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 to 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.

Metabolism
Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-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. In vitro 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.

Elimination
After oral administration, eszopiclone is eliminated with a mean t_1/2of 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.

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_max of 21%, and delayed t_max by approximately 1 hour. The half-life remained unchanged, approximately 6 hours. The effects of eszopiclone on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.

Specific Populations
Age
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_1/2 approximately 9 hours). C_max was unchanged. Therefore, in elderly patients the starting dose of eszopiclone should be decreased to 1 mg and the dose should not exceed 2 mg.

Gender
The pharmacokinetics of eszopiclone in men and women are similar.

Race
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_max and t_max were unchanged. No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. Eszopiclone should be used with caution in patients with hepatic impairment [see Dosage and Administration (2.1)].

Renal Impairment
The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and C_max 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.

Drug Interactions
Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation. There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine. 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_max by 22%. Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days, resulted in a 2.2-fold increase in exposure to eszopiclone. C_max and t_1/2 were increased 1.4-fold and 1.3-fold, respectively. Eszopiclone would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes [see Warnings and Precautions: Special Populations (5.7), Dosage and Administration (2.1) ].

Paroxetine: Coadministration of single dose of eszopiclone and paroxetine produced no pharmacokinetic or pharmacodynamic interaction. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.

Lorazepam: Coadministration of single doses of eszopiclone and lorazepam did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug. The lack of a drug interaction following single-dose administration does not predict the complete absence of a pharmacodynamic effect following chronic administration.

Drugs with a Narrow Therapeutic Index
Digoxin: A single dose of eszopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0.5 mg twice daily for one day and 0.25 mg daily for the next 6 days.

Warfarin: Eszopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of (R)- or (S)-warfarin, nor were there any changes in the pharmacodynamic profile (prothrombin time) following a single 25 mg oral dose of warfarin.

Drugs Highly Bound to Plasma Protein
Eszopiclone is not highly bound to plasma proteins (52 to 59% bound); therefore, the disposition of eszopiclone is not expected to be sensitive to alterations in protein binding. Administration of eszopiclone 3 mg to a patient taking another drug that is highly protein-bound would not be expected to cause an alteration in the free concentration of either drug.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis
In a carcinogenicity study in rats, oral administration of eszopiclone for 97 (males) or 104 (females) weeks resulted in no increases in tumors; plasma levels (AUC) of eszopiclone at the highest dose tested (16 mg/kg/day) are approximately 80 (females) and 20 (males) times those in humans at the maximum recommended human dose (MRHD) of 3 mg/day. However, in a 2-year carcinogenicity study in rats, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) resulted in increases in mammary gland adenocarcinomas (females) and thyroid gland follicular cell adenomas and carcinomas (males) at the highest dose tested. Plasma levels of eszopiclone at this dose are approximately 150 (females) and 70 (males) times those in humans at the MRHD of eszopiclone. The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones, a mechanism not considered relevant to humans.


In a 2-year carcinogenicity study in mice, oral administration of racemic zopiclone (1, 10, or 100 mg/kg/day) produced increases in pulmonary carcinomas and carcinomas plus adenomas (females) and skin fibromas and sarcomas (males) at the highest dose tested. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism not relevant to humans. A carcinogenicity study of eszopiclone was conducted in mice at oral doses up to 100 mg/kg/day. Although this study did not reach a maximum tolerated dose, and was thus inadequate for overall assessment of carcinogenic potential, no increases in either pulmonary or skin tumors were seen at doses producing plasma levels of eszopiclone approximately 90 times those in humans at the MRHD of eszopiclone (and 12 times the exposure in the racemate study).

Eszopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.

Mutagenesis
Eszopiclone was clastogenic in in vitro (mouse lymphoma and chromosomal aberration) assays in mammalian cells. Eszopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo micronucleus assay.

(S)-N-desmethyl zopiclone, a metabolite of eszopiclone, was positive in in vitro chromosomal aberration assays in mammalian cells. (S)-N-desmethyl zopiclone was negative in the in vitro bacterial gene mutation (Ames) assay and in an in vivo chromosomal aberration and micronucleus assay.

Impairment of Fertility
Oral administration of eszopiclone to rats prior to and during mating, and continuing in females to day 7 of gestation (doses up to 45 mg/kg/day to males and females or up to 180 mg/kg/day to females only) resulted in decreased fertility, with no pregnancy at the highest dose tested when both males and females were treated. In females, there was an increase in abnormal estrus cycles at the highest dose tested. In males, decreases in sperm number and motility and increases in morphologically abnormal sperm were observed at the mid and high doses. The no-effect dose for adverse effects on fertility (5 mg/kg/day) is 16 times the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

The effect of eszopiclone on reducing sleep latency and improving sleep maintenance was established in studies with 2100 subjects (ages 18 to 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 to 3 mg) and elderly dose (1 to 2 mg), eszopiclone 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).

14.1 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. Eszopiclone 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.

14.2 Chronic Insomnia (Adults and Elderly)

The effectiveness of eszopiclone 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.

Adults
In the first study, adults with chronic insomnia (n=308) were evaluated in a double-blind, parallel-group trial of 6 weeks’ duration comparing eszopiclone 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 eszopiclone 3 mg with placebo administered nightly for 6 months. Eszopiclone 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
Elderly subjects (ages 65 to 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 eszopiclone 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 eszopiclone with placebo, while the second study compared 2 mg of eszopiclone with placebo. All doses were superior to placebo on measures of sleep latency. In both studies, 2 mg of eszopiclone was superior to placebo on measures of sleep maintenance.

14.3 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 eszopiclone 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 eszopiclone 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 eszopiclone 3 mg, 8/593 subjects treated with eszopiclone 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 eszopiclone 2 mg or 3 mg or placebo, the spontaneous reporting rates for confusion were 0%, 3%, 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 eszopiclone 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 eszopiclone 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 eszopiclone nightly, with DSST assessed on the mornings following days 1, 15, and 29 of treatment. While both the placebo and eszopiclone 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 eszopiclone 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 eszopiclone 3 mg, rates of anxiety reported as an adverse event were 2.1% in the placebo arm and 3.7% in the eszopiclone arm. In a 6-week adult study of nightly administration, anxiety was reported as an adverse event in 0%, 2.9%, and 1% 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 eszopiclone 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 eszopiclone 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 eszopiclone 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 eszopiclone 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 eszopiclone and placebo were also performed. On the first night after discontinuation of eszopiclone 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 eszopiclone 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 eszopiclone discontinuation.

16 HOW SUPPLIED/STORAGE AND HANDLING

Eszopiclone tablets 1 mg are blue colored, circular, film-coated tablets, debossed with ‘S’ on one side and ‘1’ on other side.

Bottles of 30’s with Child Resistant Cap……………..NDC 47335-586-83
Bottles of 100’s with Child Resistant Cap……………NDC 47335-586-88
Bottles of 100’s with Non Child Resistant Cap………NDC 47335-586-08
Bottles of 1000’s with Non Child Resistant Cap……..NDC 47335-586-18

Eszopiclone tablets 2 mg are white colored, circular, film-coated tablets, debossed with ‘S’ on one side and ‘2’ on other side.

Bottles of 30’s with Child Resistant Cap……………..NDC 47335-587-83
Bottles of 100’s with Child Resistant Cap……………NDC 47335-587-88
Bottles of 100’s with Non Child Resistant Cap………NDC 47335-587-08
Bottles of 1000’s with Non Child Resistant Cap……..NDC 47335-587-18

Eszopiclone tablets 3 mg are dark blue colored, circular, film-coated tablets, debossed with ‘S’ on one side and ‘3’ on other side.

Bottles of 30’s with Child Resistant Cap……………..NDC 47335-588-83
Bottles of 100’s with Child Resistant Cap……………NDC 47335-588-88
Bottles of 100’s with Non Child Resistant Cap………NDC 47335-588-08
Bottles of 1000’s with Non Child Resistant Cap……..NDC 47335-588-18

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in tight container with child-resistant closure.

17 PATIENT COUNSELING INFORMATION

Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be given the following information:

Severe anaphylactic and anaphylactoid reactions
Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with eszopiclone tablets. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.

“Sleep-Driving” and other complex behaviors
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when eszopiclone tablets are taken with alcohol or other central nervous system depressants [see Warnings and Precautions (5.3)]. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

Administration instructions

• Patients should be instructed to take eszopiclone tablets immediately prior to going to bed, and only if they can dedicate 8 hours to sleep.
• Patients should be instructed not to take eszopiclone tablets with alcohol or with other sedating medications.
• Patients should be advised to consult with their physician if they have a history of depression, mental illness, or suicidal thoughts, have a history of drug or alcohol abuse, or have liver disease.
• Women should be advised to contact their physician if they become pregnant, plan to become pregnant, or if they are nursing.

Medication Guide

Eszopiclone Tablets C-IV
Read the Medication Guide that comes with eszopiclone tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about eszopiclone tablets?

After taking eszopiclone tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with eszopiclone tablets. Reported activities include:

• driving a car ("sleep-driving")
• making and eating food
• talking on the phone
• having sex
• sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking eszopiclone tablets.

Important:

1. Take eszopiclone tablets exactly as prescribed

• Do not take more eszopiclone tablets than prescribed.
• Take eszopiclone tablets right before you get in bed, not sooner.

2. Do not take eszopiclone tablets if you:

• drink alcohol
• take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take eszopiclone tablets with your other medicines
• cannot get a full night’s sleep

WHAT ARE ESZOPICLONE TABLETS?

Eszopiclone tablets are sedative-hypnotic (sleep) medicines. Eszopiclone tablets are used in adults for the treatment of a sleep problem called insomnia. Symptoms of insomnia include:

• trouble falling asleep
• waking up often during the night

Eszopiclone tablets arenot for children.

Who should not take eszopiclone tablets?
Do not take eszopiclone tablets if you are allergic to anything in it.
See the end of this Medication Guide for a complete list of ingredients in eszopiclone tablets.

Eszopiclone tablets may not be right for you. Before starting eszopiclone tablets, tell your doctor about all of your health conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have liver disease
• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take eszopiclone tablets with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take eszopiclone tablets?

• Take eszopiclone tablets exactly as prescribed. Do not take more eszopiclone tablets than prescribed for you.
• Take eszopiclone tablets right before you get into bed.
• Do not take eszopiclone tablets with or right after a meal.
• Do not take eszopiclone tablets unless you are able to get a full night’s sleep before you must be active again.
• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problems.
• If you take too many eszopiclone tablets or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of eszopiclone tablets?

Possible serious side effects of eszopiclone tablets include:

• getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See “What is the most important information I should know about eszopiclone tablets?)
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking eszopiclone tablets .

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using eszopiclone tablets.

The most common side effects of eszopiclone tablets are:

• unpleasant taste in mouth, dry mouth
• drowsiness
• dizziness
• headache
• symptoms of the common cold
• You may still feel drowsy the next day after taking eszopiclone tablets . Do not drive or do other dangerous activities after taking eszopiclone tablets until you feel fully awake.

These are not all the side effects ofeszopiclone tablets. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I Store Eszopiclone Tablets?

• Store eszopiclone tablets at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Do not use eszopiclone tablets after the expiration date.
• Keep eszopiclone tablets and all medicines out of reach of children.

General Information about Eszopiclone Tablets

• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
• Do not use eszopiclone tablets for a condition for which it was not prescribed.
• Do not share eszopiclone tablets with other people, even if you think they have the same symptoms that you have. It may harm them and is against the law.

This Medication Guide summarizes the most important information abouteszopiclone tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information abouteszopiclone tabletsthat is written for healthcare professionals.