Zolpidem

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.

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.

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 (<10 nights): Drowsiness, dizziness, and diarrhea Long-term (28-35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ACI Healthcare USA, Inc. at 1- 888-802-1213.or www.acihealthcareusa.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. Table 1: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (percentage of patients reporting) Body System Adverse Event Reactions reported by at least 1% of patients treated with Zolpidem Tartrate Tablets and at a greater frequency than placebo. Zolpidem (≤10 mg) (N=685) Placebo (N=473) Central and Peripheral Nervous System Headache 7 6 Drowsiness 2 - Dizziness 1 - Gastrointestinal System Diarrhea 1 - The following table was derived from results of three placebo-controlled long-term efficacy trials involving Zolpidem Tartrate Tablets. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with Zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and

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 )].