Edluar

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

2 DOSAGE AND ADMINISTRATION • Use the lowest dose effective for the patient ( 2.1 ) • Recommended dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime. ( 2.1 ) • Geriatric patients and patients with 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 Edluar. ( 2.3 ) • Co-administration with CNS depressants: Recommended dose is 5 mg for men and women. ( 2.3 ) • The effect of Edluar may be slowed if taken with or immediately after a meal. ( 2.4 ) • Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. ( 2.4 ) • The tablet should not be swallowed and the tablet should not be taken with water. ( 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 (5.1) ] . The total dose of Edluar should not exceed 10 mg once daily immediately before bedtime. The recommended initial doses for women and men are different because zolpidem clearance is lower in women. 2.2 Special Populations Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Edluar in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.1) ; Use in Specific Populations (8.5) ] . 2.3 Use with CNS Depressants Dosage adjustment may be necessary when Edluar is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1) ] . 2.4 Administration The effect of Edluar may be slowed by ingestion with or immediately after a meal. Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.

5 WARNINGS AND PRECAUTIONS • CNS Depressant Effects: Impairs alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Instruct patients on correct use. ( 5.2 ) • Need to Evaluate for Co-morbid Diagnosis: Reevaluate if insomnia persists after 7 to 10 days of use. ( 5.3 ) • Severe Anaphylactic and Anaphylactoid Reactions: angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.4 ) • Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation and depersonalization have been reported. Immediately evaluate any new onset behavioral changes. ( 5.5 ) • Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. ( 5.6 ) • Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. ( 5.7 ) • Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.8 , 9.3 ) 5.1 Complex Sleep Behaviors Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of zolpidem. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with zolpidem alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1) ] . Discontinue Edluar immediately if a patient experiences a complex sleep behavior . 5.2 CNS Depressant Effects and Next-Day Impairment Edluar, like other sedative-hypnotic drugs, CNS depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of Edluar and of other concomitant CNS depressants may be necessary when Edluar is administered with such agents because of the potentially additive effects. The use of Edluar with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Dosage and Administration (2.3) ] . The risk of next-day psychomotor impairment, including impaired driving, is increased if Edluar is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants; or if co-administered with other drugs that increase the blood level of zolpidem. Patients should be cautioned against driving and other activities requiring complete mental alertness if Edluar is taken in these circumstances. Because Edluar can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. 5.3 Need to Evaluate for Co-morbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem. 5.4 Severe Anaphylactic and Anaphylactoid Reactions Cases of angioedema involving the tongue, glottis or larynx have been reported in pat…

4 CONTRAINDICATIONS Edluar is contraindicated in patients: • who have experienced complex sleep behaviors after taking Edluar [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 Edluar. ( 4 , 5.1 ) • Known hypersensitivity to zolpidem. ( 4 )

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 effect ( 7.2 ) 7.1 CNS-active Drugs CNS Depressants 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, 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) ] . 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) ] . Alcohol An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1) ] . Sertraline Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamics effect of 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) ] . 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 pharmacodynamics effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem. Ketoconazole Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamics effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Drug Interactions CNS-depressants: Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.1) ] . Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. 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. 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. An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1) ] . Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C max was significantly higher (43%) and T max was significantly decreased (-53%). Ph…

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 identified a drug-associated risk of 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 Edluar 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 have not identified a drug-associated risk of 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 intra-tracheal 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 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.

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) ] • Serious Anaphylactic and Anaphylactoid Reactions [see Warning and Precautions (5.4) ] • Abnormal Thinking and Behavioral Changes [see Warning and Precautions (5.5) ] • Withdrawal Effects [see Warning and Precautions (5.8) ] 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 Meda Pharmaceuticals Inc. at 1-866-444-7799 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 tartrate 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 tartrate 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 tartrate 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 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 tartrate 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 event 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 a pool of…