Zolpidem Tartrate

RECENT MAJOR CHANGES Boxed Warning 08/2019 Contraindications ( 4 ) 08/2019 Warnings and Precautions, Complex Sleep Behaviors ( 5.1 ) 08/2019 Warnings and Precautions, CNS-Depressant Effects and Next- Day Impairment ( 5.2 ) 02/2019

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.

3 DOSAGE FORMS AND STRENGTHS Extended-Release Tablets: 6.25 mg and 12.5 mg. Tablets not scored. ( 3 ) Zolpidem tartrate extended-release tablets USP are available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored. Zolpidem tartrate extended-release tablets, USP 6.25 mg are pink colored, round, biconvex, film-coated tablets debossed with "E61" on one side and "LU" on the other side. Zolpidem tartrate extended-release tablets, USP 12.5 mg are blue colored, round, biconvex, film-coated tablets debossed with "E62" on one side and "LU" on the other side.

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 patientsZolpidem 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 )]. 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 )].

6ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • CNS-depressant effects and next-day impairment [see WARNINGS AND PRECAUTIONS (5.1) ] • Serious anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.3) ] • Abnormal thinking and behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS (5.4) ] • Withdrawal effects [see WARNINGS AND PRECAUTIONS (5.7) ] 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 Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 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 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 was 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 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 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 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 were headache, next-day somnolence, and dizziness. In the 6-month trial evaluating zolpidem tartrate extended-release 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 versus 2.6% for placebo). Adverse reactions observed at an incidence of ≥1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate extended-release 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 physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the …

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 USE IN SPECIFIC POPULATIONS Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. ( 8.1 ) Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after Zolpidem tartrate extended-release tablets administration. ( 8.2 ) Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. ( 5.5 , 8.4 ) 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%-4% and 15%-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. 8.2 Lactation Risk Summary Limited data from published literature report the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk [see Clinical Considerations ] . There is no informat …

12.1 Mechanism of Action Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ 1 receptor preferentially with a high affinity ratio of the α 1 /α 5 subunits. This selective binding of zolpidem on the BZ 1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

11 DESCRIPTION Zolpidem tartrate extended-release tablets USP contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Zolpidem tartrate extended-release tablets USP are available in 6.25 mg and 12.5 mg strength tablets for oral administration. Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure: Zolpidem tartrate is a white or almost white, crystalline powder, hygroscopic that is slightly soluble in water, sparingly soluble in methanol and practically insoluble in methylene chloride. It has a molecular weight of 764.87. Zolpidem tartrate extended-release tablets USP consist of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The 6.25 mg zolpidem tartrate extended-release tablets USP contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue # 2 aluminium lake, hypromellose, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate and titanium dioxide. The 12.5 mg zolpidem tartrate extended-release tablets USP contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue # 2 aluminium lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate and titanium dioxide. Zolpidem tartrate extended-release tablets USP meets USP Dissolution Test 6. Zolpidem Tartrate

10 OVERDOSAGE 10.1 Signs and Symptoms In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported. 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. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). 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. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Zolpidem tartrate extended-release tablets USP, 6.25 mg are composed of two layers * and are pink colored, round, biconvex, film-coated tablets debossed with "E61" on one side and "LU" on the other side and supplied as: NDC Number Package Configuration 76420-318-30 Bottle of 30 (repackaged from NDC 68180-779-XX) 76420-318-60 Bottle of 60 (repackaged from NDC 68180-779-XX) 76420-318-90 Bottle of 90 (repackaged from NDC 68180-779-XX) 76420-318-01 Bottle of 100 (relabeled from NDC 68180-779-04) Zolpidem tartrate extended-release tablets USP, 12.5 mg are composed of two layers * and are blue colored, round, biconvex, film-coated tablets debossed with "E62" on one side and "LU" on the other side and supplied as: NDC Number Package Configuration 76420-319-30 Bottle of 30 (repackaged from NDC 68180-780-XX) 76420-319-60 Bottle of 60 (repackaged from NDC 68180-780-XX) 76420-319-90 Bottle of 90 (repackaged from NDC 68180-780-XX) 76420-319-01 Bottle of 100 (relabeled from NDC 68180-780-04) *Layers are covered by the coating and are indistinguishable. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].