Eszopiclone 1 MG Oral Tablet

DRUG INTERACTIONS

7 • CNS depressants: Additive CNS-depressant effects with combination use.

Use with ethanol causes additive psychomotor impairment ( 7.1 ) • Rifampicin: Combination use may decrease exposure to and effects of eszopiclone ( 7.2 ) • Ketoconazole: Combination use increases exposure and effect of eszopiclone.

Dose reduction of eszopiclone is needed ( 7.2 ) 7.1 CNS Active Drugs Ethanol : An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol.

Olanzapine : Coadministration of eszopiclone and olanzapine produced a decrease in DSST scores.

The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug.

7.2 Drugs that Inhibit or Induce CYP3A4 Drugs That Inhibit CYP3A4 (Ketoconazole) : CYP3A4 is a major metabolic pathway for elimination of eszopiclone.

The exposure of eszopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4.

Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly.

Dose reduction of eszopiclone is needed for patient co-administered eszopiclone with potent CYP3A4 inhibitors [see Dosage and Administration ( 2.3 )].

Drugs that Induce CYP3A4 (Rifampicin) : Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4.

A similar effect would be expected with eszopiclone.

Combination use with CYP3A4 inducer may decrease exposure and effects of eszopiclone

OVERDOSAGE

10 In clinical trials with eszopiclone, one case of overdose with up to 36 mg of eszopiclone was reported in which the subject fully recovered.

Since commercial marketing began, spontaneous cases of eszopiclone overdoses up to 270 mg (90 times the maximum recommended dose of eszopiclone) have been reported, in which patients have recovered.

Fatalities related to eszopiclone overdoses were reported only in combination with other CNS drugs or alcohol.

10.1 Signs and Symptoms Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing.

Impairment of consciousness ranging from somnolence to coma has been described.

Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents.

10.2 Recommended Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate.

Intravenous fluids should be administered as needed.

Flumazenil may be useful.

As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed.

Hypotension and CNS depression should be monitored and treated by appropriate medical intervention.

The value of dialysis in the treatment of overdosage has not been determined.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered.

The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

DESCRIPTION

11 Eszopiclone Tablets are 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 17 H 17 ClN 6 O 3 .

Eszopiclone has a single chiral center with an ( S )-configuration.

It has the following chemical structure: Eszopiclone is a white to slightly yellowish 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.

Eszopiclone Tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose and Opadry II (White).

Opadry II (White) contains hypromellose, polydextrose, polyethylene glycol, titanium dioxide and triacetin.

I:DRA-MALABELINGXML FilesEszopiclone TabletsANDA Eszopiclone Exported CopyEszopiclone chem structre.wmf

CLINICAL STUDIES

14 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 Next Day Residual Effects In a double-blind study of 91 healthy adults age 25 to 40 years, the effects of eszopiclone 3 mg on psychomotor function were assessed between 7.5 and 11.5 hours the morning after dosing.

Measures included tests of psychomotor coordination that are correlated with ability to maintain a motor vehicle in the driving lane, tests of working memory, and subjective perception of sedation and coordination.

Compared with placebo, eszopiclone 3 mg was associated with next- morning psychomotor and memory impairment that was most severe at 7.5 hours, but still present and potentially clinically meaningful at 11.5 hours.

Subjective perception of sedation and coordination from eszopiclone 3 mg was not consistently different from placebo, even though subjects were objectively impaired.

In a 6-month double-blind, placebo-controlled trial of nightly administered eszopiclone 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with eszopiclone 3 mg compared to 0% (0/195) of subjects treated with placebo.

In a 6-week adult study of nightly administered eszopiclone confusion was reported by 3% of patients treated with eszopiclone 3 mg, compared to 0% of subjects treated with placebo.

In the same study, memory impairment was reported by 1% of patents treated with either 2 mg or 3 mg eszopiclone, compared to 0% treated with placebo.

In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with eszopiclone 2 mg reported memory impairment compared to 0% treated with placebo.

In another 2-week study of 231 elderly insomniacs, 2.5% of patients treated with eszopiclone 2 mg reported confusion compared to 0% treated with placebo.

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.

HOW SUPPLIED

16 /STORAGE AND HANDLING Eszopiclone Tablets are round, white, biconvex, film-coated tablets and are supplied as follows: The 1 mg tablets are debossed with product identification “54” over “746” on one side and plain on the other side.

Bottle of 7 – 68788-9361-7 Bottle of 10 – 68788-9361-1 Bottle of 15 – 68788-9361-5 Bottle of 30 – 68788-9361-3 Bottle of 60 – 68788-9361-6 Bottle of 90 – 68788-9361-9 Bottle of 100 – 68788-9361-0 Storage Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

8.5 Geriatric Use A total of 287 subjects in double-blind, parallel-group, placebo-controlled clinical trials who received eszopiclone were 65 to 86 years of age.

The overall pattern of adverse events for elderly subjects (median age = 71 years) in 2-week studies with nighttime dosing of 2 mg eszopiclone was not different from that seen in younger adults [see Adverse Reactions ( 6 )] .

Eszopiclone 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population.

Compared with non-elderly adults, subjects 65 years and older had longer elimination and higher total exposure to eszopiclone.

Therefore, dose reduction is recommended in the elderly patients [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] .

DOSAGE FORMS AND STRENGTHS

3 Eszopiclone tablets are available as 1 mg, 2 mg, and 3 mg strengths for oral administration.

Tablets: 1 mg, 2 mg and 3 mg tablets ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action 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.

INDICATIONS AND USAGE

1 Eszopiclone Tablets are indicated for the treatment of insomnia.

In controlled outpatient and sleep laboratory studies, Eszopiclone Tablets administered at bedtime decreased sleep latency and improved sleep maintenance.

The clinical trials performed in support of efficacy were up to 6 months in duration.

The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only).

Eszopiclone Tablets are indicated for the treatment of insomnia.

Eszopiclone Tablets have been shown to decrease sleep latency and improve sleep maintenance.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

The labeling for Sunovion Pharmaceutical Inc.’s eszopiclone tablets includes additional information from a clinical study in which efficacy was not demonstrated in pediatric patients.

However, due to Sunovion Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

In studies in which eszopiclone (2 to 300 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, neurobehavioral impairment (altered auditory startle response) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were observed at doses ≥ 5 mg/kg/day.

Delayed sexual maturation was noted in males and females at ≥ 10 mg/kg/day.

The no-effect dose (2 mg/kg) was associated with plasma exposures (AUC) for eszopiclone and metabolite (S)-desmethylzopiclone [(S)-DMZ] approximately 2 times plasma exposures in humans at the maximum recommended dose (MRHD) in adults (3 mg/day).

When eszopiclone (doses from 1 to 50 mg/kg/day) was orally administered to young dogs from weaning through sexual maturity, neurotoxicity (convulsions) was observed at doses ≥ 5 mg/kg/day.

Hepatotoxicity (elevated liver enzymes and hepatocellular vacuolation and degeneration) and reproductive toxicity (adverse effects on male reproductive organ weights and histopathology) were noted at dose ≥ 10 mg/kg/day.

The no-effect dose (1 mg/kg) was associated with plasma exposures (AUC) to eszopiclone and (S)-DMZ approximately 3 and 2 times, respectively, plasma exposures in humans at the MRHD in adults.

PREGNANCY

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.

Eszopiclone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of eszopiclone to pregnant rats (62.5, 125, or 250 mg/kg/day) and rabbits (4, 8, or 16 mg/kg/day) throughout organogenesis showed no evidence of teratogenicity up to the highest doses tested.

In rats, reduced fetal weight and increased incidences of skeletal variations and/or delayed ossification were observed at the mid and high doses.

The no-observed-effect dose for adverse effects on embryofetal development is 200 times the maximum recommended human dose (MRHD) of 3 mg/day on a mg/m 2 basis.

No effects on embryofetal development were observed in rabbits; the highest dose tested is approximately 100 times the MRHD on a mg/m 2 basis.

Oral administration of eszopiclone (60, 120, or 180 mg/kg/day) to pregnant rats throughout the pregnancy and lactation resulted in increased post-implantation loss, decreased postnatal pup weights and survival, and increased pup startle response at all doses.

The lowest dose tested is approximately 200 times the MRHD on a mg/m 2 basis.

Eszopiclone had no effects on other developmental measures or reproductive function in the offspring.

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential It is not known whether this drug is excreted in human milk.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • CNS depressant effects: Impaired alertness and motor coordination, including risk of morning impairment.

Risk increases with dose.

Caution patients taking 3 mg dose against driving and against activities requiring complete mental alertness during the morning after use.

( 5.1 ) • Evaluate for co-morbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use ( 5.2 ) • Severe anaphalactic/anaphylactoid reactions (angioedema and anaphylaxis have been reported): Do not rechallenge if such reactions occur ( 5.3 ) • Abnormal thinking, behavioral changes (e.g., hallucinations, complex behaviors (e.g., “sleep-driving”)): Immediately evaluate if occurs ( 5.4 ) • Worsening of depression or suicidal thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose ( 5.4 , 5.7 ) • Withdrawal effects: symptoms may occur with rapid dose reduction or discontinuation ( 5.5 , 9.3 ) • Elderly patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity ( 2.2 , 5.7 ) • Patients with hepatic impairment, impaired respiratory function, impaired drug metabolism or hemodynamic responses: Use with caution ( 5.7 ) 5.1 CNS Depressant Effects and Next-Day Impairment Eszopiclone is a central nervous system (CNS) depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed.

Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing).

While pharmacodynamic tolerance or adaptation to some adverse depressant effects of eszopiclone may develop, patients using 3 mg eszopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use.

Downward dose adjustment of eszopiclone and concomitant CNS depressants should be considered [see Dosage and Administration ( 2.4 )].

The use of eszopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended.

The risk of next-day psychomotor impairment is increased if eszopiclone is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co- administered with other CNS depressants; or co-administered with other drugs that increase the blood levels of eszopiclone [see Dosage and Administration ( 2.3 ) and Clinical Studies ( 14.3 )].

5.2 Need to Evaluate for Co-Morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient.

The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated .

Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder.

Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including eszopiclone.

Because some of the important adverse effects of eszopiclone appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly [see Dosage and Administration ( 2.1 )] .

5.3 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including eszopiclone.

Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis.

Some patients have required medical therapy in the emergency department.

If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.

Patients who develop angioedema after treatment with eszopiclone should not be rechallenged with the drug.

5.4 Abnormal Thinking and Behavioral Changes A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics.

Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants.

Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization.

Amnesia and other neuropsychiatric symptoms may occur unpredictably.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported.

These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons.

Although behaviors such as sleep-driving may occur with eszopiclone alone at therapeutic doses, the use of alcohol and other CNS depressants with eszopiclone appears to increase the risk of such behaviors, as does the use of eszopiclone at doses exceeding the maximum recommended dose.

Due to the risk to the patient and the community, discontinuation of eszopiclone should be strongly considered for patients who report a “sleep-driving” episode.

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.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above are drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder.

Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.5 Withdrawal Effects Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence ( 9 )] .

5.6 Timing of Drug Administration Eszopiclone should be taken immediately before bedtime.

Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.

5.7 Special Populations Use in Elderly and/or Debilitated Patients Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients.

The dose should not exceed 2 mg in elderly or debilitated patients [see Dosage and Administration ( 2.2 )] .

Use in Patients with Concomitant Illness Clinical experience with eszopiclone in patients with concomitant illness is limited.

Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone.

Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function.

The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects.

No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment.

No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine.

The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone.

Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects.

Use in Patients with Depression Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression.

Suicidal tendencies may be present in such patients, and protective measures may be required.

Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with eszopiclone.

Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with eszopiclone and with each prescription refill.

Review the eszopiclone Medication Guide with every patient prior to initiation of treatment.

Instruct patients or caregivers that eszopiclone should be taken only as prescribed.

CNS Depressant Effects and Next-Day Impairment : Tell patients that eszopiclone can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed.

Caution patients taking the 3 mg dose against driving and other activities requiring complete mental alertness the day after use.

Inform patients that impairment can be present despite feeling fully awake.

Severe Anaphylactic and Anaphylactoid Reactions : Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with eszopiclone.

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 : Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex).

Tell patients to call you immediately if they develop any of these symptoms.

Suicide : Tell patients to immediately report any suicidal thoughts.

Alcohol and Other Drugs : Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription.

Advise patients not to use eszopiclone if they drank alcohol that evening or before bed.

Tolerance, Abuse, and Dependence : Tell patients not to increase the dose of eszopiclone on their own, and to inform you if they believe the drug “does not work”.

Administration Instructions : Patients should be counseled to take eszopiclone right before they get into bed and only when they are able to stay in bed a full night (7 to 8 hours) before being active again.

Eszopiclone tablets should not be taken with or immediately after a meal.

Advise patients NOT to take eszopiclone if they drank alcohol that evening.

Distr.

by: West-Ward Pharmaceuticals Corp.

Eatontown, NJ 07724 10005923/03 Revised January 2016 Repackaged By: Preferred Pharmaceuticals Inc.

DOSAGE AND ADMINISTRATION

2 Use the lowest effective dose for the patient.

• Use the lowest dose effective for the patient ( 2 ) • Recommended initial dose is 1 mg, immediately before bedtime, with at least 7-8 hours remaining before the planned time of awakening.

May increase dose if clinically indicated, to a maximum of 3 mg ( 2.1 ) • Geriatric or debilitated patients: Dose should not exceed 2 mg ( 2.2 ) • Patients with severe hepatic impairment, or taking potent CYP3A4 inhibitors: Dose should not exceed 2 mg ( 2.3 ) • Do not take with or immediately after a meal ( 2.5 ) 2.1 Dosage in Adults The recommended starting dose is 1 mg.

Dosing can be raised to 2 mg or 3 mg if clinically indicated.

In some patients, the higher morning blood levels of eszopiclone following use of the 2 mg or 3 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions ( 5.1 )] .

The total dose of eszopiclone should not exceed 3 mg, once daily immediately before bedtime [see Warnings and Precautions ( 5.6 )] .

2.2 Geriatric or Debilitated Patients The total dose of eszopiclone should not exceed 2 mg in elderly or debilitated patients.

2.3 Patients with Severe Hepatic Impairment, or Taking Potent CYP3A4 Inhibitors In patients with severe hepatic impairment, or in patients coadministered eszopiclone with potent CYP3A4 inhibitors, the total dose of eszopiclone should not exceed 2 mg [see Warning and Precautions ( 5.7 )] .

2.4 Use with CNS Depressants Dosage adjustments may be necessary when eszopiclone is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.1 )].

2.5 Administration with Food Taking eszopiclone with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone on sleep latency [see Clinical Pharmacology ( 12.3 )].