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TORRENT PHARMAC
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zolpidem tartrate 10 mg tablet (generic ambien)

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Uses

Zolpidem tartrate as conventional tablets, oral spray, or sublingual tablets (Edluar) is used as a hypnotic agent in the short-term management of insomnia characterized by difficulties with sleep initiation. Because zolpidem has a short half-life, the drug may be of particular benefit in the initiation of sleep (i.e., decreasing sleep latency). In controlled clinical studies of 4-5 weeks' duration, the drug reportedly has been effective in decreasing sleep latency for periods up to 35 days in duration.

Zolpidem tartrate as extended-release tablets is used in the management of insomnia characterized by difficulty with sleep onset or sleep maintenance. However, zolpidem tartrate extended-release tablets may not be an appropriate treatment choice for patients (men or women) with insomnia who need to drive or perform activities that require full alertness the next morning (see Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications and also Next-day Impairment under Cautions: Nervous System Effects). In two 3-week, randomized, double-blind, placebo-controlled clinical trials in patients with chronic primary insomnia, zolpidem tartrate given as extended-release tablets improved sleep induction (as measured by latency to persistent sleep [LPS]) and sleep maintenance (as measured by wake time after sleep onset [WASO]). In one study in adults 18-64 years of age, zolpidem tartrate 12.5 mg as extended-release tablets at bedtime decreased WASO for the first 7 hours during the first 2 nights of use and for the first 5 hours after 2 weeks of treatment. In a similarly designed study in patients 65 years of age or older, a 6.25-mg dosage of the drug decreased WASO for the first 6 hours during the first 2 nights of use and for the first 4 hours after 2 weeks of treatment. In both studies, the drug decreased LPS during the first 2 nights of use and after 2 weeks of treatment and improved wakefulness at the end of the night (both measured by polysomnographic recordings) compared with placebo, and the drug was rated by patients as superior to placebo on a global impressions measure after 2 nights and after 3 weeks of use. In a 24-week, randomized, double-blind, placebo-controlled clinical trial in adults 18-64 years of age with chronic primary insomnia, zolpidem tartrate 12.5-mg extended-release tablets administered as needed 3-7 nights per week were superior to placebo on a patient-rated global impressions measure and on specific patient-reported parameters for sleep induction and maintenance; no substantial increase in frequency of drug use over time was observed.

Zolpidem tartrate as sublingual tablets (Intermezzo) is used as needed for the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep. The drug should be used in this manner only when 4 or more hours remain before the patient plans to awaken. In 2 randomized, double-blind, placebo-controlled clinical trials in patients with primary insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening, sublingual zolpidem tartrate improved sleep latency (as measured by polysomnography and patient-estimated reports) after middle-of-the-night awakening compared with placebo. In one crossover study, adults 19-64 years of age received each of 3 treatments (a 1.75- or 3.5-mg dose of zolpidem tartrate sublingual tablets or placebo) after a scheduled middle-of-the-night awakening on 2 consecutive nights in a sleep laboratory; the effect on sleep latency was similar for women receiving a 1.75-mg dose and men receiving a 3.5-mg dose. In the second study, adults 18-64 years of age received a 3.5-mg dose of zolpidem tartrate sublingual tablets or placebo on an as-needed basis over 4 weeks in an outpatient setting when the patient had difficulty returning to sleep after awakening in the middle of the night, provided at least 4 hours remained before the patient planned to awaken.

The choice of hypnotic agent must be individualized based on patient tolerance and response, taking into consideration pharmacokinetic and pharmacodynamic characteristics of the drug, patient age and other characteristics, and the underlying sleep disorder being treated.

Hypnotics with a relatively short half-life may be more likely to result in transient rebound insomnia after discontinuance and in pharmacodynamic tolerance and adaptation to the hypnotic effect, with resultant diminished effectiveness during the end of each night's use (early morning insomnia) and, possibly, increased daytime anxiety. However, despite zolpidem's short half-life, the manufacturer states that increased wakefulness during the last third of the night and objective evidence of rebound insomnia following discontinuance of zolpidem tartrate as conventional tablets have not been observed in clinical trials to date, although there was subjective evidence of impaired sleep on the first posttreatment night in geriatric patients receiving zolpidem tartrate as conventional tablets in doses that exceeded the recommended geriatric dose of 5 mg. Rebound insomnia was observed in two 3-week clinical trials on the first night after abrupt discontinuance of zolpidem tartrate as extended-release tablets, but there was no worsening compared with baseline on the second night. In a 24-week clinical trial evaluating zolpidem tartrate extended-release tablets administered as needed 3-7 nights per week, a rebound effect was observed within the first month for total sleep time, but not for WASO, during the first night that the drug was not used; however, no further rebound insomnia was observed after the first month or after final treatment discontinuance.

In addition, hypnotics with relatively short half-lives may be less likely to result in residual daytime sedative effects and in impaired psychomotor and mental performance during continued therapy. Residual daytime sedative effects of zolpidem were evaluated in several placebo-controlled studies in healthy adults and in geriatric individuals. A small but statistically significant decrease in performance (determined by the Digit Symbol Substitution test [DSST]) was observed in some adults and geriatric individuals receiving zolpidem tartrate as conventional tablets compared with those receiving placebo. Several studies of zolpidem tartrate as conventional tablets in adults with insomnia found no evidence of residual daytime sedative effects, determined by DSST, the Multiple Sleep Latency Test (MSLT), and patient rating of alertness. In studies of zolpidem tartrate extended-release tablets (given at recommended doses) in adult and geriatric patients, neurocognitive tests performed 8 hours after a dose and patient reports of sedation revealed no evidence of decreased performance or next-day residual effects. However, during the 3-week clinical trials evaluating the extended-release tablets, next-day somnolence was reported by 15 or 2% of adults receiving zolpidem or placebo, respectively, and by 6 or 5% of geriatric patients receiving zolpidem or placebo, respectively. In the 24-week clinical trial, the overall incidence of next-day somnolence was 5.7 or 2% in patients receiving zolpidem tartrate as extended-release tablets or placebo, respectively. The minimal effect of zolpidem on sleep stages at usual hypnotic dosages may offer a therapeutic advantage. However, the fact that zolpidem has minimal anxiolytic and muscle relaxant properties at usual hypnotic doses also should be considered. Blood concentrations of zolpidem may be high enough in some patients on the morning after use to impair performance of activities that require alertness, including driving, and the US Food and Drug Administration (FDA) states that all drugs used in the management of insomnia can impair driving and performance of activities that require alertness on the morning after use. For additional information, see Next-day Impairment under Cautions: Nervous System Effects and also Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.

Additional experience is needed to elucidate more fully the comparative efficacy and safety of zolpidem and benzodiazepines. For additional information on the management of insomnia, .

Dosage and Administration

Administration

Zolpidem tartrate is administered orally (as conventional tablets, extended-release tablets, or an oral solution using a metered-dose spray pump) or sublingually (as sublingual tablets).

Oral Administration

Zolpidem tartrate is administered orally at bedtime. Zolpidem tartrate should be taken only once per night immediately before bedtime and at least 7-8 hours before the planned time of awakening; patients should be advised of the importance of only taking the drug at such time. In addition, because food can reduce both the rate and extent of GI absorption of zolpidem tartrate, the drug should not be administered with or immediately after a meal in order to facilitate the onset of sleep.

Zolpidem tartrate extended-release tablets are commercially available as a coated bilayer formulation in which a portion of the labeled dose is contained in an immediate-release layer and the remaining portion is contained in a layer that slowly releases the drug. Following oral administration, the extended-release tablets exhibit biphasic absorption with a rapid initial absorption that is similar to that of immediate-release (conventional) tablets and extended absorption exceeding 3 hours after administration.

Zolpidem tartrate extended-release tablets should be swallowed whole and should not be divided, crushed, or chewed.

The manufacturer's instructions for patients should be consulted for detailed information on use of zolpidem tartrate oral spray. Prior to initial use, the spray pump must be primed by actuating 5 sprays while pointing the spray opening away from the patient's face and other individuals. If the oral spray has not been used for 14 days or longer, the pump must be primed again by actuating 1 spray. To administer the drug, the patient should hold the container upright with the spray opening pointed directly into the mouth, then fully press down on the pump to ensure that a full dose of the drug is sprayed directly into the mouth over the tongue. Based on the indicated dose of zolpidem tartrate, the appropriate number of sprays of the drug should be administered. Zolpidem tartrate oral spray delivers 5 mg of zolpidem tartrate per metered spray.

The commercially available zolpidem tartrate oral spray delivers about 60 metered sprays per 8.2-g container after 5 initial priming actuations. The total number of available doses is dependent on the number of sprays per dose (1 or 2 actuations) and the frequency of priming. Zolpidem tartrate oral spray should be discarded when the labeled number of actuations (60 sprays) have been used. The manufacturer states that there are no special requirements for cleaning and maintaining the zolpidem tartrate oral spray pump.

Sublingual Administration

Zolpidem tartrate is administered sublingually.

Zolpidem tartrate 5- and 10-mg sublingual tablets (Edluar) should be taken only once per night immediately before bedtime and at least 7-8 hours before the planned time of awakening; patients should be advised of the importance of only taking the drug at such time. The tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed or administered with water. In addition, because food can reduce both the rate and extent of absorption of zolpidem tartrate, the drug should not be administered with or immediately after a meal in order to facilitate the onset of sleep.

Zolpidem tartrate 1.75- and 3.5-mg sublingual tablets (Intermezzo) should be taken in bed, only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep, and only if at least 4 hours remain before the planned time of awakening; patients should be advised of the importance of only taking the drug at such time. The tablet should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. In addition, because food can reduce both the rate and extent of absorption of zolpidem tartrate, the drug should not be administered with or immediately after a meal for optimal effect. The tablet should be removed from the pouch just prior to administration.

Dosage

The smallest effective dosage of zolpidem tartrate should be used.

Because manifestations of withdrawal have been reported following abrupt discontinuance or rapid reduction in dosage of zolpidem, patients should be monitored for tolerance, abuse, and dependence.(See Tolerance, Dependence, and Abuse under Cautions: Precautions and Contraindications.)There also is evidence that abrupt discontinuance of sedative and hypnotic drugs, including zolpidem tartrate, may result in rebound insomnia, which usually persists for 1 or 2 nights; this effect may occur with some sedative and hypnotic drugs even after relatively short periods of therapy (e.g., 1 week). Therefore, some clinicians suggest that gradual dosage reduction (e.g., over several nights) be considered when discontinuing therapy, since the development of rebound insomnia can perpetuate continued use of hypnotics in patients with insomnia.

Oral Dosage

For the management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate as an oral immediate-release preparation (conventional tablets or oral spray) is 5 mg in women and either 5 or 10 mg in men. For the management of insomnia characterized by difficulty with sleep initiation or sleep maintenance, the recommended initial dose of zolpidem tartrate as extended-release tablets is 6.25 mg in women and either 6.25 or 12.5 mg in men. The lower doses (5 or 6.25 mg) should be effective in most women and many men. However, if the 5-mg dose of immediate-release zolpidem tartrate is not effective in men or women, the dose may be increased to 10 mg. If the 6.25-mg dose of extended-release zolpidem tartrate is not effective in men or women, the dose may be increased to 12.5 mg. In some patients, higher morning blood concentrations following use of a 10-mg dose of immediate-release zolpidem tartrate or a 12.5-mg dose of extended-release zolpidem tartrate increase the risk of next-day impairment of driving and other activities that require full alertness.(See Next-day Impairment under Cautions: Nervous System Effects and also Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.)Total dosage should not exceed 10 mg of immediate-release zolpidem tartrate or 12.5 mg of extended-release zolpidem tartrate given once daily immediately before bedtime. The recommended initial doses of zolpidem tartrate for women and men differ because clearance of the drug is slower in women.(See Special Populations under Pharmacokinetics: Elimination.)

In geriatric or debilitated patients, the recommended bedtime dosage of zolpidem tartrate is 5 mg as an immediate-release preparation or 6.25 mg as extended-release tablets given once daily immediately before bedtime.

When oral formulations of zolpidem tartrate are used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.(See Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.)

Sublingual Dosage

For the short-term management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate sublingual tablets (Edluar) is 5 mg for women and either 5 or 10 mg for men. The 5-mg dose should be effective in most women and many men. However, if the 5-mg dose is not effective in men or women, the dose may be increased to 10 mg. In some patients, higher morning blood concentrations following use of a 10-mg dose increase the risk of next-day impairment of driving and other activities that require full alertness.(See Next-day Impairment under Cautions: Nervous System Effects and also Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.) Total dosage should not exceed 10 mg given once daily immediately before bedtime. The recommended initial doses of zolpidem tartrate for women and men differ because clearance of the drug is slower in women.(See Special Populations under Pharmacokinetics: Elimination.)In geriatric or debilitated patients, the recommended sublingual dose of zolpidem tartrate for management of insomnia characterized by difficulties with sleep initiation is 5 mg once daily immediately before bedtime. When zolpidem tartrate sublingual tablets (Edluar) are used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.(See Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.)

For as-needed use in the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep, the recommended and maximum dose of zolpidem tartrate sublingual tablets (Intermezzo) is 1.75 mg for women and 3.5 mg for men. The recommended doses for women and men differ because clearance of the drug is slower in women.(See Special Populations under Pharmacokinetics: Elimination and also Next-day Impairment under Cautions: Nervous System Effects.) In men and women older than 65 years of age, the recommended sublingual dosage of zolpidem tartrate for middle-of-the-night awakening is 1.75 mg taken only once per night if needed. In men and women receiving other CNS depressants concomitantly, the recommended sublingual dose of zolpidem tartrate for middle-of-the-night awakening is 1.75 mg; dosage adjustment of the concomitant CNS depressant may be necessary because of potentially additive effects.(See Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.)

Dosage in Renal and Hepatic Impairment

Elimination of zolpidem tartrate is prolonged in patients with hepatic impairment. For the management of insomnia characterized by difficulties with sleep initiation in patients with hepatic impairment, the recommended dosage of zolpidem tartrate as an immediate-release preparation (conventional tablets, oral spray, sublingual tablets) is 5 mg once daily immediately before bedtime. For the management of insomnia characterized by difficulty with sleep initiation or sleep maintenance in patients with hepatic impairment, the recommended dosage of zolpidem tartrate as extended-release tablets is 6.25 mg once daily immediately before bedtime. For use in the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep, the recommended sublingual dosage of zolpidem tartrate in patients with hepatic impairment is 1.75 mg once per night if needed.

The manufacturers and some clinicians state that dosage adjustment is not necessary in patients with renal impairment. Other clinicians, however, state that the possibility that dosage reduction may be needed for patients with renal disease should be considered because of slower zolpidem elimination rates and other pharmacokinetic alterations observed in nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis.

Cautions

Zolpidem tartrate conventional tablets generally are well tolerated at recommended doses (i.e., up to 10 mg). Adverse effects of the drug tend to be dose related, particularly in geriatric patients and at doses exceeding those recommended.(See Cautions: Geriatric Precautions.) The most common adverse effects of zolpidem tartrate as conventional tablets, including those that most frequently require discontinuance of the drug, involve the nervous system and GI tract. In controlled clinical trials of short-term (up to 10 days) treatment with recommended doses of zolpidem tartrate conventional tablets, the most frequent adverse effects and those that were substantially more frequent with the drug than with placebo were drowsiness, dizziness, and diarrhea, which occurred in 2, 1, and 1% of patients, respectively. In controlled clinical trials of prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets, the most frequent adverse effects and those that were substantially more frequent with the drug than with placebo were dizziness and drugged feelings, which occurred in 5 and 3% of patients, respectively. The frequencies of many adverse nervous system and GI effects were similar to those of placebo in clinical trials of the drug at recommended doses. Adverse effects have required discontinuance of zolpidem tartrate as conventional tablets in approximately 4% of patients overall in worldwide clinical trials at doses ranging from 1-90 mg. These adverse effects included daytime drowsiness, headache, amnesia, dizziness, vertigo, falls, nausea, and vomiting.

Adverse effects of zolpidem tartrate as extended-release tablets also tend to be dose related, particularly for certain adverse nervous system and GI effects. The most common adverse effects of zolpidem tartrate as extended-release tablets, including those that most frequently require discontinuance of the drug, involve the nervous system. In 3-week controlled clinical trials of zolpidem tartrate administered as extended-release tablets at recommended doses, the most frequent adverse effects were headache, next-day somnolence, and dizziness, which occurred in 19, 15, and 12% of adults, respectively, and in 14, 6, and 8% of geriatric patients, respectively. In a 24-week clinical trial of zolpidem tartrate administered as extended-release tablets, the most frequent adverse effects were consistent with those reported in the 3-week clinical trials, except for a higher incidence of anxiety (6.3%). Adverse effects have required discontinuance of zolpidem tartrate when given as extended-release tablets at recommended doses in approximately 3.5% of patients in the 3-week clinical trials and 8.5% of patients in the 24-week clinical trial; the adverse effects most frequently associated with discontinuance of the drug were somnolence, which required discontinuance in 1% of patients in the 3-week clinical trials, and anxiety (anxiety, restlessness, or agitation) and depression (depression, major depression, or depressed mood), which each required discontinuance in 1.5% of patients in the 24-week clinical trial. The manufacturers state that adverse effects reported at frequencies of less than 1% in clinical trials of zolpidem tartrate extended-release tablets do not appear to differ substantially from those seen in studies with the conventional tablets.

The incidence of adverse effects in patients receiving zolpidem tartrate 1.75 mg as sublingual tablets on 2 consecutive nights in a sleep laboratory study was similar to the incidence observed in patients receiving 3.5-mg sublingual doses as needed after middle-of-the-night awakenings in a 4-week outpatient study. The most frequent adverse effects in patients receiving zolpidem tartrate as 1.75- or 3.5-mg sublingual tablets were headache, fatigue, and nausea.

Nervous System Effects

Headache, drowsiness or somnolence (i.e., drowsiness and drugged feeling), and dizziness were the most frequent adverse nervous system effects of zolpidem tartrate in clinical trials, and among the most frequent adverse effects requiring discontinuance of the drug. Headache occurred in 7% of patients receiving short-term (up to 10 days) treatment with recommended doses of zolpidem tartrate conventional tablets, 19% of adults and 14% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets in clinical trials of 3 weeks' duration, 3% of patients receiving as-needed therapy with zolpidem tartrate 3.5-mg sublingual tablets in an outpatient study of 4 weeks' duration, and 1-22% of patients receiving placebo. Headache has required discontinuance of zolpidem tartrate conventional tablets in about 0.4-0.5% of patients. Drowsiness occurred in 2 or 8% of patients receiving short-term or prolonged (4-5 weeks) treatment, respectively, with recommended doses of zolpidem tartrate conventional tablets and in 5% of those receiving placebo. Drowsiness has required discontinuance of zolpidem tartrate conventional tablets in about 0.5-1.1% of patients. Somnolence occurred in 15% of adults and 6% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets and in 2-5% of those receiving placebo. Somnolence has required discontinuance of zolpidem tartrate extended-release tablets in about 1% of patients in clinical trials of 3 weeks' duration. Dizziness occurred in 1 or 5% of patients receiving short-term or prolonged treatment, respectively, with recommended doses of zolpidem tartrate conventional tablets; 12% of adults and 8% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets; and 1-5% of those receiving placebo. Dizziness has required discontinuance of therapy in about 0.4-0.8% of patients receiving zolpidem tartrate conventional tablets.

Lethargy and drugged feeling occurred in 3% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets in clinical trials, and lethargy occurred in 1% of patients receiving placebo. Drugged feeling was one of the most frequent adverse effects of short-term treatment with zolpidem tartrate conventional tablets. Lightheadedness and depression occurred in 2% of patients receiving prolonged therapy with recommended doses of zolpidem tartrate conventional tablets and 1% of patients receiving placebo. Depression also occurred in 1-2% of patients receiving recommended doses of zolpidem tartrate extended-release tablets.

Amnesia, sleep disorder, and abnormal dreams occurred in 1% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets. Memory disorders (i.e., memory impairment, amnesia, anterograde amnesia) occurred in 1-3% of patients receiving recommended doses of zolpidem tartrate extended-release tablets. Anxiety occurred in 2-3% of patients receiving recommended doses of zolpidem tartrate extended-release tablets and in 2% of those receiving placebo.

Ataxia, asthenia, disorientation, euphoria, balance disorder, and vertigo have been reported in 1-3% of adults receiving recommended doses of zolpidem tartrate extended-release tablets, and disorientation occurred in 2% of placebo-treated patients. Ataxia, asthenia, confusion, euphoria, headache, insomnia, and vertigo have been reported in more than 1% of patients receiving zolpidem tartrate as conventional tablets. Agitation, anxiety, decreased cognition, detached feeling, difficulty concentrating, dysarthria, emotional lability, fatigue, hallucination, hypoesthesia, illusion, malaise, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, increased sweating, and tremor have been reported in 0.1-1% of patients receiving zolpidem tartrate as conventional tablets. Hallucinations, fatigue, disturbance in attention, hypoesthesia, and psychomotor retardation each have been reported in 2-4% of adults receiving recommended doses of zolpidem tartrate extended-release tablets, and fatigue and hypoesthesia have been reported in 1-2% of placebo-treated patients. Psychomotor retardation also has been reported in 2% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Appetite disorder, binge eating, paresthesia, depersonalization, disinhibition, mood swings, and stress symptoms each occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Apathy, burning sensation, postural dizziness, involuntary muscle contractions, paresthesia, and tremor each occurred in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Fatigue has been reported in 1% of patients receiving zolpidem tartrate as 3.5-mg sublingual tablets and in none of those receiving placebo. Abnormal gait, abnormal thinking, aggressive reaction, apathy, increased appetite, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, pain, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, and yawning have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets. Psychotic reactions also have been reported rarely in patients receiving zolpidem tartrate as conventional tablets.

Abnormal thinking and behavioral changes have been reported in patients receiving sedative and hypnotic drugs, including zolpidem. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation, depersonalization, and visual and auditory hallucinations. Complex behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative and hypnotic drug, with no memory of the event) have been reported in sedative and hypnotic drug-naive as well as in sedative and hypnotic drug-experienced patients. Although behaviors such as sleep-driving have occurred with zolpidem alone at therapeutic dosages, the concomitant use of alcohol and other CNS depressants with zolpidem or the use of zolpidem at dosages exceeding the maximum recommended dosage appears to increase the risk of such behaviors. Because of the risk to the patient and community, discontinuance of zolpidem should be strongly considered for patients who report a sleep-driving episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, having sex) have been reported in patients who are not fully awake after taking a sedative and hypnotic drug, and usually with no memory of the event. Amnesia, anxiety, and other neuropsychiatric symptoms also may occur.(See Mood, Thought, and Behavioral Changes under Cautions: Precautions and Contraindications.)

Although no consistent objective evidence for anterograde amnesia was found in controlled studies in adults receiving zolpidem tartrate as conventional tablets, results of one study indicate that the day following administration of 10- and 20-mg doses of zolpidem tartrate conventional tablets, substantial memory loss was reported regarding information presented to these individuals during periods of maximal sedative effect (i.e., 90 minutes after administration of zolpidem). In addition, although there is subjective evidence for anterograde amnesia occurring in association with zolpidem tartrate as conventional tablets (predominantly at doses exceeding 10 mg), limited studies involving objective measures of memory yielded little evidence for memory impairment following administration of the drug.

Next-day Impairment

Driving simulation and laboratory studies indicate that blood zolpidem concentrations exceeding approximately 50 ng/mL appear to be capable of impairing driving performance to a degree that increases the risk of a motor vehicle accident. The risk for next-morning impairment is highest for patients receiving extended-release preparations of the drug. In addition, women appear to be more susceptible to this risk because clearance of zolpidem is slower in women than in men. In pharmacokinetic studies evaluating 10-mg doses of immediate-release zolpidem tartrate (i.e., conventional tablet or bioequivalent preparations) in approximately 250 men and 250 women, zolpidem concentrations measured approximately 8 hours after a dose exceeded 50 ng/mL in 15% of women and 3% of men; results of 3 concentration measurements in women and 1 concentration measurement in men were at least 90 ng/mL. In pharmacokinetic studies evaluating 12.5-mg doses of extended-release zolpidem tartrate, zolpidem concentrations measured approximately 8 hours after a dose exceeded 50 ng/mL in 33% of women and 25% of men, and were at least 100 ng/mL in about 5% of patients. In studies evaluating 6.25-mg doses of extended-release zolpidem tartrate, zolpidem concentrations measured approximately 8 hours after a dose were 50 ng/mL or higher in about 15% of nongeriatric women, 5% of nongeriatric men, and 10% of both geriatric men and women. Because of these findings, currently recommended bedtime doses of zolpidem tartrate (see Dosage and Administration: Dosage)are lower than the original labeled doses, and all patients (including both men and women) receiving zolpidem should be cautioned about the risks of next-morning impairment for activities (e.g., driving) that require complete mental alertness.(See Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.)

The effect of middle-of-the-night sublingual administration of zolpidem tartrate on next-morning driving performance has been evaluated in a randomized, double-blind, placebo- and active-controlled crossover study in healthy individuals. In this study, individuals received a 3.5-mg sublingual dose of zolpidem tartrate 3 or 4 hours before driving, placebo, or an active control 9 hours before driving. When the driving test began 3 hours after the zolpidem dose, impairment (as measured by a standard test of road tracking precision [''weaving'']) was significantly worse than during the placebo test period, and testing was terminated for one individual (a 23-year-old woman) because of somnolence. When the driving test began 4 hours after the zolpidem dose, results were numerically worse than during the placebo period, but statistical significance was not established. Blood concentrations of zolpidem were not measured. However, the manufacturer states that the estimated zolpidem concentration in individuals with worse driving performance during the zolpidem test period is considered to present a risk for driving impairment. In some women, zolpidem concentrations remain at or sometimes considerably higher than this concentration for 4 or more hours after a 3.5-mg sublingual dose of the drug; therefore, the recommended dose of zolpidem tartrate for management of middle-of-the-night awakening in women is 1.75 mg (see Sublingual Dosage under Dosage and Administration: Dosage). Because a small adverse effect on road tracking precision may remain 4 hours after a 1.75-mg dose in women or a 3.5-mg dose in men, potential impairment of driving performance at these recommended dosages cannot be completely excluded.

GI Effects

Diarrhea was one of the most frequent adverse effects of short-term (up to 10 days) treatment with recommended doses of zolpidem tartrate conventional tablets in clinical trials, occurring in 1% of patients. Diarrhea occurred in 3% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets in clinical trials and in 2% of those receiving placebo. Frequent bowel movements occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Nausea occurred in more than 1% of patients receiving zolpidem tartrate as conventional tablets, 7% of adults receiving recommended doses of zolpidem tartrate extended-release tablets, 1% of patients receiving zolpidem tartrate as 3.5-mg sublingual tablets, and 1-4% of patients receiving placebo. Dry mouth occurred in 3% of patients receiving prolonged therapy with recommended doses of zolpidem tartrate conventional tablets in clinical trials and in 1% of those receiving placebo. Dry throat or throat irritation occurred in 1% of patients receiving recommended doses of zolpidem tartrate extended-release tablets. Nausea was one of the most frequent adverse effects requiring discontinuance of zolpidem tartrate as conventional tablets in clinical trials, with 0.5-0.6% of patients discontinuing therapy. Vomiting occurred in 0.1-1% of patients receiving zolpidem tartrate as conventional tablets and in 1% of patients receiving recommended doses of zolpidem tartrate extended-release tablets; however, it was one of the most frequent adverse effects requiring discontinuance of zolpidem tartrate conventional tablets in clinical trials, with 0.5% of patients discontinuing therapy.

Constipation occurred in 2% of patients receiving prolonged therapy with recommended doses of zolpidem tartrate conventional tablets in clinical trials and in 1% of those receiving placebo. Constipation occurred in 2% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Abdominal pain occurred in 2% of patients receiving prolonged therapy with recommended doses of zolpidem tartrate conventional tablets in clinical trials and in 2% of those receiving placebo. Abdominal discomfort, abdominal tenderness, gastroesophageal reflux disease (GERD), and gastroenteritis each occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Dyspepsia and hiccup have been reported in more than 1% of patients receiving zolpidem tartrate as conventional tablets. Flatulence has occurred in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Anorexia, constipation, dysphagia, flatulence, gastroenteritis, and taste perversion have been reported in 0.1-1% of patients, and altered or increased saliva, enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tenesmus, and dental caries have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Musculoskeletal Effects

Myalgia has been reported in more than 1% of patients receiving zolpidem tartrate as conventional tablets and in 4% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Arthralgia has been reported in more than 1% of patients receiving zolpidem tartrate as conventional tablets and in 2% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Back pain occurred in 3% of patients receiving prolonged therapy with recommended doses of zolpidem tartrate conventional tablets, 4% of adults receiving recommended doses of zolpidem tartrate extended-release tablets, and 2-3% of those receiving placebo. Neck pain occurred in 1-2% of patients receiving recommended doses of zolpidem tartrate extended-release tablets. Muscle cramps occurred in 2% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Arthritis and leg cramps have been reported in 0.1-1% of patients, and arthrosis, muscle weakness, sciatica, tendinitis, and restless legs have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Respiratory Effects

Sinusitis and pharyngitis occurred in 3-4% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets in clinical trials, frequencies slightly higher than those reported in individuals receiving placebo. Nasopharyngitis occurred in 6% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets and in 4% of those receiving placebo. Upper and lower respiratory tract infections each occurred in more than 1% of patients receiving zolpidem tartrate as conventional tablets and in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Bronchitis, coughing, dyspnea, and rhinitis have been reported in 0.1-1% of patients, and bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia, and respiratory depression have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Cardiovascular Effects

Palpitation was reported in 2% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets and in 2% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Increased blood pressure occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Cerebrovascular disorder, hypertension, postural hypotension, edema, chest pain, syncope, and tachycardia have been reported in 0.1-1% of patients, and angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, flushing, hypotension, aggravated hypertension, myocardial infarction, phlebitis, pulmonary embolism, pulmonary or facial edema, varicose veins, and ventricular tachycardia have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Dermatologic and Sensitivity Reactions

Rash occurred in 2% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets, and rash and urticaria each occurred in 1% of patients receiving recommended doses of zolpidem tartrate extended-release tablets. Skin wrinkling occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Pruritus has been reported in 0.1-1% of patients and acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, and urticaria have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Allergy occurred in 4% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets in clinical trials and in 1% of those receiving placebo. Allergic reaction, aggravated allergy, photosensitivity reaction, and anaphylactic shock have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Angioedema involving the tongue, glottis, or larynx has been reported following initial or subsequent doses of sedative and hypnotic drugs, including zolpidem. Some patients have experienced additional symptoms (e.g., dyspnea, closing of the throat, nausea and vomiting) suggestive of anaphylaxis, and some individuals have required medical treatment in an emergency department.(See Cautions: Precautions and Contraindications.)

Local Effects

The effect of chronic daily administration of zolpidem tartrate oral spray on oral tissue has not been established; however, in a pharmacokinetic study in healthy individuals, examination of the oral mucosa following administration of single doses of the oral spray did not reveal evidence of irritation. The effect of chronic daily administration of zolpidem tartrate 5- and 10-mg sublingual tablets on oral tissue has been evaluated in an open-label study of 60 days' duration in 60 patients with insomnia; transient sublingual erythema and transient paresthesia of the tongue each occurred in one patient.

Genitourinary and Renal Effects

Urinary tract infection occurred in more than 1% of patients receiving zolpidem tartrate conventional tablets. Dysuria and vulvovaginal dryness each occurred in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Menorrhagia occurred in 1% of adults receiving recommended doses of zolpidem tartrate extended-release tablets. Cystitis, menstrual disorder, urinary incontinence, and vaginitis have been reported in 0.1-1% of patients, and increased BUN, acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention, and impotence have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Ocular and Otic Effects

Visual disturbance, eye redness, blurred vision, altered visual depth perception, and asthenopia occurred in 1-3% of patients receiving recommended doses of zolpidem tartrate extended-release tablets. Diplopia and abnormal vision were reported in more than 1% of patients; eye irritation, ocular pain, and scleritis were reported in 0.1-1% of patients; and abnormal accommodation, conjunctivitis, corneal ulceration, glaucoma, abnormal lacrimation, periorbital edema, and photopsia were reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Tinnitus and labyrinthitis each have been reported in 1% of adults and otitis externa has been reported in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Tinnitus has been reported in 0.1-1% of patients, and otitis externa and otitis media have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Hepatic Effects

Increased serum concentrations of ALT (SGPT) and abnormal liver function test results have been reported in 0.1-1% of patients, and bilirubinemia, increased serum concentrations of AST (SGOT), and increased serum alkaline phosphatase have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Hematologic Effects

Increased erythrocyte sedimentation rate, anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, and thrombosis have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Other Adverse Effects

Influenza was reported in 3% of adults receiving recommended doses of zolpidem tartrate extended-release tablets in clinical trials. Flu-like symptoms occurred in 2% of patients receiving prolonged therapy (4-5 weeks) with recommended doses of zolpidem tartrate conventional tablets and in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Infection occurred in 0.1-1% of patients receiving zolpidem tartrate as conventional tablets. Chest discomfort, increased body temperature, contusion, and exposure to poisonous plant each occurred in 1% of adults and pyrexia and neck injury each occurred in 1% of geriatric patients receiving recommended doses of zolpidem tartrate extended-release tablets. Falling, fever, hyperglycemia, pallor, thirst, and trauma have been reported in 0.1-1% of patients, and hot flushes, rigors, parosmia, increased drug tolerance, abscess, herpes simplex, herpes zoster, breast fibroadenosis, breast neoplasm, breast pain, gout, hypercholesterolemia, hyperlipidemia, and weight decrease have been reported in less than 0.1% of patients receiving zolpidem tartrate as conventional tablets.

Precautions and Contraindications

Patients and their families should be advised of the benefits and risks of zolpidem therapy. Patients should be instructed about the proper use of zolpidem and that the drug should be taken only as prescribed. Patients should be given a copy of the medication guide provided by the manufacturer, and the contents of this information should be discussed with every patient prior to initiation of therapy. Patients should be instructed to read the medication guide prior to initiation of therapy and each time the prescription is refilled.

Cognitive and Psychomotor Impairment

Zolpidem, like other sedative and hypnotic drugs, has CNS depressant effects and may impair daytime function in some patients even when used as prescribed.(See Next-day Impairment under Cautions: Nervous System Effects.) To decrease the potential risk of next-day impairment, clinicians should prescribe and patients should take the smallest effective dose of zolpidem capable of managing the patient's insomnia. Bedtime dosages of zolpidem that currently are recommended by the manufacturers and the US Food and Drug Administration (FDA) (see Dosage and Administration: Dosage) are lower than the original labeled dosages; the dosage reductions were prompted by concerns about excessively high concentrations of the drug in some patients on the morning after use and the attendant risks of next-day psychomotor impairment. Patients receiving zolpidem should be monitored for excessive CNS depressant effects; however, impairment may occur in the absence of symptoms and may not be reliably detected by ordinary clinical examination (i.e., formal psychomotor testing may be required). Concomitant use of zolpidem with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) increases the risk of additive CNS depression, and reductions in dosage of zolpidem and any concomitant CNS depressants may be necessary. The use of zolpidem with other sedative and hypnotic drugs (including other zolpidem-containing preparations) at bedtime or in the middle of the night is not recommended.

The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem preparations intended for bedtime administration (e.g., conventional tablets, extended-release tablets, oral spray, 5- or 10-mg sublingual tablets) are administered with less than 7-8 hours of sleep time remaining or if zolpidem preparations intended for middle-of-the-night administration (e.g., 1.75- or 3.5-mg sublingual tablets) are administered with less than 4 hours of sleep time remaining. The risk of next-day impairment also is increased if a higher than recommended dose of zolpidem is administered or when zolpidem is used concomitantly with other CNS depressants or with drugs capable of increasing zolpidem concentrations. Women appear to be more susceptible to next-day psychomotor impairment because zolpidem clearance is slower in women than in men.(See Special Populations under Pharmacokinetics: Elimination.) Patients receiving zolpidem should be cautioned against driving a motor vehicle or performing other activities requiring complete mental alertness if the drug is taken in any of the aforementioned circumstances.

Administration of zolpidem as extended-release tablets also increases the risk of next-day impairment and may impair daytime function in some patients even when used as prescribed. Concomitant use of extended-release zolpidem with other CNS depressants, including daytime use of CNS depressants, results in additive effects; reduced dosages of extended-release zolpidem and any concomitant CNS depressants should be considered. Zolpidem tartrate extended-release tablets may not be an appropriate treatment choice for patients who need to drive or perform activities that require full alertness the next morning. While pharmacodynamic tolerance or adaptation to some adverse CNS depressant effects of extended-release zolpidem may develop, concentrations of the drug may remain high enough the next day to impair performance of these activities.

All patients (men and women) receiving zolpidem should be informed of the potential for next-day impairment, that the risk is increased if dosing instructions are not carefully followed, and that impairment may be present despite feeling fully awake. Patients receiving zolpidem tartrate immediate-release preparations intended for bedtime administration (e.g., conventional tablets, oral spray, 5- or 10-mg sublingual tablets) should be advised to wait at least 8 hours after administering zolpidem before driving or engaging in other activities requiring full mental alertness, and those receiving zolpidem tartrate preparations intended for middle-of-the-night administration (e.g., 1.75- or 3.5-mg sublingual tablets) should be advised to wait at least 4 hours and until they feel fully awake before engaging in such activities. Patients receiving zolpidem tartrate extended-release tablets should be cautioned against driving a motor vehicle or performing other activities requiring complete mental alertness on the day after using the drug. Patients should be advised not to use zolpidem if they have consumed alcohol that evening or before bedtime.

Adequate Patient Evaluation

Because sleep disturbances may be a manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7-10 days of zolpidem therapy may indicate the presence of an underlying psychiatric and/or medical condition that should be evaluated. Prolonged use of hypnotics (e.g., for longer than 2-3 weeks) usually is not indicated and should be undertaken only on further evaluation of the patient. Worsening of insomnia or emergence of new thinking or behavioral abnormalities during therapy with sedative and hypnotic drugs, including zolpidem, may be the consequence of an unrecognized psychiatric or physical disorder.

Mood, Thought, and Behavioral Changes

Abnormal thinking and behavioral changes have been reported in patients receiving sedative and hypnotic drugs, including zolpidem. In addition, complex behaviors such as sleep-driving (i.e., driving while not fully awake after ingesting a sedative and hypnotic drug, with no memory of the event), making phone calls, preparing and eating food, or having sex have been reported in patients who were not fully awake after receiving zolpidem. Decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), bizarre behavior, agitation, depersonalization, and visual and auditory hallucinations also have been associated with use of these drugs; amnesia, anxiety, and other neuropsychiatric symptoms also may occur. Therefore, the emergence of any new behavioral sign or symptom of concern in patients receiving zolpidem requires careful and immediate evaluation. Patients should be advised of the potential risk of abnormal thinking and behavioral changes, and to immediately inform their clinician if any such changes occur. Because of the risk to the patient and the community, discontinuance of zolpidem should be strongly considered for patients who report a sleep-driving episode.

In primarily depressed patients receiving treatment with sedative and hypnotic drugs, 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 patient population; therefore, the least amount of zolpidem that is feasible should be prescribed for such patients at any one time. Patients should be advised to immediately inform their clinician if any suicidal thoughts occur.

Respiratory Depression

Although clinical studies did not reveal respiratory depressant effects following 10-mg doses of zolpidem tartrate in healthy individuals or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), decreased oxygen saturation was observed in patients with mild-to-moderate sleep apnea. Respiratory insufficiency has been reported during postmarketing experience in patients receiving 10-mg doses of zolpidem tartrate, most of whom had preexisting respiratory impairment. Since sedative and hypnotic drugs have the capacity to depress respiratory drive, the drug should be used with caution in patients with compromised respiratory function. The risk of respiratory depression should be considered prior to use of zolpidem in patients with respiratory impairment, including those with sleep apnea or myasthenia gravis.

Tolerance, Dependence, and Abuse

Because manifestations of withdrawal have been reported following abrupt discontinuance or rapid reduction in dosage of zolpidem, patients should be monitored for tolerance, abuse, and dependence. Withdrawal symptoms associated with sedative and hypnotic drugs range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and seizures. In clinical trials with zolpidem in the US, manifestations of uncomplicated sedative and hypnotic withdrawal, including fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort, were reported after placebo substitution within 48 hours following the last dose of the drug. These adverse events occurred in 1% or less of patients. Available data cannot provide a reliable estimate of the frequency, if any, of dependency during therapy with recommended dosages of zolpidem. Studies of abuse potential in former drug abusers found that the effects of single 40-mg doses of zolpidem tartrate and 20-mg doses of diazepam were similar but not identical, while the effects of a 10-mg dose of zolpidem tartrate were difficult to distinguish from those of placebo. Because patients with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse or abuse of or addiction to zolpidem, such patients should be monitored carefully when receiving zolpidem or any other hypnotic drug. Patients should be advised not to increase the dosage of zolpidem and to inform their clinician if the drug is not effective.

Other Precautions and Contraindications

Angioedema involving the tongue, glottis, or larynx has been reported following initial or subsequent doses of sedative and hypnotic drugs, including zolpidem, and may result in airway obstruction and death. Anaphylaxis also has occurred. Patients who develop angioedema following treatment with zolpidem should not be rechallenged with the drug. Patients should be informed of the potential risk of severe anaphylactic and anaphylactoid reactions, informed of the signs and symptoms of such reactions, and advised to immediately seek medical attention if such reactions occur.

Because elimination of zolpidem is prolonged in patients with hepatic impairment, reduced doses of the drug should be used in patients with hepatic impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) The manufacturers and some clinicians state that dosage adjustment is not necessary in patients with renal impairment. Other clinicians, however, state that the possibility that dosage reduction may be needed for patients with renal disease should be considered because of slower zolpidem elimination rates and other pharmacokinetic alterations observed in nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis.

Zolpidem tartrate is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Zolpidem tartrate is not recommended for use in pediatric patients. Safety and efficacy of the drug have not been established in pediatric patients younger than 18 years of age. In an 8-week clinical study in pediatric patients (6-17 years of age) with insomnia associated with attention deficit hyperactivity disorder (ADHD), zolpidem tartrate (0.25 mg/kg administered as an oral solution at bedtime) did not appear to decrease sleep latency as compared with placebo. In this study, the most frequent treatment-emergent adverse effects (compared with placebo) were nervous system effects, including dizziness (23.5 versus 1.5%), headache (12.5 versus 9.2%), and hallucinations (7 versus 0%).

Geriatric Precautions

Safety and efficacy of zolpidem for the treatment of insomnia in geriatric patients has been evaluated in controlled, double-blind studies. Geriatric or debilitated patients may be particularly sensitive to the effects of zolpidem. Adverse effects of the drug tend to be dose related, particularly in geriatric patients. In addition, peak plasma zolpidem concentrations, elimination half-life, and area under the plasma concentration-time curve (AUC) are increased substantially in geriatric patients compared with younger adults receiving zolpidem tartrate as conventional tablets.

In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate doses of 10 mg or less (as conventional tablets), the most frequent adverse effects were dizziness, drowsiness, and diarrhea. Dizziness, drowsiness, or diarrhea was reported in 3, 5, or 3% of patients receiving the drug, respectively, while such adverse effects occurred in 0, 2, or 1% of patients receiving placebo, respectively. In placebo-controlled clinical trials in geriatric patients receiving zolpidem tartrate 6.25 mg as extended-release tablets, the most frequent adverse effects were headache, dizziness, and next-day somnolence. Headache, dizziness, or next-day somnolence was reported in 14, 8, or 6% of patients receiving the drug, respectively, while such adverse effects occurred in 11, 3, or 5% of patients receiving placebo, respectively. In clinical trials performed outside the US, involving approximately 2000 patients, falls were reported in about 1.5% of patients (93% of those being 70 years of age or older); 82% of the patients 70 years of age or older who experienced falls received zolpidem tartrate doses exceeding 10 mg (as conventional tablets). In these clinical trials, confusion was reported in 1.2% of patients (75% of those being 70 years of age or older); 78% of the patients 70 years of age or older who experienced confusion were receiving doses exceeding 10 mg (as conventional tablets).

The manufacturers recommend that zolpidem dosage be reduced in geriatric and/or debilitated patients to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative and hypnotic drugs.(See Dosage and Administration: Dosage.) Sedatives may cause confusion and oversedation in geriatric patients; geriatric patients should be observed closely.

Mutagenicity and Carcinogenicity

Zolpidem was not mutagenic when tested in vitro in bacterial reverse mutation, mouse lymphoma, and chromosomal aberration assays or in vivo in the mouse micronucleus assay.

Carcinogenicity studies in animals were performed using zolpidem rather than zolpidem tartrate; dosages in these studies are expressed in terms of the base. Studies to determine the carcinogenic potential of zolpidem were performed in mice and rats receiving oral dosages of 4, 18, and 80 mg/kg daily for 2 years. In mice, these dosages were approximately 2.5, 10, and 50 times, respectively, the maximum recommended human dosage (MRHD) of zolpidem tartrate as conventional tablets (10 mg daily) on a mg/m basis. In rats, these dosages were approximately 5, 20, and 100 times, respectively, the MRHD of zolpidem tartrate as conventional tablets on a mg/m basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were observed at the mid- and high-dosage levels.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies to date evaluating zolpidem tartrate in pregnant women, and the drug should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, severe neonatal respiratory depression has been reported when zolpidem was used at the end of pregnancy, particularly when used concomitantly with other CNS depressants. In addition, children born to women receiving sedative or hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity also has been reported in infants whose mothers received sedative or hypnotic drugs during pregnancy. Zolpidem has no established use in labor and delivery.

Reproduction studies in animals were performed using zolpidem rather than zolpidem tartrate; dosages are expressed in terms of the base. Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at dosages exceeding the maximum recommended human dosage (MRHD) of zolpidem tartrate as conventional tablets (10 mg daily); however, teratogenicity was not observed. When zolpidem was administered at oral dosages of 4, 20, and 100 mg/kg daily to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dosage (4 mg/kg daily, which is approximately 5 times the MRHD of zolpidem tartrate as conventional tablets on a mg/m basis). In addition, administration of zolpidem to rats at oral dosages of 4, 20, and 100 mg/kg daily during the latter part of pregnancy and throughout lactation decreased offspring growth and survival at all but the lowest dosage. In rabbits receiving zolpidem during organogenesis at oral dosages of 1, 4, and 16 mg/kg daily, increased embryofetal death and incomplete fetal skeletal ossification occurred at the highest dosage studied. The no-effect dosage for embryofetal toxicity in rabbits is approximately 10 times the MRHD of zolpidem tartrate as conventional tablets on a mg/m basis.

Fertility

Oral administration of zolpidem at dosages of 4, 20, and 100 mg/kg daily to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dosage studied. The no-effect dosage for these findings is approximately 24 times the MRHD of zolpidem tartrate as conventional tablets on a mg/m basis. There was no evidence of impaired fertility at any dosage studied.

Lactation

Zolpidem is distributed into milk in small amounts in humans. The effect, if any, of zolpidem on the nursing infant is not known. Caution should be exercised when zolpidem is used in nursing women, and infants should be monitored closely for increased sedation, lethargy, and changes in feeding habits.

Drug Interactions

Zolpidem is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP1A2 and CYP2D6.

Drugs Affecting Hepatic Microsomal Enzymes

Some drugs that inhibit CYP3A may increase systemic exposure to zolpidem.(See Drug Interactions: Ketoconazole.) The effect of inhibitors of other CYP isoenzymes on the pharmacokinetics (e.g., systemic exposure) of zolpidem is not known.

CNS Depressants

Concomitant use of zolpidem with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, tricyclic antidepressants) increases the risk of CNS depression.(See Cognitive and Psychomotor Impairment under Cautions: Precautions and Contraindications.) Concomitant use of alcohol with zolpidem results in an additive adverse effect on psychomotor performance. When zolpidem is used concomitantly with other CNS depressants, dosage adjustments of zolpidem and the concomitant CNS depressant may be necessary because of potentially additive effects.(See Dosage and Administration: Dosage.) Concomitant use of zolpidem with other sedative and hypnotic drugs (including other zolpidem-containing preparations) at bedtime or in the middle of the night is not recommended.

Chlorpromazine

Pharmacokinetic interactions have not been observed during concomitant use of zolpidem and chlorpromazine; however, additive effects in reducing alertness and psychomotor performance have been observed.

Cimetidine

Cimetidine does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem.

Digoxin

Zolpidem had no effect on digoxin pharmacokinetics in healthy individuals.

Fluoxetine

Clinically important pharmacokinetic or pharmacodynamic interactions have not been observed when zolpidem was used concomitantly with fluoxetine in healthy individuals. In healthy men, concomitant use of fluoxetine (20 mg once daily for 17 days) with zolpidem tartrate (single 10-mg dose) resulted in no clinically important changes in the pharmacokinetics of zolpidem or fluoxetine, and no substantial changes in performance on psychomotor tests were observed. In healthy women, concomitant use of fluoxetine (20 mg once daily for 30 days) with zolpidem tartrate (10 mg once daily for 5 days) increased the half-life of zolpidem by 17%, but there was no evidence of additive effects on psychomotor function.

Haloperidol

Haloperidol does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem. However, the lack of an interaction following single-dose administration does not predict the absence of an effect following chronic administration.

Imipramine

Concomitant use of zolpidem and imipramine has been associated with a 20% decrease in peak plasma concentrations of imipramine; although other pharmacokinetic interactions have not been observed, an additive effect in reducing alertness has been observed during concomitant use.

Itraconazole

Concomitant use of the potent CYP3A4 inhibitor itraconazole (200 mg once daily for 4 days) with zolpidem tartrate (single 10-mg dose) in healthy individuals increased the area under the serum concentration-time curve (AUC) of zolpidem by 34% but did not substantially alter patient ratings of drowsiness, performance on psychomotor tests, or postural sway compared with zolpidem alone.

Ketoconazole

Concomitant use of the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily for 2 days) with zolpidem tartrate (single 5-mg dose) increased the peak plasma concentration, AUC, and elimination half-life of zolpidem by 30, 70, and 30%, respectively, and also increased pharmacodynamic effects of zolpidem. Because concomitant use may increase the hypnotic effects of zolpidem, a lower dose of zolpidem should be considered when the drug is used concomitantly with ketoconazole.

Ranitidine

Ranitidine does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem.

Rifampin

Rifampin, a potent CYP3A4 inducer, substantially reduces systemic exposure to and pharmacodynamic effects of zolpidem. Concomitant use with rifampin may decrease the hypnotic efficacy of zolpidem. In healthy women, concomitant use of zolpidem tartrate (single 20-mg dose) and rifampin (600 mg once daily for 5 days) reduced AUC, peak plasma concentration, and half-life of zolpidem by 73, 58, and 36%, respectively; substantial reductions in the effects of zolpidem on psychomotor performance also were observed.

Sertraline

Concomitant use of zolpidem and sertraline increases systemic exposure to zolpidem and may increase the pharmacodynamic effects of zolpidem, potentially resulting in earlier hypnotic onset and greater hypnotic effect. When zolpidem tartrate (10 mg daily at bedtime for 5 days) was used concomitantly with sertraline (50 mg daily in the morning for 17 days) in healthy women, peak plasma concentration of zolpidem was increased by 43% and time to peak plasma concentration of zolpidem was decreased by 53%. Zolpidem did not appear to have clinically important effects on the pharmacokinetics of sertraline or N-desmethylsertraline.

Warfarin

Zolpidem did not appear to affect prothrombin time (PT) when used concomitantly with warfarin in healthy individuals.

Pharmacokinetics

Absorption

Bioavailability

Conventional tablets: Zolpidem is rapidly absorbed from the GI tract following oral administration as conventional tablets, with peak plasma concentrations attained in about 1.6 hours. Absolute bioavailability is about 70%.

Extended-release tablets: The extended-release tablets exhibit biphasic absorption characteristics; there is rapid initial absorption following oral administration (similar to conventional tablets), but with extended plasma concentrations beyond 3 hours after administration. Peak plasma concentrations are attained in about 1.5 hours.

Oral spray: The oral spray is bioequivalent to conventional tablets. Zolpidem is rapidly absorbed from the oral mucosa and GI tract, with peak plasma concentrations attained in about 0.9 hours.

Sublingual tablets (Edluar): The sublingual tablets are bioequivalent to conventional tablets with respect to peak plasma concentration and area under the concentration-time curve (AUC). Like conventional tablets, the sublingual tablets result in a pharmacokinetic profile characterized by rapid absorption. Peak plasma concentrations are attained in approximately 82 minutes.

Sublingual tablets (Intermezzo): The sublingual tablets disintegrate in the sublingual cavity following administration and the drug is rapidly absorbed in both men and women, with peak plasma concentrations attained in about 35-75 minutes.

Food

Conventional tablets: Food decreases AUC by 15%, decreases peak plasma concentration by 25%, and prolongs time to peak plasma concentration by 60%.

Extended-release tablets: Food decreases AUC by 23%, decreases peak plasma concentration by 30%, and prolongs time to peak plasma concentration by about 2 hours (from 2 hours to 4 hours).

Oral spray: Food decreases AUC by 27%, decreases peak plasma concentration by 58%, and prolongs time to peak plasma concentration by 225% (from 0.8 hours to 2.6 hours).

Sublingual tablets (Edluar): Food decreases AUC by 20%, decreases peak plasma concentration by 31%, and prolongs time to peak plasma concentration by 28% (from 82 minutes to 105 minutes).

Sublingual tablets (Intermezzo): Food decreases AUC by 19%, decreases peak plasma concentration by 42%, and prolongs time to peak plasma concentration to nearly 3 hours.

Plasma Concentrations

Driving simulation and laboratory studies indicate that zolpidem blood concentrations exceeding approximately 50 ng/mL appear to be capable of impairing driving to a degree that increases the risk of a motor vehicle accident.(See Next-day Impairment under Cautions: Nervous System Effects.)

Special Populations

In women receiving zolpidem tartrate as an immediate-release formulation, peak plasma concentration and AUC of zolpidem are approximately 45% higher than values attained in men receiving the same dose. In women receiving zolpidem tartrate as extended-release tablets, peak plasma concentration and AUC of zolpidem are approximately 50 and 75% higher, respectively, than values attained in men receiving the same dose. Zolpidem concentrations measured 6-12 hours after administration of zolpidem tartrate as extended-release tablets are 2-3 times higher in women compared with men.(See Special Populations under Pharmacokinetics: Elimination.)

In geriatric individuals receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are increased by 50 and 64%, respectively, compared with younger adults receiving the same dose. In geriatric individuals receiving a 3.5-mg dose of zolpidem tartrate as sublingual tablets, peak plasma concentration and AUC are increased by 34 and 30%, respectively, compared with younger adults receiving the same dose; likewise, peak plasma concentration and AUC are consistently higher in geriatric individuals receiving a 1.75-mg dose than in younger adults receiving a 1.75-mg dose, but are consistently lower in geriatric individuals receiving a 1.75-mg dose than in younger adults receiving a 3.5-mg dose.

In patients with chronic hepatic impairment receiving zolpidem tartrate as conventional tablets, peak plasma concentration and AUC are 2 and 5 times higher, respectively, than in healthy individuals. Zolpidem tartrate extended-release tablets have not been studied to date in patients with hepatic impairment.

Distribution

Extent

Zolpidem is distributed into milk in small amounts.

Plasma Protein Binding

Zolpidem is approximately 92-93% bound to plasma proteins.

Elimination

Metabolism

Zolpidem is metabolized in the liver via oxidation and hydroxylation, principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP1A2 and CYP2D6, to form inactive metabolites.

Elimination Route

Zolpidem is excreted principally in urine as inactive metabolites.

Half-life

The half-life of zolpidem is approximately 2.5-3 hours.

Special Populations

Zolpidem is eliminated more slowly in women than in men. Lower doses are recommended for women since use of the same dose in women and men would result in greater drug exposure and increased susceptibility to next-day impairment in women. In the geriatric population, clearance of zolpidem is similar in men and women and dosage is not gender specific.(See Special Populations under Pharmacokinetics: Absorption; see Next-day Impairment under Cautions: Nervous System Effects; and see Dosage and Administration: Dosage.)

In geriatric patients receiving zolpidem tartrate as conventional or extended-release tablets, the half-life of the drug is 2.9 hours. In geriatric patients receiving the drug as conventional tablets, the half-life reportedly is increased by 32% compared with younger adults; in those receiving the drug as sublingual tablets (Intermezzo), the half-life reportedly is unchanged compared with younger adults.

In patients with cirrhosis receiving zolpidem tartrate as conventional tablets, half-life is about 9.9 hours. Zolpidem tartrate extended-release tablets have not been studied to date in patients with hepatic impairment.

In nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis, slower elimination rates have been reported with IV zolpidem (not commercially available in the US). No substantial pharmacokinetic alterations have been reported with oral zolpidem in patients with end-stage renal failure undergoing hemodialysis. Zolpidem tartrate extended-release tablets have not been studied to date in patients with renal impairment.

Zolpidem is not removed by hemodialysis.

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