ZOLPIDEM TARTRATE

1 INDICATIONS AND USAGE Zolpidem tartrate extended-release tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).) The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see CLINICAL STUDIES ( 14 )]. Zolpidem tartrate extended-release tablet, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. ( 1 )

2 DOSAGE AND ADMINISTRATION • Use the lowest dose effective for the patient and must not exceed a total of 12.5 mg daily ( 2.1 ) • Treatment should be as short as possible ( 2.1 ) • Recommended initial dose is a single dose of 6.25 mg for women, and a single dose of 6.25 or 12.5 mg for men, immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening ( 2.1 ) • Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 6.25 mg for men and women ( 2.2 ) • Lower doses of CNS depressants may be necessary when taken concomitantly with zolpidem tartrate extended-release tablets ( 2.3 ) • Tablets to be swallowed whole, not to be crushed, divided or chewed ( 2.4 ) • The effect of zolpidem tartrate extended-release tablets may be slowed if taken with or immediately after a meal ( 2.4 ) 2.1 Dosage in Adults Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness [see WARNINGS AND PRECAUTIONS ( 5.2 )]. The total dose of zolpidem tartrate extended-release tablets should not exceed 12.5 mg once daily immediately before bedtime. Zolpidem tartrate extended-release tablets should be taken as a single dose and should not be readministered during the same night. The recommended initial doses for women and men are different because zolpidem clearance is lower in women. Treatment with zolpidem tartrate extended-release tablet should be as short as possible. Extended treatment should not take place without re-evaluation of the patient's status, since the risk of abuse and dependence increases with duration of treatment [see DRUG ABUSE AND DEPENDENCE ( 9.3 )] . 2.2 Special Populations Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of zolpidem tartrate extended-release tablet in these patients is 6.25 mg once daily immediately before bedtime [see WARNINGS AND PRECAUTIONS ( 5.2 ), USE IN SPECIFIC POPULATIONS ( 8.5 )]. Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate extended-release tablets in these patients is 6.25 mg once daily immediately before bedtime. Avoid zolpidem tartrate extended-release tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy [see WARNINGS AND PRECAUTIONS ( 5.8 ), USE IN SPECIFIC POPULATIONS ( 8.7 ), CLINICAL PHARMACOLOGY ( 12.3 )]. 2.3 Use with CNS Depressants Dosage adjustment may be necessary when zolpidem tartrate extended-release tablets are combined with other CNS-depressant drugs because of the potentially additive effects [see WARNINGS AND PRECAUTIONS ( 5.2 )( 5.7 )]. 2.4 Administration Zolpidem tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of zolpidem tartrate extended-release tablets may be slowed by ingestion with or immediately after a meal.

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 against driving and other activities requiring complete mental alertness the morning after use. Instruct patients on correct use. ( 5.2 ) • Need to 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 behavioral changes. ( 5.5 ) • Depression: Worsening of depression or, suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. ( 5.6 ) • Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. ( 5.7 ) • Hepatic Impairment: Avoid zolpidem tartrate extended-release tablets use in patients with severe hepatic impairment. ( 5.8 ) • Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.9 , 9.3 ) 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 zolpidem tartrate extended-release tablets. 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. Postmarketing reports have shown that complex sleep behaviors may occur with zolpidem tartrate extended-release tablets alone at recommended doses, with or without the concomitant use of alcohol or other Central Nervous System (CNS) depressants [see DRUG INTERACTIONS ( 7.1 )]. Discontinue zolpidem tartrate extended-release tablets immediately if a patient experiences a complex sleep behavior [see CONTRAINDICATIONS ( 4 )]. 5.2 CNS-Depressant Effects and Next-Day Impairment Zolpidem tartrate extended-release tablets are CNS depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and 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 zolpidem tartrate extended-release tablets may develop, patients using zolpidem tartrate extended-release tablets 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 [see DRUG INTERACTIONS ( 7.1 )]. Downward dose adjustment of zolpidem tartrate extended-release tablets and concomitant CNS depressants should be considered [see DOSAGE AND ADMINISTRATION ( 2.3 )]. The use of zolpidem tartrate extended-release tablet with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended. The risk of next-day psychomotor impairment is increased if zolpidem tartrate extended-release tablet 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 alcohol; or coadministered with other drugs that increase the blood levels of zolpidem. Patients should be warned aga…

4 CONTRAINDICATIONS • Patients who have experienced complex sleep behaviors after taking zolpidem tartrate extended-release tablets ( 4 ) • Known hypersensitivity to zolpidem ( 4 ) Zolpidem tartrate extended-release tablets are contraindicated in patients • who have experienced complex sleep behaviors after taking zolpidem tartrate extended-release tablets [see WARNINGS AND PRECAUTIONS ( 5.1 )]. • with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see WARNINGS AND PRECAUTIONS ( 5.4 )].

7 DRUG INTERACTIONS • CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects ( 5.2 , 7.1 ) • Opioids: Concomitant use may increase risk of respiratory depression ( 5.7 , 7.1 ) • Imipramine: Decreased alertness observed ( 7.1 ) • Chlorpromazine: Impaired alertness and psychomotor performance observed ( 7.1 ) • CYP3A4 inducers (rifampin or St. John's wort): Combination use may decrease effect ( 7.2 ) • Ketoconazole: Combination use may increase effect ( 7.2 ) 7.1 CNS-Active Drugs CNS Depressants Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability [see WARNINGS AND PRECAUTIONS ( 5.1 , 5.2 )]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see WARNINGS AND PRECAUTIONS ( 5.1 , 5.2 )]. Opioids The concomitant use of zolpidem tartrate extended-release tablets with opioids may increase the risk of respiratory depression. Limit dosage and duration of concomitant use of zolpidem tartrate extended-release tablets and opioids [see DOSAGE AND ADMINISTRATION ( 2.3 ), WARNINGS AND PRECAUTIONS ( 5.7 )] . Imipramine, Chlorpromazine Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance [see CLINICAL PHARMACOLOGY ( 12.3 )]. Sertraline Concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see CLINICAL PHARMACOLOGY ( 12.3 )]. Fluoxetine After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance [see CLINICAL PHARMACOLOGY ( 12.3 )]. Haloperidol A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration [see CLINICAL PHARMACOLOGY ( 12.3 )]. 7.2 Drugs that Affect Drug Metabolism via Cytochrome P450 Some compounds known to induce or inhibit CYP3A may affect exposure to zolpidem. The effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not known. CYP3A4 Inducers Rifampin: Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem and is not recommended [see CLINICAL PHARMACOLOGY ( 12.3 )]. St. John's wort: Use of St. John's wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended. CYP3A4 Inhibitors Ketoconazole: Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor and zolpidem are given together [see CLINICAL PHARMACOLOGY ( 12.3 )] .

8.1 Pregnancy Risk Summary Neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see Clinical Considerations and Data] . Published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects [see Data] . Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations are 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. Clinical Considerations Fetal/neonatal adverse reactions: Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to zolpidem tartrate extended-release tablets during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly. Data Human data: Published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a clear association with zolpidem and major birth defects. There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated. Zolpidem has been shown to cross the placenta. Animal data: Oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 20 and 100 times the MRHD based on mg/m 2 body surface area. Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2, 8, and 30 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m 2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 30 times the MRHD based on mg/m 2 body surface area. Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 4, 20, and 100 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on a mg/m 2 body surface area, delayed offspring growth and decreased survival at doses 20 and 100 times, respectively, the MRHD based on mg/m 2 body surface area.

6 ADVERSE REACTIONS Most commonly observed adverse reactions (> 10% in either elderly or adult patients) are: headache, next-day somnolence and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Complex Sleep Behaviors [see WARNINGS AND PRECAUTIONS ( 5.1 )] • CNS-Depressant Effects and Next-Day Impairment [see WARNINGS AND PRECAUTIONS ( 5.2 )] • Severe Anaphylactic and Anaphylactoid Reactions [see WARNINGS AND PRECAUTIONS ( 5.4 )] • Abnormal Thinking and Behavior Changes [see WARNINGS AND PRECAUTIONS ( 5.5 )] • Withdrawal Effects [see WARNINGS AND PRECAUTIONS ( 5.9 )] 6.1 Clinical Trials Experience Associated with Discontinuation of Treatment In 3-week clinical trials in adults and elderly patients (> 65 years), 3.5% (7/201) patients receiving zolpidem tartrate extended-release tablets 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with zolpidem tartrate extended-release tablets were somnolence (1%). In a 6-month study in adult patients (18 to 64 years of age), 8.5% (57/669) of patients receiving zolpidem tartrate extended-release tablets 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of zolpidem tartrate extended-release tablets included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo. Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)- treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide. Most Commonly Observed Adverse Reactions in Controlled Trials During treatment with zolpidem tartrate extended-release tablets in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of zolpidem tartrate extended-release tablets were headache, next-day somnolence, and dizziness. In the 6-month trial evaluating zolpidem tartrate extended-release tablets 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for zolpidem tartrate extended-release tablets versus 2.6% for placebo). Adverse Reactions Observed at an Incidence of ≥ 1% in Controlled Trials The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate extended-release tablets in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physic…