ESZOPICLONE

Eszopiclone, USP is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-(5S)-6-(5chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methylpiperazine-1carboxylate. Its molecular weight is 388.81, and its empirical formula is C 17 H 17 C l N 6 O 3 . Eszopiclone, USP has a single chiral center with an (S)-configuration. It has the following chemical structure: Eszopiclone, USP 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, USP is formulated as film-coated tablets for oral administration. Eszopiclone tablets, USP contain 1 mg, 2 mg, or 3 mg eszopiclone, USP and the following inactive ingredients: dibasic calcium phosphate dihydrate, 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. eszopiclone-structure

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 ( 1 )

DOSAGE & ADMINISTRATION 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 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 )] .

• tablets are contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone tablets [ ]. • Eszopiclone tablets are contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema [ ]. • 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 ( 4 ) • Known hypersensitivity to eszopiclone ( 4 )

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 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 System Dry Mouth 3 5 7 Dyspepsia 4 4 5 Nausea 4 5 4 Vomiting 1 3 0 Nervous System Anxiety 0 3 1 Confusion 0 0 3 Depression 0 4 1 Dizziness 4 5 7 Hallucinations 0 1 3 Libido Decreased 0 0 3 Nervousness 3 5 0 Somnolence 3 10 8 Respiratory System Infection 3 5 10 Skin and Appendages Rash 1 3 4 Special Senses Unpleasant Taste 3 17 34 Urogenital System Dysmenorrhea * 0 3 0 Gynecomastia ** 0 3 0 1 Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abnormal dreams, accidental injury, back pain, diarrhea, flu syndrome, myalgia, pain, pharyngitis, and rhinitis. * Gender-specific adverse reaction in females ** Gender-specific adverse reaction in males Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste. Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of eszopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 1 mg or 2 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients. Table 2: Incidence (%) of Adverse Reactions in Elderly Adults (Ages 65 to 86 Years) in 2-Week Placebo-Controlled Trials with Eszopiclone 1 Adverse Reactions Placebo (n=208) Eszopiclone 1 mg (n=72) Eszopiclone 2 mg (n=215) Body as a Whole Accidental Injury 1 0 3 Headache 14 15 13 Pain 2 4 5 Digestive System Diarrhea 2 4 2 Dry Mouth 2 3 7 Dyspepsia 2 6 2 Nervous System Abnormal Dreams 0 3 1 Dizziness 2 1 6 Nervousness 1 0 2 Neuralgia 0 3 0 Skin and Appendages Pruritus 1 4 1 Special Senses Unpleasant Taste 0 8 12 Urogenital System Urinary Tract Infection 0 3 0 1 Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abdominal pain, asthenia, nausea, rash, and somnolence. Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste. These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and nondrug factors to the adverse reaction incidence rate in the population studied. Other Reactions Observed During the Premarketing Evaluation of Eszopiclone . Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1550 subjects treated with eszopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug related. Although the reactions reported occurred during treatment with eszopiclone, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rare adverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender. Body as a Whole : Frequent : chest pain; Infrequent : allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity. Cardiovascular System : Frequent : migraine; Infrequent : hypertension; Rare : thrombophlebitis. Digestive System : Infrequent : anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare : colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage. Hemic and Lymphatic System : Infrequent: anemia, lymphadenopathy. Metabolic and Nutritional : Frequent : peripheral edema; Infrequent : hypercholesteremia, weight gain, weight loss; Rare : dehydration, gout, hyperlipemia, hypokalemia. Musculoskeletal System : Infrequent : arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching; Rare : arthrosis, myopathy, ptosis. Nervous System : Infrequent : agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare : abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor. Respiratory System : Infrequent : asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis. Skin and Appendages : Infrequent : acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare : erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash. Special Senses : Infrequent : conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder; Rare : hyperacusis, iritis, mydriasis, photophobia. Urogenital System : Infrequent : amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare : oliguria, pyelonephritis, urethritis. 6.2 Postmarketing Experience In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during postmarketing surveillance with eszopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event.

• 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 to 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 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 after exposure and effects of eszopiclone.