Zolpidem Tartrate 10 mg Tablet, 90-count — NDC 68071-5063-9 (Billing 68071-5063-09)

5 WARNINGS AND PRECAUTIONS CNS-depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. ( 5.1 ) Need to evaluate for comorbid diagnoses: Re-evaluate if insomnia persists after 7 to 10 days of use.

( 5.2 ) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.3 ) "Sleep-driving" and other complex behaviors while not fully awake.

Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. ( 5.4 ) Depression: Worsening of depression or suicidal thinking may occur.

Prescribe the least amount of tablets feasible to avoid intentional overdose. ( 5.5 ) Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. ( 5.6 ) Hepatic Impairment: Avoid zolpidem tartrate tablets use in patients with severe hepatic impairment.

( 5.7 ) Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.8 , 9.3 )

5.1CNS-Depressant Effects and Next-Day Impairment Zolpidem tartrate tablets, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant effects. Coadministration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem tartrate tablets and of other concomitant CNS depressants may be necessary when zolpidem tartrate tablets are administered with such agents because of the potentially additive effects.

The use of zolpidem tartrate tablets 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 zolpidem tartrate tablets are taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or if coadministered with other drugs that increase the blood levels of zolpidem.

Patients should be warned against driving and other activities requiring complete mental alertness if zolpidem tartrate tablets are taken in these circumstances [see Dosage and Administration ( 2 ) and Clinical Studies ( 14.3 )]. Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy.

In order to minimize this risk a full night of sleep (7 to 8 hours) is recommended. Because zolpidem can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.

5.2Need to Evaluate for Comorbid 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.

5.3Severe Anaphylactic and Anaphylactoid Reactions Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required m… [Excerpted — this section continues on DailyMed.]

6 ADVERSE REACTIONS Most commonly observed adverse reactions were: Short-term (<10 nights): Drowsiness, dizziness, and diarrheaShort-term (<10 nights): Drowsiness, dizziness, and diarrhea Long-term (28 to 35 nights): Dizziness and drugged feelings ( ) Long-term (28 to 35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma, Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch The following serious adverse 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 ( 5.8 )]

6.1Clinical 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… [Excerpted — this section continues on DailyMed.]

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 ) CYP3A4 inducers (rifampin or St. John's wort): Combination use may decrease effect ( 7.2 ) Ketoconazole: Combination use may increase effect ( 7.2 )

7.1CNS-Active Drugs 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 )]. 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 [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 )] .

7.2Drugs 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 )] .

9 DRUG ABUSE AND DEPENDENCE

9.1Controlled Substance Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

9.2Abuse Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time.

Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. Its characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common. Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo. Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

9.3Dependence Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions.

The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses.

Postmarketing reports of abuse, dependence and withdrawal have been received.

9.1Controlled Substance Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.