Eszopiclone

1 INDICATIONS & USAGE 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 has been shown to decrease sleep latency and improve sleep maintenance ()

2 DOSAGE & ADMINISTRATION Use the lowest effective dose for the patient. · Use the lowest dose effective for the patient () · 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 tablets 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 tablets 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 tablets 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 tablets should not exceed 2 mg [ see Warnings and Precautions ( 5.7 ) ]. 2.4 Use with CNS Depressants Dosage adjustments may be necessary when eszopiclone tablets are combined with other central nervous system (CNS) depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.1 )]. 2.5 Administration with Food Taking eszopiclone tablets with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of eszopiclone tablets on sleep latency [see Clinical Pharmacology ( 12.3 )] .

5 WARNINGS AND PRECAUTIONS • 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 ) 5.1 Complex Sleep Behaviors 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 eszopiclone. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in fatal outcomes. 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 eszopiclone alone at recommended dosages, with or without the concomitant use of alcohol or other CNS depressants [ see Drug Interactions ( 7.1 ) ]. Discontinue eszopiclone immediately if a patient experiences a complex sleep behavior. 5.2 CNS Depressant Effects and Next-Day Impairment Eszopiclone 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 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 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 eszopiclone can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. 5.3 Need to Evaluate for Comorbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric di…

4 CONTRAINDICATIONS • Eszopiclone tablets are contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone tablets [ see Warnings and Precautions ( 5.1 ) ]. • Eszopiclone tablets are 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 eszopiclone () • Known hypersensitivity to eszopiclone ()

7 DRUG INTERACTIONS • 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 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 [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. 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 the exposure and effects of eszopiclone.

8.1 Pregnancy Risk Summary Available pharmacovigilance data with eszopiclone 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/m2 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.

6 ADVERSE REACTIONS The following are described in more detail in the Warnings and Precautions section of the label: • Complex Sleep Behaviors [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] • CNS Depressant Effects and Next-Day Impairment [ see Warnings and Precautions ( 5.2 ) ] • Need to Evaluate for Comorbid Diagnoses [ see Warnings and Precautions ( 5.3 ) ] • Severe Anaphylactic and Anaphylactoid Reactions [ see Warnings and Precautions ( 5.4 ) ] • Abnormal Thinking and Behavioral Changes [ see Warnings and Precautions ( 5.5 ) ] • Withdrawal Effects [see Warnings and Precautions ( 5.6 ) ] • Timing of Drug Administration [see Warnings and Precautions ( 5.7 ) ] • Special Populations [ see Warnings and Precautions ( 5.8 ) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The premarketing development program for eszopiclone tablets included eszopiclone exposures in patients and/or normal subjects from two different groups of studies: approximately 400 normal subjects in clinical pharmacology/pharmacokinetic studies, and approximately 1550 patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 263 patient-exposure years. The conditions and duration of treatment with eszopiclone varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term and longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation. Most commonly observed adverse reactions (incidence ≥2%) were unpleasant taste, headache, somnolence, respiratory infection, dizziness, dry mouth, rash, anxiety, hallucinations, and viral infections ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment In placebo-controlled, parallel-group clinical trials in the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg eszopiclone, and 1.4% of 72 patients who received 1 mg eszopiclone discontinued treatment due to an adverse reaction. In the 6-week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg eszopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%. Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of eszopiclone at doses of 2 or 3 mg in nonelderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 2 mg or 3 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients. Table 1: Incidence (%) of Adverse Reactions in a 6-Week Placebo-Controlled Study in Nonelderly Adults with Eszopiclone 1 Adverse Reaction Placebo (n=99) Eszopiclone 2 mg (n=104) Eszopiclone 3 mg (n=105) Body as a Whole Headache 13 21 17 Viral Infection 1 3 3 Digestive…