DailyMed Label: Lunesta

DailyMed Label: Lunesta

2023

DailyMed Prescription

Lunesta

ESZOPICLONE

Sumitomo Pharma America, Inc.

NDC: 63402-190

NDC: 63402-190

NDC: 63402-191

NDC: 63402-191

NDC: 63402-193

NDC: 63402-193

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 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 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. Chemical Structure

LUNESTA ® (eszopiclone) is indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, LUNESTA 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). LUNESTA is indicated for the treatment of insomnia. LUNESTA has been shown to decrease sleep latency and improve sleep maintenance ( 1 )

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 ) 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 LUNESTA 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 LUNESTA should not exceed 3 mg, once daily immediately before bedtime [ see Warnings and Precautions ( 5.6 ) ]. The total dose of LUNESTA should not exceed 2 mg in elderly or debilitated patients. In patients with severe hepatic impairment, or in patients coadministered LUNESTA with potent CYP3A4 inhibitors, the total dose of LUNESTA should not exceed 2 mg [ see Warnings and Precautions ( 5.7 ) ]. Dosage adjustments may be necessary when LUNESTA is combined with other central nervous system (CNS) depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.1 )]. Taking LUNESTA with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of LUNESTA on sleep latency [see Clinical Pharmacology ( 12.3 )] .

LUNESTA is available in 1 mg, 2 mg and 3 mg strengths for oral administration. LUNESTA 3 mg tablets are round, dark blue, film-coated, and identified with debossed markings of S193 on one side. LUNESTA 2 mg tablets are round, white, film-coated, and identified with debossed markings of S191 on one side. LUNESTA 1 mg tablets are round, light blue, film-coated, and identified with debossed markings of S190 on one side. Tablets: 1 mg, 2 mg, and 3 mg ( 3 )

LUNESTA is contraindicated in patients who have experienced complex sleep behaviors after taking LUNESTA [see Warnings and Precautions ( 5.1 )]. LUNESTA is contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema [see Warnings and Precautions ( 5.3 )] . Patients who have experienced complex sleep behaviors after taking LUNESTA ( 4 ) Known hypersensitivity to eszopiclone ( 4 )

CNS Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients taking 3 mg dose against driving and against activities requiring complete mental alertness during the morning after use. ( 5.2 ) Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use ( 5.3 ) Severe Anaphylactic/Anaphylactoid Reactions (angioedema and anaphylaxis have been reported): Do not rechallenge if such reactions occur ( 5.4 ) Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation and depersonalization have been reported. Immediately evaluate any new onset of behavioral changes ( 5.5 ) Worsening of Depression or Suicidal Thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose ( 5.5 , 5.8 ) Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation ( 5.6 , 9.3 ) Elderly Patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity ( 2.2 , 5.8 ) Patients with Hepatic Impairment, Impaired Respiratory Function, Impaired Drug Metabolism or Hemodynamic Responses: Use with caution ( 5.8 ) Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the first or any subsequent use of LUNESTA. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with LUNESTA alone at recommended dosages, with or without the concomitant use of alcohol or other CNS depressants [see Drug Interactions ( 7.1 )] . Discontinue LUNESTA immediately if a patient experiences a complex sleep behavior. LUNESTA is a 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 LUNESTA may develop, patients using 3 mg LUNESTA 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 LUNESTA and concomitant CNS depressants should be considered [see Dosage and Administration ( 2.4 )]. The use of LUNESTA 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 LUNESTA is taken with less than a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants; or coadministered with other drugs that increase the blood levels of eszopiclone [see Dosage and Administration ( 2.3 ) and Clinical Studies ( 14.3 )]. Because Lunesta can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. 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 LUNESTA. Because some of the important adverse effects of LUNESTA 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 )]. 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 LUNESTA. 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 LUNESTA should not be rechallenged with the drug. 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. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is 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. 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 )] . LUNESTA 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. 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 LUNESTA is prescribed to patients with compromised respiratory function. The dose of LUNESTA 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 LUNESTA should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking LUNESTA. Downward dose adjustment is also recommended when LUNESTA is administered with agents having known CNS-depressant effects. Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported in association with the use of sedative/hypnotics. 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.

The following are described in more detail in the

CNS Depressants: Additive CNS-depressant effects with combination use. Use with ethanol causes additive psychomotor impairment ( 7.1 ) Rifampicin: Combination use may decrease exposure and effects of LUNESTA ( 7.2 ) Ketoconazole: Combination use increases exposure and effect of LUNESTA. Dose reduction of LUNESTA is needed ( 7.2 ) Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol [see Warnings and Precautions ( 5.1 , 5.2 )] . 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. 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 LUNESTA is needed for patient co-administered LUNESTA 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 the exposure and effects of LUNESTA.

Pediatric Use: Safety and effectiveness not established. Dizziness, dysgeusia, hallucinations, suicidal ideation reported ( 8.4 ) Risk Summary Available pharmacovigilance data with LUNESTA use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits throughout organogenesis, there was no evidence of teratogenicity. Administration of eszopiclone to rats throughout pregnancy and lactation resulted in offspring toxicities at all doses tested; the lowest dose was approximately 200 times the maximum recommended human dose (MRHD) of 3 mg/day based on mg/m 2 body surface area (See Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data 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 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. Risk Summary There are no data on the presence of eszopiclone in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUNESTA and any potential adverse effects on the breastfed infant from LUNESTA or from the underlying maternal condition. Safety and effectiveness of LUNESTA have not been established in pediatric patients. LUNESTA failed to demonstrate efficacy in controlled clinical studies of pediatric patients with Attention-Deficit/Hyperactivity (ADHD) associated insomnia. In a 12-week controlled study, 483 pediatric patients (aged 6-17 years) with insomnia associated with ADHD (with 65% of the patients using concomitant ADHD treatments) were treated with oral tablets of LUNESTA (1, 2 or 3 mg tablets, n=323), or placebo (n=160). LUNESTA did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 12 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent treatment-emergent adverse reactions observed with LUNESTA versus placebo and included dysgeusia (9% vs. 1%), dizziness (6% vs. 2%), hallucinations (2% vs. 0%) and suicidal ideation (0.3% vs. 0%). Nine patients on LUNESTA (3%) discontinued treatment due to an adverse reaction compared to 3 patients on placebo (2%). 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 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 doses ≥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. 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 )] . LUNESTA 2 mg exhibited significant reduction in sleep latency and improvement in sleep maintenance in the elderly population. Compared with nonelderly adults, subjects 65 years and older had longer elimination and higher total exposure to eszopiclone. Therefore, dose reduction is recommended in elderly patients [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] . No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Exposure was increased in severely impaired patients compared with healthy volunteers. The dose of LUNESTA should not exceed 2 mg in patients with severe hepatic impairment. LUNESTA should be used with caution in patients with hepatic impairment [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )] .

LUNESTA 3 mg tablets are round, dark blue, film-coated, and identified with debossed markings of S193 on one side, and are supplied as: NDC 63402-193-10 bottle of 100 tablets NDC 63402-193-03 bottle of 30 tablets LUNESTA 2 mg tablets are round, white, film-coated, and identified with debossed markings of S191 on one side, and are supplied as: NDC 63402-191-10 bottle of 100 tablets NDC 63402-191-03 bottle of 30 tablets LUNESTA 1 mg tablets are round, light blue, film-coated, and identified with debossed markings of S190 on one side, and are supplied as: NDC 63402-190-30 bottle of 30 tablets Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

The mechanism of action of eszopiclone as a hypnotic is unclear; however, its effect could be related to its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors. 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 max ) of approximately 1 hour and a terminal-phase elimination half-life (t 1/2 ) 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. 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. 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 1/2 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. 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 LUNESTA on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal. Specific Populations Age Compared with nonelderly 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 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. LUNESTA should be used with caution in patients with hepatic impairment [see Dosage and Administration ( 2.3 )] . 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. LUNESTA would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes [see Warnings and Precautions ( 5.7 ), Dosage and Administration ( 2.3 )] . 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 (52-59% 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.

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 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/m 2 basis.

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 WASO and subjectively measured as total sleep time). 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. 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. 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 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 crossover 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 65-86 years) 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. Next-Day Residual Effects In a double-blind study of 91 healthy adults age 25- to 40 years, the effects of LUNESTA 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, LUNESTA 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 LUNESTA 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 LUNESTA 3 mg, memory impairment was reported by 1.3% (8/593) of subjects treated with LUNESTA 3 mg compared to 0% (0/195) of subjects treated with placebo. In a 6-week adult study of nightly administered LUNESTA confusion was reported by 3.0% of patients treated with LUNESTA 3 mg, compared to 0% of subjects treated with placebo. In the same study, memory impairment was reported by 1% of patients treated with either 2 mg or 3 mg LUNESTA, compared to 0% treated with placebo. In a 2-week study of 264 elderly insomniacs, 1.5% of patients treated with LUNESTA 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 LUNESTA 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 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.

1 MG BOTTLE LABEL – PRINCIPAL DISPLAY PANEL – 1mg NDC 63402-190-30 30 Tablets Lunesta ® (eszopiclone) Tablets 1 mg C-IV DISPENSER: Each time Lunesta is dispensed give the patient a medication guide, also provided at www.Lunesta.com or 1-888-394-7377. SUNOVION Rx Only ______________________________________________________________________________ 1 MG BOTTLE LABEL – PRINCIPAL DISPLAY PANEL – 1mg