary worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. Rebound insomnia following discontinuation of LUNESTA relative to placebo and baseline was examined objectively in a 6-week adult study on the first 2 nights of discontinuation (nights 45 and 46) following 44 nights of active treatment with 2 mg or 3 mg. In the LUNESTA 2 mg group, compared with baseline, there was a significant increase in WASO and a decrease in sleep efficiency, both occurring only on the first night after discontinuation of treatment. No changes from baseline were noted in the LUNESTA 3 mg group on the first night after discontinuation, and there was a significant improvement in LPS and sleep efficiency compared with baseline following the second night of discontinuation. Comparisons of changes from baseline between LUNESTA and placebo were also performed. On the first night after discontinuation of LUNESTA 2 mg, LPS and WASO were significantly increased and sleep efficiency was reduced; there were no significant differences on the second night. On the first night following discontinuation of LUNESTA 3 mg, sleep efficiency was significantly reduced. No other differences from placebo were noted in any other sleep parameter on either the first or second night following discontinuation. For both doses, the discontinuation-emergent effect was mild, had the characteristics of the return of the symptoms of chronic insomnia, and appeared to resolve by the second night after LUNESTA discontinuation.

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