Zolpidem Tartrate 5 mg Tablet, Film Coated, 15-count

5 WARNINGS AND PRECAUTIONS • CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. ( 5.1 ) • Need to evaluate for co-morbid diagnosis: Reevaluate 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 ) • Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation ( 5.7 , 9.3 ) • Severe Injuries: Drowsiness may lead to fall including severe injuries ( 5.8 )

5.1CNS Depressant Effects and Next-Day Impairment Zolpidem tartrate, 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 and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects.

The use of zolpidem tartrate 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 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 coadministered with other CNS depressants; or if coadministered with other drugs that increase the blood levels of zolpidem.

Patients should be cautioned against driving and other activities requiring complete mental alertness if zolpidem tartrate is taken in these circumstances [see Dosage and Administration ( 2 ) and Clinical Studies ( 14.3 ) ].

5.2Need 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.

5.3Severe 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 medical therapy in the emergency department.

If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

5.4Abnormal Thinking and Behavioral Changes Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization…

6 ADVERSE REACTIONS 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 andPrecautions ( 5.4 ) ] • Withdrawal effects [see Warnings and Precautions ( 5.7 ) ] Most commonly observed adverse reactions were: Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea Long-term (28 to 35 nights): Dizziness and drugged feelings ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 s…

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 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 [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 inhibit CYP3A may increase exposure to zolpidem. The effect of drugs on 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.