zolpidem tartrate

Dosage and Administration, Special Populations (2.2) 8/2016 Warnings and Precautions, CNS Depressant Effects and Next- Day Impairment (5.1) 12/2016 Warnings and Precautions, Precipitation of Hepatic 8/2016 Encephalopathy (5.7) 12/2016

1. INDICATIONS AND USAGE Zolpidem tartrate tablets, USP are gamma-amino butyric acid (GABA) A agonist, are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP have been shown to decrease sleep latency for up to 35 days in controlled clinical studies. ( 1) Zolpidem tartrate tablets, USP are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP have been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14) ]. The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

2 DOSAGE AND ADMINISTRATION Take only if 4 hours of bedtime remain before the planned time of waking ( 2.1 , 5.1 ) Zolpidem Tartrate Sublingual Tablets should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. ( 2.1 ) The effect of Zolpidem Tartrate Sublingual Tablets may be slowed if taken with or immediately after a meal ( 2.1 ) Recommended dose is 1.75 mg for women and 3.5 mg for men, taken only once per night if needed ( 2.2 ) Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Sublingual Tablets ( 2.3 ) Co-administration with CNS depressants: Recommended dose is 1.75 mg for men and women ( 2.3 ) Geriatric patients and patients with hepatic impairment: Recommended dose is 1.75 mg for men and women ( 2.4 , 2.5 ) 2.1 Important Administration Instructions Zolpidem Tartrate Sublingual Tablet is to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. Zolpidem Tartrate Sublingual Tablet should only be taken if the patient has at least 4 hours of bedtime remaining before the planned time of waking [see Warnings and Precautions (5.1) ]. Zolpidem Tartrate Sublingual Tablet should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. For optimal effect, Zolpidem Tartrate Sublingual Tablet should not be administered with or immediately after a meal. The blister should be removed from the pouch just prior to dosing. 2.2 Basic Dosing Information The recommended and maximum dose of Zolpidem Tartrate Sublingual Tablet is 1.75 mg for women and 3.5 mg for men, taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep. The recommended doses for women and men are different because women clear zolpidem from the body at a lower rate than men [see Use in Specific Populations (8.6) ] . 2.3 Use with CNS Depressants The recommended Zolpidem Tartrate Sublingual Tablet dose for men and women who are taking concomitant CNS depressants is 1.75 mg. Dose adjustment of concomitant CNS depressants may be necessary when co-administered with Zolpidem Tartrate Sublingual Tablet because of potentially additive effects. The use of Zolpidem Tartrate Sublingual Tablet with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Warnings and Precautions (5.1) ]. 2.4 Use in Geriatric Patients Geriatric patients may be especially sensitive to the effects of zolpidem. The recommended dose of Zolpidem Tartrate Sublingual Tablets in men and women over 65 years old is 1.75 mg, taken only once per night if needed [see Use in Specific Populations (8.5) ]. 2.5 Use in Patients with Hepatic Impairment The recommended dose of Zolpidem Tartrate Sublingual Tablet in patients with hepatic impairment is 1.75 mg, taken only once per night if needed [see Clinical Pharmacology (12.3) ].

3. DOSAGE FORMS AND STRENGTHS 5 mg and 10 mg tablets. Tablets not scored. ( 3 ) Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored. Zolpidem tartrate 5 mg tablets are red colored, capsule shaped tablets with the Torrent logo debossed on one side and '5 MG' debossed on the other side. Zolpidem tartrate 10 mg tablets are peach-yellow colored, capsule shaped tablets with the Torrent logo debossed on one side and '10 MG' debossed on the other side.

4 CONTRAINDICATIONS Patients who have experienced complex sleep behaviors after taking zolpidem tartare tablets ( 4 ) Known hypersensitivity to zolpidem ( 4 ) Zolpidem tartrate tablets are contraindicated in patients Zolpidem tartrate tablets are contraindicated in patients who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. who have experienced complex sleep behaviors after taking zolpidem tartrate tablets [see Warnings and Precautions ( 5.1 )]. with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions ( 5.4 )].

6. ADVERSE REACTIONS Most commonly observed adverse reactions were: Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea Long-term (28 - 35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-269-544-2299 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious 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)] 6.1 Clinical Trials Experience Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%). Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%). 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 short-term treatment (up to 10 nights) with zolpidem tartrate tablets at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%). 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 and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms 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 population studied. The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in …

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 tablets with opioids may increase the risk of respiratory depression. Limit dosage and duration of concomitant use of zolpidem tartrate 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 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 Considerationsand 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 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 5, 25, and 120 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m 2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 25 and 120 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 2.5, 10, and 40 times the MRHD of 10 mg/day (8 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 40 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 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m 2 body surface area, delayed offspring growth and decreased survival at doses 25 and 120 times, respectively, the MRHD based on mg/m2 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 information on the effects of zolpidem on milk …

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 Sublingual Tablets contains zolpidem tartrate, a non-benzodiazepine hypnotic of the imidazopyridine class. Zolpidem Tartrate Sublingual Tablets are available in 1.75 mg and 3.5 mg strength tablets for sublingual administration. Zolpidem Tartrate Sublingual Tablets are intended to be placed under the tongue where they will disintegrate. Zolpidem Tartrate Sublingual Tablets contain a bicarbonate-carbonate buffer. Chemically, zolpidem tartrate is N,N -6-trimethyl-2- p -tolylimidazo[1,2- α ]pyridine-3-acetamide L-(+)-tartrate (2:1). Zolpidem tartrate is a white to almost white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88. Each Zolpidem Tartrate Sublingual Tablet includes the following inactive ingredients: Crospovidone, Povidone, Mannitol, Polyvinylacetate, colloidal silicon dioxide, sodium carbonate anhydrous, sodium bicarbonate, natural and artificial spearmint flavor, aspartame, and magnesium stearate. Structure

10. Overdosage Section 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 5 mg tablets, USP are red colored, capsule shaped tablets with the Torrent logo debossed on one side and '5 MG' debossed on the other side and supplied as: NDC Number Size 76420-233-30 bottle of 30 (repackaged from NDC 13668-007-XX) 76420-233-60 bottle of 60 (repackaged from NDC 13668-007-XX) 76420-233-90 bottle of 90 (repackaged/relabeled from NDC 13668-007-XX/NDC 13668-007-90) 76420-233-01 bottle of 100 (relabeled from NDC 13668-007-01) 76420-233-05 bottle of 500 (relabeled from NDC 13668-007-05) 76420-233-00 bottle of 1000 (relabeled from NDC 13668-007-10) 76420-233-15 bottle of 1500 (relabeled from NDC 13668-007-15) Zolpidem tartrate 10 mg tablets, USP are peach-yellow colored, capsule shaped tablets with the Torrent logo debossed on one side and '10 MG' debossed on the other side and supplied as: NDC Number Size 76420-263-30 bottle of 30 (repackaged from NDC 13668-008-XX) 76420-263-60 bottle of 60 (repackaged from NDC 13668-008-XX) 76420-263-90 bottle of 90 (repackaged from NDC 13668-008-XX) 76420-263-01 bottle of 100 (relabeled from NDC 13668-008-01) 76420-263-05 bottle of 500 (relabeled from NDC 13668-008-05) 76420-263-00 bottle of 1000 (relabeled from NDC 13668-008-10) 76420-263-15 bottle of 1500 (relabeled from NDC 13668-008-15) Store at 20o to 25°C (68o to 77°F); excursions permitted to 15° to 30°C (59o to 86°F) [see USP Controlled Room Temperature].