Zolpidem tartrate sublingual

1 INDICATIONS AND USAGE Zolpidem tartrate sublingual tablets are indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep. Limitations of Us e: Zolpidem tartrate sublingual tablets are not indicated for the treatment of middle-of-the-night insomnia when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking. Zolpidem tartrate sublingual tablets are a GABA A agonist indicated for use as needed for the treatment of insomnia when a middle-of-the-night awakening is followed by difficulty returning to sleep Limitation of Use : Not indicated for the treatment of middle-of-the night awakening when the patient has fewer than 4 hours of bedtime remaining before the planned time of waking

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 tablets are to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. Zolpidem tartrate sublingual tablets 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 tablets 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 tablets should not be administered with or immediately after a meal. The tablet should be removed from the pouch just prior to dosing. 2.2 Basic Dosing Information The recommended and maximum dose of zolpidem tartrate sublingual tablets are 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 tablets 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 tablets because of potentially additive effects. The use of zolpidem tartrate sublingual tablets 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 tablets in patients with hepatic impairment is 1.75 mg, taken only once per night if needed [see Clinical Pharmacology (12.3)].

2.1 Important Administration Instructions Zolpidem tartrate sublingual tablets are to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. Zolpidem tartrate sublingual tablets 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 tablets 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 tablets should not be administered with or immediately after a meal. The tablet should be removed from the pouch just prior to dosing.

2.2 Basic Dosing Information The recommended and maximum dose of zolpidem tartrate sublingual tablets are 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 …

3 DOSAGE FORMS AND STRENGTHS Zolpidem tartrate is available as 1.75 mg and 3.5 mg tablets for sublingual administration. Zolpidem tartrate sublingual tablets, 1.75 mg are white, round tablets, flat-faced, bevel-edged with debossed “NT” on one side and “124” on the other side. Zolpidem tartrate sublingual tablets, 3.5 mg are white, round tablets, flat-faced, bevel-edged with debossed “P” & “350” on one side and plain on the other side. 1.75 mg and 3.5 mg sublingual tablets

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

6 ADVERSE REACTIONS The following serious adverse reactions in zolpidem-treated patients 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)] Serious Anaphylactic and Anaphylactoid Reactions [See Warnings and Precautions (5.2)] Abnormal Thinking and Behavioral Changes [See Warnings and Precautions (5.5)] Withdrawal Effects [See Warnings and Precautions (5.8)] Most commonly observed adverse reactions (> 1% in adult patients) are headache, nausea, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or http://w ww.fda.gov/medwatch . 6.1 Clinical Trials Experience The safety data described below are based on two double-blind placebo-controlled trials of zolpidem tartrate in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening [see Clinical Studies (14.1)]. These two trials included 230 and 82 patients treated with 3.5 mg and 1.75 mg of zolpidem tartrate, respectively. The first study was a 3-way crossover sleep-laboratory study in 82 patients (58 female and 24 male; median age 47 years; 51% Caucasian, 44% African-American) of 1.75 mg and 3.5 mg of zolpidem tartrate compared to placebo (Study 1). The second study was a 4-week, parallel-group at-home study in 295 patients (201 female and 94 male; median age 43 years) of 3.5 mg of zolpidem tartrate compared to placebo, used on an as-needed basis after spontaneous middle-of-the-night awakenings (Study 2). In Study 2, patients took zolpidem tartrate during the night on 62% of study nights. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice. Table 1 shows the incidence of adverse reactions reported in Study 2 that occurred in 2% or more of zolpidem tartrate-treated (3.5 mg) patients in which the incidence was greater than the incidence in placebo-treated patients. For women and other patients taking the 1.75 mg dose in Study 1, the incidence of adverse reactions was similar to the incidence seen with 3.5 mg of zolpidem tartrate in Table 1. The most commonly reported adverse reactions in all treatment groups were headache, nausea, and fatigue. Table 1: Summary of Adverse Reactions (≥ 2%) in Outpatient, Double-Blind, Parallel-Group, Placebo-Controlled Study (Study 2) MedDRA System Organ Class Preferred Term 3.5 mg Z olpidem Tartrate (n=150) Placebo (n=145) Gastrointestinal Disorders 4% 2% Nausea 1% 1% General Disorders and Administration Site Conditions 3% 0% Fatigue 1% 0% Nervous System Disorders 5% 3% Headache 3% 1%

6.1 Clinical Trials Experience The safety data described below are based on two double-blind placebo-controlled trials of zolpidem tartrate in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening [see Clinical Studies (14.1)]. These two trials included 230 and 82 patients treated with 3.5 mg and 1.75 mg of zolpidem tartrate, respectively. The first study was a 3-way crossover sleep-laboratory study in 82 patients (58 female and 24 male; median age 47 years; 51% Caucasian, 44% African-American) of 1.75 mg and 3.5 mg of zolpidem tartrate compared to placebo (Study 1). The second study was a 4-week, parallel-group at-home study in 295 patients (201 female and 94 male; median age 43 years) of 3.5 mg of zolpidem tartrate compared to placebo, used on an as-needed basis after spontaneous middle-of-the-night awakenings (Study 2). In Study 2, patients took zolpidem tartrate during the night on 62% of study nights. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the cli …

7 DRUG INTERACTIONS CNS depressants, including alcohol: Possible adverse additive CNS depressant effects (5.1, 7.1) Imipramine: Decreased alertness observed (7.1) Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1) Rifampin: Combination use may decrease effects (7.2) Ketoconazole: Combination use may increase effects (7.2) 7.1 CNS-active Drugs Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.1, 5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine 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. 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. Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1, 5.2)]. Sertraline Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem. 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)]. 7.2 Drugs that Affect Drug Metabolism via Cytochrome P450 Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of other P450 enzymes on the exposure to zolpidem is not known. 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. Ketoconazole Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

7.1 CNS-active Drugs Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.1, 5.2)]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. Imipramine 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. 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. Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1, 5.2)]. Sertraline Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem. 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)].

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, zolpidem may cause fetal harm. (8.1) Pediatric use: Safety and effectiveness of zolpidem tartrate not established. With bedtime dosing of zolpidem, hallucinations observed (incidence 7%) (8.4) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of zolpidem in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Zolpidem tartrate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however, teratogenicity was not observed. When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the lowest dose, which is approximately 15 times the RHD on a mg/m 2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m 2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 15 times the RHD on a mg/m 2 basis. 8.3 Nursing Mothers Zolpidem is excreted in human milk. The effect of zolpidem on the nursing infant is not known. 8.4 Pediatric Use Zolpidem tartrate is not recommended for use in children. Safety and effectiveness of zolpidem tartrate have not been established in pediatric patients below the age of 18. In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations. 8.5 Geriatric Use Zolpidem tartrate dosage adjustment is necessary in geriatric patients. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of zolpidem tartrate and observed closely [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)]. Clinical trial experience with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime: A total of 154 patients in U.S.-controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving oral zolpidem tartrate at doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (see Table 2). Table 2: Adverse Reactions in Geriatric Patients in Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime Adverse Reaction 5 to 10 mg Oral Zolpidem tartrate Placebo Dizziness 3% 0% Drowsiness 5% 2% Diarrhea 3% 1% Falls in geriatric patients: A total of 30/1,959 (2%) non …

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 complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ 1 receptor preferentially with a high affinity ratio of the alpha 1 /alpha 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 at hypnotic doses.

11 DESCRIPTION Zolpidem tartrate sublingual tablets contain zolpidem tartrate, USP 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. Chemically, zolpidem tartrate, USP is N,N -6-trimethyl-2- p -tolylimidazo[1,2- α ]pyridine-3-acetamide L-(+)-tartrate (2:1). Zolpidem tartrate, USP is a white or almost white, crystalline, hygroscopic powder that is slightly soluble in water, sparingly soluble in methanol and practically insoluble in methylene chloride. It has a molecular weight of 764.9. Each zolpidem tartrate sublingual tablet includes the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, pregelatinized starch, mannitol, peppermint flavor, saccharin sodium and corn starch. ZOLPIDEM

10 OVERDOSAGE 10.1 Signs and Symptoms In post-marketing experience of overdose with oral 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 flumazenil 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 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 management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage.

10.1 Signs and Symptoms In post-marketing experience of overdose with oral 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 flumazenil 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 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 management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage.

16 HOW SUPPLIED/ STORAGE AND HANDLING Each sublingual tablet is individually packaged in a unit-dose pouch. Zolpidem tartrate sublingual tablets 1.75 mg are white, round tablets, flat-faced, bevel-edged with debossed “NT” on one side and “124” on the other side and supplied as: NDC Number Size 49884-898-11 Carton of 30 unit-dose pouches Zolpidem tartrate sublingual tablets 3.5 mg are white, round tablets, flat-faced, bevel-edged with debossed “P” & “350” on one side and plain on the other side and supplied as: NDC Number Size 49884-899-11 Carton of 30 unit-dose pouches Storage and Handling Store between 20° to 25°C (68° to 77°F). Excursions permitted between 15° to 30°C (59° to 86°F). Protect from moisture. The patient should be instructed not to remove the sublingual tablet from the unit-dose pouch until the patient is ready to consume it.