Zolpidem Tartrate Extended-release Tablets. These Highlights Do Not Include All The Information Needed To Use Zolpidem Tartrate Safely And Effectively. See Full Prescribing Information For Zolpidem Tartrate.

Carcinogenesis

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2, 9, and 40 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m ²body surface area and in rats, these doses are approximately 4, 18, and 80 times the MRHD based on mg/m ²body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.

Associated with Discontinuation of Treatment

In 3-week clinical trials in adults and elderly patients (>65 years), 3.5% (7/201) patients receiving Zolpidem Tartrate 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with Zolpidem Tartrate was somnolence (1%).

In a 6-month study in adult patients (18–64 years of age), 8.5% (57/669) of patients receiving Zolpidem Tartrate 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of Zolpidem Tartrate included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

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.

Store between 15°C–25°C (59°F–77°F). Limited excursions permissible up to 30°C (86°F).

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. It is 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 effects were 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.

Zolpidem Tartrate contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Zolpidem Tartrate extended-release tablets is available in 6.25 mg and 12.5 mg strength tablets for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.

Zolpidem Tartrate consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The 6.25 mg Zolpidem Tartrate tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5 mg Zolpidem Tartrate tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.

Use of Zolpidem Tartrate may lead to development of physical and/or psychological dependence. This risk of dependence increases with dose and duration of treatment. The risk of abuse and dependence is also greater in patients with history of alcohol or drug abuse. Zolpidem Tartrate should be used with extreme caution in patients with current or past alcohol or drug abuse.

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, convulsions, and delirium.

The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during Zolpidem Tartrate 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. There have been postmarketing reports of abuse, dependence and withdrawal with zolpidem.

Zolpidem Tartrate is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.

In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.5)] . Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

FDA has not required pediatric studies of Zolpidem Tartrate in the pediatric population based on these efficacy and safety findings.

A total of 99 elderly (≥65 years of age) received daily doses of 6.25 mg Zolpidem Tartrate in a 3-week placebo-controlled study. The adverse reaction profile of Zolpidem Tartrate 6.25 mg in this population was similar to that of Zolpidem Tartrate 12.5 mg in younger adults (≤64 years of age). Dizziness was reported in 8% of Zolpidem Tartrate–treated patients compared with 3% of those treated with placebo.

The dose of Zolpidem Tartrate in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.2)] .

Zolpidem Tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of Zolpidem Tartrate may be slowed by ingestion with or immediately after a meal.

Zolpidem Tartrate is contraindicated in patients

• who have experienced complex sleep behaviors after taking Zolpidem Tartrate [see Warnings and Precautions (5.1)].
• with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4)].

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)]

• CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects ( 5.2, 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)

Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 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 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 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 should not exceed 12.5 mg once daily immediately before bedtime. AZolpidem Tartrate 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.

Treatment with Zolpidem Tartrate should be as short as possible. Extended treatment should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with duration of treatment [see Drug Abuse and Dependence (9.3)].

Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3 subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT ₂, adrenergic, histaminergic or muscarinic receptors.

Zolpidem Tartrate exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Zolpidem Tartrate 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Zolpidem Tartrate (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration-time profiles are shown in Figure 1.

Figure 1: Mean Plasma Concentration-Time Profiles for Zolpidem Tartrate (12.5 mg) and Immediate-Release Zolpidem Tartrate (10 mg)

In adult and elderly patients treated with Zolpidem Tartrate, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.

There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see Drug Abuse and Dependence (9.2, 9.3)] .

The recommended dose of Zolpidem Tartrate in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Clinical Pharmacology (12.3)] .

Zolpidem tartrate extended-release tablets is indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient reported assessment in adult patients only) in duration [see Clinical Studies (14)].

In postmarketing experience of overdose with 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.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of Zolpidem Tartrate in these patients is 6.25 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 in these patients is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate 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)] .

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.

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

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 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 monitored and 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 the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

• CNS-Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients against driving and other activities requiring complete mental alertness the morning after use. Instruct patients on correct use. ( 5.2)
• Need to Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. ( 5.3)
• Severe Anaphylactic/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)
• Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment. ( 5.8)
• Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.9, 9.3)

Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild to moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem Tartrate is prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. Postmarketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risk of respiratory depression should be considered prior to prescribing Zolpidem Tartrate in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use [see Dosage and Administration (2.3), Drug Interactions (7.1)].

• Use the lowest dose effective for the patient and must not exceed a total of 12.5 mg daily ( 2.1)
• Treatment should be as short as possible ( 2.1)
• Recommended initial dose is a single dose of 6.25 mg for women and a single dose of 6.25 or 12.5 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 6.25 mg for men and women ( 2.2)
• Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN CR ( 2.3)
• Tablets to be swallowed whole, not to be crushed, divided or chewed ( 2.4)
• The effect of AMBIEN CR may be slowed if taken with or immediately after a meal ( 2.4)

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of Zolpidem Tartrate. 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. Postmarketing reports have shown that complex sleep behaviors may occur with Zolpidem Tartrate alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)] . Discontinue Zolpidem Tartrate immediately if a patient experiences a complex sleep behavior [see Contraindications (4)] .

Dosage adjustment may be necessary when Zolpidem Tartrate is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.2, 5.7)] .

Zolpidem Tartrate is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored.

Zolpidem Tartrate 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.

Zolpidem Tartrate 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.

The following adverse reactions have been identified during postapproval use of Zolpidem Tartrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system:acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN).

Psychiatric disorders:delirium

• Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. ( 8.1)
• Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after AMBIEN CR administration. ( 8.2)
• Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. ( 5.5, 8.4)

Zolpidem Tartrate was evaluated in three placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV™).

Adult outpatients (18–64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Zolpidem Tartrate 12.5 mg and placebo. Zolpidem Tartrate 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. Zolpidem Tartrate 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment. Zolpidem Tartrate 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

Elderly outpatients (≥65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Zolpidem Tartrate 6.25 mg and placebo. Zolpidem Tartrate 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. Zolpidem Tartrate 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing LPS) during the first 2 nights of treatment and after 2 weeks on treatment. Zolpidem Tartrate 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

In both studies, in patients treated with Zolpidem Tartrate, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.

In a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18–64 years) with primary insomnia (N=1025), Zolpidem Tartrate 12.5 mg administered as needed (3 to 7 nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time.

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of Zolpidem Tartrate. Some of these events may result in serious injuries, including death. Discontinue Zolpidem Tartrate immediately if a patient experiences a complex sleep behavior [see Contraindications (4)and Warnings and Precautions (5.1)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with Zolpidem Tartrate. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Zolpidem Tartrate and with each prescription refill. Review the Zolpidem Tartrate Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Zolpidem Tartrate should be taken only as prescribed.

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.

Zolpidem Tartrate 6.25 mg extended-release tablets are composed of two layers* and are coated, pink, round, biconvex, debossed with A~ on one side and supplied as:

Zolpidem Tartrate 12.5 mg extended-release tablets are composed of two layers* and are coated, blue, round, biconvex, debossed with A~ on one side and supplied as:

*Layers are covered by the coating and are indistinguishable.

Women clear zolpidem tartrate from the body at a lower rate than men. C _maxand AUC parameters of zolpidem from Zolpidem Tartrate were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2 to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of Zolpidem Tartrate for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of Zolpidem Tartrate in geriatric patients is 6.25 mg regardless of gender.

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.

Drugs affecting GABA receptors, such as zolpidem tartrate, have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid Zolpidem Tartrate use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .

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. Visual and auditory hallucinations have been reported.

In controlled trials, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with Zolpidem Tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)]. There have been postmarketing reports of delirium with zolpidem use [see Adverse Reactions (6.2)].

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Zolpidem Tartrate is a CNS depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Zolpidem Tartrate may develop, patients using Zolpidem Tartrate should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use [see Drug Interactions (7.1)] . Downward dose adjustment of Zolpidem Tartrate and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)] .

The use of Zolpidem Tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

The risk of next-day psychomotor impairment is increased if Zolpidem Tartrate is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or 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 is taken in these circumstances [see Dosage and Administration (2), Clinical Studies (14.2)] .

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 (7–8 hours) is recommended.

Because Zolpidem Tartrate can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.

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.

NDC 51407-762-01

(ZOLPIDEM TARTRATE EXTENDED-RELEASE) CIV

12.5 mg Tablets

Dispense with Medication Guide

Rx only 100 Tablets

NDC 51407-761-01

(ZOLPIDEM TARTRATE EXTENDED-RELEASE) CIV

6.25 mg Tablets

Dispense with Medication Guide

Rx only

100 Tablets

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.

Carcinogenesis

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2, 9, and 40 times the MRHD of 12.5 mg/day (10 mg zolpidem base) based on mg/m ²body surface area and in rats, these doses are approximately 4, 18, and 80 times the MRHD based on mg/m ²body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.

Associated with Discontinuation of Treatment

In 3-week clinical trials in adults and elderly patients (>65 years), 3.5% (7/201) patients receiving Zolpidem Tartrate 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with Zolpidem Tartrate was somnolence (1%).

In a 6-month study in adult patients (18–64 years of age), 8.5% (57/669) of patients receiving Zolpidem Tartrate 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of Zolpidem Tartrate included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

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.

Store between 15°C–25°C (59°F–77°F). Limited excursions permissible up to 30°C (86°F).

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. It is 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 effects were 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.

Zolpidem Tartrate contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Zolpidem Tartrate extended-release tablets is available in 6.25 mg and 12.5 mg strength tablets for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.

Zolpidem Tartrate consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The 6.25 mg Zolpidem Tartrate tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5 mg Zolpidem Tartrate tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.

Use of Zolpidem Tartrate may lead to development of physical and/or psychological dependence. This risk of dependence increases with dose and duration of treatment. The risk of abuse and dependence is also greater in patients with history of alcohol or drug abuse. Zolpidem Tartrate should be used with extreme caution in patients with current or past alcohol or drug abuse.

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, convulsions, and delirium.

The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during Zolpidem Tartrate 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. There have been postmarketing reports of abuse, dependence and withdrawal with zolpidem.

Zolpidem Tartrate is not recommended for use in children. Safety and effectiveness of zolpidem in pediatric patients below the age of 18 years have not been established.

In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.5)] . Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

FDA has not required pediatric studies of Zolpidem Tartrate in the pediatric population based on these efficacy and safety findings.

A total of 99 elderly (≥65 years of age) received daily doses of 6.25 mg Zolpidem Tartrate in a 3-week placebo-controlled study. The adverse reaction profile of Zolpidem Tartrate 6.25 mg in this population was similar to that of Zolpidem Tartrate 12.5 mg in younger adults (≤64 years of age). Dizziness was reported in 8% of Zolpidem Tartrate–treated patients compared with 3% of those treated with placebo.

The dose of Zolpidem Tartrate in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.2)] .

Zolpidem Tartrate extended-release tablets should be swallowed whole, and not be divided, crushed, or chewed. The effect of Zolpidem Tartrate may be slowed by ingestion with or immediately after a meal.

Zolpidem Tartrate is contraindicated in patients

• who have experienced complex sleep behaviors after taking Zolpidem Tartrate [see Warnings and Precautions (5.1)].
• with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4)].

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)]

• CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects ( 5.2, 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)

Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 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 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 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 should not exceed 12.5 mg once daily immediately before bedtime. AZolpidem Tartrate 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.

Treatment with Zolpidem Tartrate should be as short as possible. Extended treatment should not take place without re-evaluation of the patient’s status, since the risk of abuse and dependence increases with duration of treatment [see Drug Abuse and Dependence (9.3)].

Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3 subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT ₂, adrenergic, histaminergic or muscarinic receptors.

Zolpidem Tartrate exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Zolpidem Tartrate 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Zolpidem Tartrate (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration-time profiles are shown in Figure 1.

Figure 1: Mean Plasma Concentration-Time Profiles for Zolpidem Tartrate (12.5 mg) and Immediate-Release Zolpidem Tartrate (10 mg)

In adult and elderly patients treated with Zolpidem Tartrate, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.

There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see Drug Abuse and Dependence (9.2, 9.3)] .

The recommended dose of Zolpidem Tartrate in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Clinical Pharmacology (12.3)] .

Zolpidem tartrate extended-release tablets is indicated for the short-term treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient reported assessment in adult patients only) in duration [see Clinical Studies (14)].

In postmarketing experience of overdose with 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.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of Zolpidem Tartrate in these patients is 6.25 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 in these patients is 6.25 mg once daily immediately before bedtime. Avoid Zolpidem Tartrate 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)] .

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.

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

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 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 monitored and 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 the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

• CNS-Depressant Effects: Impaired alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Caution patients against driving and other activities requiring complete mental alertness the morning after use. Instruct patients on correct use. ( 5.2)
• Need to Evaluate for Comorbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. ( 5.3)
• Severe Anaphylactic/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)
• Hepatic Impairment: Avoid AMBIEN CR use in patients with severe hepatic impairment. ( 5.8)
• Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. ( 5.9, 9.3)

Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild to moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if Zolpidem Tartrate is prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. Postmarketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risk of respiratory depression should be considered prior to prescribing Zolpidem Tartrate in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use [see Dosage and Administration (2.3), Drug Interactions (7.1)].

• Use the lowest dose effective for the patient and must not exceed a total of 12.5 mg daily ( 2.1)
• Treatment should be as short as possible ( 2.1)
• Recommended initial dose is a single dose of 6.25 mg for women and a single dose of 6.25 or 12.5 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 6.25 mg for men and women ( 2.2)
• Lower doses of CNS depressants may be necessary when taken concomitantly with AMBIEN CR ( 2.3)
• Tablets to be swallowed whole, not to be crushed, divided or chewed ( 2.4)
• The effect of AMBIEN CR may be slowed if taken with or immediately after a meal ( 2.4)

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of Zolpidem Tartrate. 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. Postmarketing reports have shown that complex sleep behaviors may occur with Zolpidem Tartrate alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)] . Discontinue Zolpidem Tartrate immediately if a patient experiences a complex sleep behavior [see Contraindications (4)] .

Dosage adjustment may be necessary when Zolpidem Tartrate is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.2, 5.7)] .

Zolpidem Tartrate is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored.

Zolpidem Tartrate 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.

Zolpidem Tartrate 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.

The following adverse reactions have been identified during postapproval use of Zolpidem Tartrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system:acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN).

Psychiatric disorders:delirium

• Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in the third trimester. ( 8.1)
• Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after AMBIEN CR administration. ( 8.2)
• Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. ( 5.5, 8.4)

Zolpidem Tartrate was evaluated in three placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV™).

Adult outpatients (18–64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Zolpidem Tartrate 12.5 mg and placebo. Zolpidem Tartrate 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. Zolpidem Tartrate 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment. Zolpidem Tartrate 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

Elderly outpatients (≥65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Zolpidem Tartrate 6.25 mg and placebo. Zolpidem Tartrate 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. Zolpidem Tartrate 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing LPS) during the first 2 nights of treatment and after 2 weeks on treatment. Zolpidem Tartrate 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

In both studies, in patients treated with Zolpidem Tartrate, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.

In a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18–64 years) with primary insomnia (N=1025), Zolpidem Tartrate 12.5 mg administered as needed (3 to 7 nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time.

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of Zolpidem Tartrate. Some of these events may result in serious injuries, including death. Discontinue Zolpidem Tartrate immediately if a patient experiences a complex sleep behavior [see Contraindications (4)and Warnings and Precautions (5.1)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with Zolpidem Tartrate. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Zolpidem Tartrate and with each prescription refill. Review the Zolpidem Tartrate Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Zolpidem Tartrate should be taken only as prescribed.

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.

Zolpidem Tartrate 6.25 mg extended-release tablets are composed of two layers* and are coated, pink, round, biconvex, debossed with A~ on one side and supplied as:

Zolpidem Tartrate 12.5 mg extended-release tablets are composed of two layers* and are coated, blue, round, biconvex, debossed with A~ on one side and supplied as:

*Layers are covered by the coating and are indistinguishable.

Women clear zolpidem tartrate from the body at a lower rate than men. C _maxand AUC parameters of zolpidem from Zolpidem Tartrate were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2 to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of Zolpidem Tartrate for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of Zolpidem Tartrate in geriatric patients is 6.25 mg regardless of gender.

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.

Drugs affecting GABA receptors, such as zolpidem tartrate, have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid Zolpidem Tartrate use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .

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. Visual and auditory hallucinations have been reported.

In controlled trials, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with Zolpidem Tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)]. There have been postmarketing reports of delirium with zolpidem use [see Adverse Reactions (6.2)].

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Zolpidem Tartrate is a CNS depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of Zolpidem Tartrate may develop, patients using Zolpidem Tartrate should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use [see Drug Interactions (7.1)] . Downward dose adjustment of Zolpidem Tartrate and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)] .

The use of Zolpidem Tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

The risk of next-day psychomotor impairment is increased if Zolpidem Tartrate is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or 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 is taken in these circumstances [see Dosage and Administration (2), Clinical Studies (14.2)] .

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 (7–8 hours) is recommended.

Because Zolpidem Tartrate can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.

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.

NDC 51407-762-01

(ZOLPIDEM TARTRATE EXTENDED-RELEASE) CIV

12.5 mg Tablets

Dispense with Medication Guide

Rx only 100 Tablets

NDC 51407-761-01

(ZOLPIDEM TARTRATE EXTENDED-RELEASE) CIV

6.25 mg Tablets

Dispense with Medication Guide

Rx only

100 Tablets

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.