Zolpidem

RECENT MAJOR CHANGES Dosage and Administration ( 2.1 ) 2/2022 Warnings and Precautions ( 5.5 ) 2/2022 Warnings and Precautions ( 5.7 ) 2/2022

1 INDICATIONS AND USAGE Zolpidem Tartrate Tablets is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem Tartrate Tablets has 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. Zolpidem Tartrate Tablets, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. ( 1 )

2 DOSAGE AND ADMINISTRATION • Use the lowest dose effective for the patient and must not exceed a total of 10 mg daily ( 2.1 ) • Treatment should be as short as possible ( 2.1 ) • Recommended initial dose is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening ( 2.1 ) • Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 5 mg for men and women ( 2.2 ) • Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Tablets ( 2.3 ) • The effect of Zolpidem Tartrate 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 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 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 Tablets should not exceed 10 mg once daily immediately before bedtime. Zolpidem Tartrate 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. Long-term use of Zolpidem Tartrate Tablets is not recommended. Treatment should be as short as possible. Extended treatment should not take place without re-evaluation of the patient's status because the risk of abuse and dependence increase with the 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 Tablets in these patients is 5 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 Tablets in these patients is 5 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate 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 Tablets is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions ( 5.2 , 5.7 )]. 2.4 Administration The effect of Zolpidem Tartrate Tablets may be slowed by ingestion with or immediately after a meal.

3 DOSAGE FORMS AND STRENGTHS Zolpidem Tartrate Tablets, USP is available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored. Zolpidem Tartrate Tablets, USP 5 mg is pink film coated, round biconvex tab lets, debossed "IT 117" on one side, other side is plain. Zolpidem Tartrate Tablets, USP 10 mg is white film coated, round biconvex tab lets, debossed "IT 118" on one side, other side is plain. 5 mg and 10 mg tablets. Tablets not scored. ( 3 )

4 CONTRAINDICATIONS Zolpidem Tartrate Tablets is contraindicated in patients • 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 )] • Patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Tablets ( 4 ) • Known hypersensitivity to Zolpidem ( 4 )

6 ADVERSE REACTIONS 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 )] Most commonly observed adverse reactions were: Short-term (2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN). Psychiatric disorders: delirium

7 DRUG INTERACTIONS • CNS depressants, including alcohol: Possible adverse additive CNS- depressant effects ( 5.1 , 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. ( 5.4 , 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 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/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 information on the effects of Zolpidem on milk produ …

12.1 Mechanism of Action Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.

11 DESCRIPTION Zolpidem Tartrate Tablets, USP contains Zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Zolpidem Tartrate Tablets, USP is available in 5 mg and 10 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 to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88. Each Zolpidem Tartrate Tablet, USP includes the following inactive ingredients: lactose anhydrous, sodium starch glycolate, colloidal silicon dioxide, microcrystalline cellulose, magnesium stearate. The 10 mg tablets also contain Opadry II (white) and the 5 mg tablets contain Opadry II (pink). Opadry II (white) contains hypromellose, polyeth ylene glycol, polydextrose, titanium dioxide, and triacetin. Opadry II (pink) contains hypromellose, FD&C Red no. 40 aluminum lake, FD&C Blue no. 2 aluminum lake, FD&C Yellow no. 6 aluminum lake, polyeth ylene glycol, polydextrose, titanium dioxide, and triacetin. Meets USP Dissolution Test 3. Image

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 Tablets, USP 10 mg is white film coated, round biconvex tab lets, debossed "IT 118" on one side, other side is plain. NDC: 71335-9684-1: 30 Tablets in a BOTTLE NDC: 71335-9684-2: 60 Tablets in a BOTTLE NDC: 71335-9684-3: 100 Tablets in a BOTTLE NDC: 71335-9684-4: 50 Tablets in a BOTTLE NDC: 71335-9684-5: 90 Tablets in a BOTTLE NDC: 71335-9684-6: 10 Tablets in a BOTTLE NDC: 71335-9684-7: 15 Tablets in a BOTTLE NDC: 71335-9684-8: 28 Tablets in a BOTTLE NDC: 71335-9684-9: 120 Tablets in a BOTTLE NDC: 71335-9684-0: 5 Tablets in a BOTTLE Store at controlled room temperature 20°C-25°C (68°F-77°F). Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504