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Zolpidem Tartrate Extended-Release Tablet

DEA Controlled Substance Schedule C-IV

TABLE OF CONTENTS

1. DESCRIPTION 8. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 9. DRUG ABUSE AND DEPENDENCE
3. DOSAGE AND ADMINISTRATION 10. OVERDOSAGE
4. CONTRAINDICATIONS 11. DRUG INTERACTIONS
5. MECHANISM OF ACTION 12. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. WARNINGS AND PRECAUTIONS  

 

1. DESCRIPTION

Zolpidem tartrate is a non-benzodiazepine hypnotic of the imidazopyridine class.

Chemically, zolpidem tartrate 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 ER 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 ER 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.

2. INDICATIONS AND USAGE

Zolpidem tartrate extended-release tablet is indicated for the 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.

3. DOSAGE AND ADMINISTRATION

The dose of zolpidem tartrate ER should be individualized.

3.1 Dosage in adults

The recommended dose of zolpidem tartrate ER for adults is 12.5 mg once daily immediately before bedtime. The total zolpidem tartrate ER dose should not exceed 12.5 mg per day.

3.2 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 normals. The recommended dose of zolpidem tartrate ER in both of these patient populations is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions].

3.3 Use with CNS depressants

Dosage adjustments may be necessary when zolpidem tartrate ER is combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions].

3.4 Administration

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

4. CONTRAINDICATIONS

Zolpidem tartrate ER is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation.

5. MECHANISM OF ACTION

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The BZ1 receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.2 Nursing Mothers

Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young normal volunteers (2.6± 0.3 hr). Between 0.004% and 0.019% of the total administered dose is excreted into milk, but the effect of zolpidem on the infant is unknown.

The use of zolpidem tartrate ER in nursing mothers is not recommended.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

6.4 Geriatric Use

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

7. WARNINGS AND PRECAUTIONS

7.1 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.

7.2 Severe anaphylactic and anaphylactoid reactions

Rare 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.

7.3 Abnormal thinking and behavioral changes

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g. aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, < 1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attentiondeficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use in Specific Populations].

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedativehypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with zolpidem tartrate ER alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem tartrate ER appears to increase the risk of such behaviors, as does the use of zolpidem tartrate ER at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate ER should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions including completed suicides), have been reported in association with the use of sedative/hypnotics.

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.

7.4 Withdrawal effects

Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence].

7.5 CNS depressant effects

Zolpidem tartrate ER, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, zolpidem tartrate ER should only be taken immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of zolpidem tartrate ER. Zolpidem tartrate ER showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when zolpidem tartrate ER is administered with such agents because of the potentially additive effects.

7.6 Special populations

Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended zolpidem tartrate ER dosage is 6.25 mg in such patients to decrease the possibility of side effects [see Dosage and Administration]. These patients should be closely monitored.

Use in patients with concomitant illness: Clinical experience with zolpidem tartrate ER in patients with concomitant systemic illness is limited. Caution is advisable in using zolpidem tartrate ER in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normals 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 an immediate-release formulation of zolpidem tartrate (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate ER is prescribed to patients with compromised respiratory function. Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. Zolpidem tartrate ER should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

Data in end-stage renal failure patients repeatedly treated with an immediate-release formulation of zolpidem tartrate (10 mg) did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored.

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with zolpidem tartrate ER 6.25 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration].

Use in patients with depression: As with other sedative/hypnotic drugs, zolpidem tartrate ER should be administered with caution to patients exhibiting signs or symptoms of depression. 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 least amount of drug that is feasible should be prescribed for the patient at any one time.

Use in pediatric patients: Safety and effectiveness of zolpidem has not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD given an immediate-release oral solution of zolpidem tartrate, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations].

8. ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions)

• Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions]

• Withdrawal effects [see Warnings and Precautions]

• CNS-depressant effects [see Warnings and Precautions

8.1 Clinical trials experience

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 ER 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 ER 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 ER 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 ER 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.

Most commonly observed adverse reactions in controlled trials: During treatment with zolpidem tartrate ER in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of zolpidem tartrate ER were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating zolpidem tartrate ER 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for zolpidem tartrate ER versus 2.6% for placebo).

Adverse reactions observed at an incidence of ≥1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate ER in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary 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 tables were derived from results of two placebo-controlled efficacy trials involving zolpidem tartrate ER. These trials involved patients with primary insomnia who were treated for 3 weeks with zolpidem tartrate ER at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively. The tables include only adverse reactions occurring at an incidence of at least 1% for zolpidem tartrate ER patients and with an incidence greater than that seen in the placebo patients.

* Reactions reported by at least 1% of patients treated with zolpidem tartrate ER and at greater frequency than in the placebo group.

** Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations.

*** Memory disorders include: memory impairment, amnesia, anterograde amnesia.

* Reactions reported by at least 1% of patients treated with zolpidem tartrate ER and at greater frequency than in the placebo group.

** Memory disorders include: memory impairment, amnesia, anterograde amnesia.

Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

9. DRUG ABUSE AND DEPENDENCE

Controlled substance: Zolpidem tartrate is classified as a Schedule IV controlled substance under the controlled Substances Act.

Abuse and dependence: Studies of abuse potential in former drug abusers found that the effects of single doses of an immediate-release formulation 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.

10. OVERDOSAGE

Signs and symptoms: In postmarketing reports of overdose with immediate-release zolpidem tartrate alone, impairment of consciousness has ranged from somnolence to light coma. There was one case each of cardiovascular and respiratory compromise. Individuals have fully recovered from zolpidem tartrate overdoses up to 400 mg (40 times the maximum recommended dose of the immediate-release product). Overdose cases involving multiple CNS-depressant agents, including zolpidem tartrate, have resulted in more severe symptomatology, including fatal outcomes.

Recommended treatment: General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. 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 tartrate 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.

11. DRUG INTERACTIONS

CNS-active drugs

An immediate-release formulation of zolpidem tartrate was evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. A study involving haloperidol and zolpidem tartrate revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem tartrate 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 tartrate produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem tartrate was demonstrated.

A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male subjects did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem tartrate and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.

Following five consecutive nightly doses of zolpidem tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female subjects), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Since the systematic evaluations of zolpidem tartrate ER in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.

Drugs that affect drug metabolism via cytochrome P450

Compounds that inhibit cytochrome P450 may enhance the activity of zolpidem.

A randomized, double-blind, crossover interaction study in ten healthy subjects between itraconazole (200 mg once daily for 4 days) and a single dose of an immediate-release formulation of zolpidem tartrate (10 mg) given five hours after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized double blind crossover interaction study in twelve healthy subjects showed that co-administration of 5 mg of immediate-release zolpidem tartrate with ketoconazole (200 mg twice daily), a potent CYP3A4 inhibitor, increased the total AUC of zolpidem by a factor 1.83 compared to zolpidem alone, prolonged the elimination half life and decreased oral clearance to 64% along with an increase in the pharmacodynamic effects of zolpidem. A routine dosage adjustment is not considered necessary, however, patients should be advised that use of zolpidem tartrate ER with ketoconazole may enhance the sedative effects.

A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of an immediate-release formulation of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (-73%), Cmax (-58%), and T½ (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.

Other drugs

A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. Zolpidem had no effect on digoxin kinetics and did not affect prothrombin time when given with warfarin in normal subjects. Zolpidem's sedative/hypnotic effect was reversed by flumazenil; however, no significant alterations in zolpidem pharmacokinetics were found.

Drug/Laboratory test interactions

Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

12. PHARMACOKINETICS

Zolpidem tartrate ER 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 ER (12.5 mg) and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with zolpidem tartrate ER (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg).

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

Absorption

Following administration of zolpidem tartrate ER, administered as a single 12.5-mg dose in healthy male adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at a median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740 ng·hr/mL (range: 295 to 1359 ng·hr/mL).

A food-effect study in 45 healthy subjects compared the pharmacokinetics of zolpidem tartrate ER 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median Tmax was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, zolpidem tartrate ER should not be administered with or immediately after a meal.

Distribution

Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.

Metabolism

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.

Elimination

Zolpidem tartrate ER administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).

Special Populations

Elderly

In 24 elderly (≥ 65 years) healthy subjects administered a single 6.25-mg dose of zolpidem tartrate ER, the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring at a median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 ng·hr/mL (range: 124 to 1190 ng·hr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).

Hepatic Impairment

Zolpidem tartrate ER was not studied in patients with hepatic impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20-mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency (see Precautions and Dosage and Administration).

Renal Impairment

Zolpidem tartrate ER was not studied in patients with renal impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally-impaired patients. No dosage adjustment is necessary in patients with compromised renal function. However, as a general precaution, these patients should be closely monitored.

13. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: AMBIEN CR, by Sanofi-Winthrop.

b) Generic drugs: Zolpidem tartrate, by various manufacturers.

2) How Supplied:

Zolpidem tartrate extended-release tablets (by ANCHEN PHARM), 12.5 mg are available as white to off-white round film coated tablets engraved with ”A116” on one side and plain on the other side. They are supplied as follows:

NDC Number - Size

10370-116-10 bottle of 100

10370-116-50 bottle of 500

10370-116-00 bottle of 1000

3) Storage: Store between 20°-25° C (68°-77°F). Limited excursions permissible up to 30° C (86°F).

Rx only

Rev 12/10