section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Zolpidem tartrate, a type A γ-aminobutyric acid (GABAA)-receptor positive modulator of the imidazopyridine class, is a sedative and hypnotic agent structurally unrelated to the benzodiazepines and other sedative and hypnotic agents.1,2,3,4,89,93,94

Uses ⬆ ⬇

[Section Outline]

Insomnia !!navigator!!

Zolpidem tartrate as conventional tablets or sublingual tablets (5 and 10 mg) is used as a hypnotic agent in the short-term management of insomnia characterized by difficulties with sleep initiation.1,93 Because zolpidem has a short half-life, the drug may be of particular benefit in the initiation of sleep (i.e., decreasing sleep latency).1,3,22 In controlled clinical studies, the drug reportedly has been effective in decreasing sleep latency1,2,3,22 for periods up to 35 days in duration.1

Zolpidem tartrate as extended-release tablets is used for the short-term treatment of insomnia characterized by difficulty with sleep onset or sleep maintenance.89 However, the extended-release tablets may not be an appropriate treatment choice for patients with insomnia who need to drive or perform activities that require full alertness the next morning.95 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]).89 In one study in 212 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.89 In a similarly designed study in 205 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.89 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.89 In a 24-week, randomized, double-blind, placebo-controlled clinical trial in 1025 adults 18-64 years of age with chronic primary insomnia, zolpidem tartrate (12.5-mg administered as needed 3-7 nights per week as extended-release tablets) was 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.89,97

Zolpidem tartrate as sublingual tablets (1.75 and 3.5 mg) is used as needed for the management of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep.94 The drug should be used in this manner only when 4 or more hours remain before the patient plans to awaken.94 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.94,98,99 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;94,98 the effect on sleep latency was similar for women receiving a 1.75-mg dose and men receiving a 3.5-mg dose.94 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.94,99

Hypnotics with a relatively short half-life may be more likely to result in transient rebound insomnia after discontinuance23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,45,47,54,55,56,58,60,61,62,63,64,65,66,68,70,71,72,73,74,75,76 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.23,24,25,27,28,30,34,43,47,48,50,51,53,55,56,57,58,59,60,61,62,63,68 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,1,14,19,20 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.1 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.89 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.89

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.23,24,25,26,27,28,34,41,42,44,45,46,47,49,52,53,54,55,58,59,60,61,62,65,67,68,69 Residual daytime sedative effects of zolpidem were evaluated in several placebo-controlled studies in healthy adults and in geriatric individuals.1 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.1 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.1 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.89 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.89 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.89,97 The minimal effect of zolpidem on sleep stages at usual hypnotic dosages may offer a therapeutic advantage. 2,3,4 However, the fact that zolpidem has minimal anxiolytic and muscle relaxant properties at usual hypnotic doses also should be considered.1,2,3,4,6,7 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 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.95

Clinical Perspective

The American Academy of Sleep Medicine (AASM) and the American College of Physicians (ACP) have published clinical guidelines for the treatment of insomnia in adults.204,205,206 According to these guidelines, the goals of insomnia treatment are to improve sleep quality and quantity and to reduce insomnia-related daytime impairment, distress, and dysfunction.204,206 When possible, psychological and behavioral interventions are recommended as initial treatment.204,205,206 Pharmacologic therapy should be considered mainly in patients who are unable or unwilling to participate in cognitive behavioral therapy, are unresponsive to such therapy, or, in select cases, as a temporary adjunct to such therapy.205 When pharmacologic therapy is indicated, the choice of agent should be directed by symptoms, treatment goals, past treatment response, patient preference, drug cost and availability, comorbid conditions/contraindications, concomitant drug therapy/interactions, and potential adverse effects.204,205 Data on comparative efficacy of various sedative hypnotic agents are limited, and an individualized and shared decision-making approach between patients and clinicians is advised.205,206

Zolpidem is among several agents recommended for the treatment of sleep onset or sleep maintenance insomnia.204,205,206 Pharmacologic therapy should be used at the lowest effective dosage and should be short-term (e.g., 4-5 weeks) in duration;204,206 chronic use should be reserved for those individuals for whom cognitive behavioral therapy is either inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term benefits with medication, and who are followed regularly.205 Patient monitoring should include ongoing assessment of effectiveness, monitoring for adverse effects, and evaluation for new onset or exacerbation of existing comorbid disorders.204

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Other General Considerations

Administration !!navigator!!

Zolpidem tartrate is administered orally (as conventional tablets or extended-release tablets) or sublingually (as sublingual tablets).1,89,93,94

Oral Administration

Zolpidem tartrate is administered orally at bedtime.1,89 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.1,89 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.1,89

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.89 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.89

Zolpidem tartrate extended-release tablets should be swallowed whole and should not be divided, crushed, or chewed.89

Sublingual Administration

Zolpidem tartrate 5- and 10-mg sublingual tablets 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.93 The tablet should be placed under the tongue, where it will disintegrate.93 The tablet should not be swallowed or administered with water.93 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.93

Zolpidem tartrate 1.75- and 3.5-mg sublingual tablets 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.94 The tablet should be placed under the tongue and allowed to disintegrate completely before swallowing.94 The tablet should not be swallowed whole.94 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.94 The tablet should be removed from the pouch just prior to administration.94

Dosage !!navigator!!

The lowest effective dosage of zolpidem tartrate should be used.1,89,93,95,200 Long-term use of zolpidem is not recommended; treatment duration should be as short as possible.1,89 Extended treatment should not take place without re-evaluation of the patient's status; risk of abuse and dependence increases with the duration of treatment.1,89

The recommended initial doses of zolpidem tartrate for women and men differ because clearance of the drug is slower in women.1,89,94,95

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.1,89 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;1,4,23,77,78,89 this effect may occur with some sedative and hypnotic drugs even after relatively short periods of therapy (e.g., 1 week).1,23,77,78,89 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.1,77,78

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) is a single dose of 5 mg in women and either 5 or 10 mg in men.1,95 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.1,95

For the management of insomnia characterized by difficulties 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.89,95 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.89,95

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.1,89,95 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.1,89

If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.1,89

Sublingual Dosage

For the short-term management of insomnia characterized by difficulties with sleep initiation, the recommended initial dose of zolpidem tartrate sublingual tablets is 5 mg for women and either 5 or 10 mg for men.93,95 If the 5-mg dose is not effective in men or women, the dose may be increased to 10 mg.93,95 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.93,95 Total dosage should not exceed 10 mg given once daily immediately before bedtime.93 If zolpidem is used concomitantly with other CNS depressants, dosage adjustment of zolpidem and the concomitantly administered agent(s) may be necessary because of potentially additive effects.93

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 is 1.75 mg for women and 3.5 mg for men.94

In patients 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.94

Special Populations !!navigator!!

Hepatic Impairment

Zolpidem tartrate conventional tablets: For the management of insomnia characterized by difficulties with sleep initiation, the recommended dosage of zolpidem tartrate conventional tablets in patients with mild or moderate hepatic impairment is 5 mg once daily immediately before bedtime.1

Zolpidem tartrate sublingual tablets: For the management of insomnia characterized by difficulties with sleep initiation, the recommended dosage of zolpidem tartrate sublingual tablets in patients with any degree of hepatic impairment is 5 mg once daily immediately before bedtime.93

Zolpidem tartrate sublingual tablets: 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 any degree of hepatic impairment is 1.75 mg once per night if needed.94

Zolpidem tartrate extended-release tablets: For the management of insomnia characterized by difficulty with sleep initiation or sleep maintenance in patients with mild or moderate hepatic impairment, the recommended dosage of zolpidem tartrate as extended-release tablets is 6.25 mg once daily immediately before bedtime.89

In patients with severe hepatic impairment, zolpidem may contribute to the occurrence of encephalopathy; the manufacturer of zolpidem conventional and extended-release tablets states that use should be avoided in such patients.1,89

Renal Impairment

The manufacturers and some clinicians state that dosage adjustment is not necessary in patients with renal impairment.1,80,89,93,94 Other clinicians, however, state that the possibility that dosage reduction may be needed for patients with renal disease should be considered2,3,81 because of slower zolpidem elimination rates and other pharmacokinetic alterations observed in nondialyzed patients with chronic renal disease and in patients undergoing periodic dialysis.2,3,81

Geriatric or Debilitated Patients

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.1,89

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.93

In patients >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.94

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Complex Sleep Behaviors

Complex sleep behaviors such as sleepwalking, sleep driving (i.e., driving while not fully awake after ingesting a sedative-hypnotic drug, with no memory of the event), and engaging in other activities (e.g., making phone calls, preparing and eating food) while not fully awake have been reported in patients receiving sedative and hypnotic drugs.1,89,91,93,94,200 A boxed warning about the risk of complex sleep behaviors is included in the prescribing information for zolpidem.1,89,93,94 Such complex sleep behaviors can result in serious injury and/or death.1,89,93,94,200 Complex sleep behaviors appear to be more common with eszopiclone, zaleplon, and zolpidem than other prescription medicines used for sleep.200 Patients usually have no memory of the events.1 These behaviors may occur when zolpidem is used alone at recommended doses or when used concomitantly with alcohol or other CNS depressants.1,89,93,94,200,1 Serious injuries and fatalities from complex sleep behaviors have occurred in patients with and without a history of such behaviors and can occur even at the lowest recommended dosages and after just one dose of the hypnotic agent.200 Discontinue zolpidem immediately in patients who experience a complex sleep behavior.1,89,93,94,200

A total of 66 cases of complex sleep behaviors resulting in serious injuries or death in patients who took eszopiclone, zaleplon, or zolpidem were reported to the FDA Adverse Event Reporting System (FAERS) database and/or in published literature between December 1992 and March 2018.200,201,202,203 Of the 66 cases, 20 were reported as resulting in fatal outcomes and 46 reported serious nonfatal injuries; in the nonfatal cases, patients usually did not remember experiencing these complex sleep behaviors.200 These cases included falls with serious injuries such as intracranial hemorrhages, vertebral fractures, and hip fractures as well as fatal falls, self-injuries, accidental overdoses, hypothermia, suicide attempts and apparent completed suicides, fatal motor vehicle collisions, gunshot wounds, carbon monoxide poisoning, drowning or near drowning, burns, and homicide.200,201,202,203 Most of the patients in these cases reported using zolpidem (about 92%) when they experienced the complex sleep behavior; the remaining patients took eszopiclone (about 5%) or zaleplon (about 3%), reflecting the higher number of zolpidem prescriptions that were dispensed over this period compared with eszopiclone and zaleplon.200 The underlying mechanisms by which these drugs cause complex sleep behaviors are not fully understood.200

Other Warnings and Precautions

CNS Depression and Next-day Impairment

Like other sedative-hypnotic drugs, zolpidem has CNS-depressant effects and may impair daytime function in some patients even when used as prescribed.1,89,93,94,95,96 To decrease the potential risk of next-day impairment, clinicians should prescribe and patients should take the smallest effective dose.95 Bedtime dosages of zolpidem that currently are recommended by the manufacturers and FDA are lower than the original labeled dosages; such 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.95,96 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).89 Drowsiness and decreased levels of consciousness associated with zolpidem may result in an increased risk of falls, particularly in geriatric patients.1,89,93,94 In order to minimize the risk of CNS effects, a full night of sleep (7-8 hours) is recommended.1,89

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.1,89,93,94 Patients taking zolpidem should be advised of the importance of not consuming alcohol in the evening or before bedtime.1,89,93,94 The use of zolpidem with other sedative and hypnotic drugs (including other zolpidem-containing preparations and OTC preparations used to treat insomnia at bedtime or in the middle of the night) also is not recommended.1,89,93,94,200

All patients 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.1,89,93,94,95 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, 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.1,89,93,94 Therefore, patients receiving zolpidem tartrate immediate-release preparations intended for bedtime administration (e.g., conventional tablets, 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.1,93,94 Patients receiving zolpidem tartrate extended-release tablets should also be cautioned against driving a motor vehicle or performing other activities requiring complete mental alertness on the day after using the drug.89 Patients should be advised not to use zolpidem if they have consumed alcohol that evening or before bedtime.1,89,93,94

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.95 The risk for next-morning impairment is highest for patients receiving extended-release preparations of the drug.95 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.95 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.89,96 In addition, women appear to be more susceptible than men to next-day psychomotor impairment because clearance of zolpidem is slower in women than in men.95 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.95 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.95 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.95

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.94 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.94 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.94 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.94 Blood concentrations of zolpidem were not measured.94 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.94 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.94 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.94

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.1,89 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.1,89 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.23,79 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.1,89

Severe Hypersensitivity Reactions

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.1,89,91 Anaphylaxis also has occurred.1,89 Patients who develop angioedema following treatment with zolpidem should not be rechallenged with the drug.1,89,91

Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavioral changes have been reported in patients receiving sedative and hypnotic drugs, including zolpidem.1,89 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.1,89 Amnesia, anxiety, and other neuropsychiatric symptoms also may occur.1,89 Cases of delirium also have been reported.1,89

The emergence of any new behavioral sign or symptom of concern in patients receiving zolpidem requires careful and immediate evaluation.1,89

Use in Patients with Depression

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.1,89 Suicidal tendencies may be present in such patients, and protective measures may be required.1,89 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.1,89 Patients should be advised to immediately inform their clinician if any suicidal thoughts occur.1,89

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),1,85 decreased oxygen saturation was observed in patients with mild-to-moderate sleep apnea.1,86,89 Respiratory insufficiency has been reported during postmarketing experience in patients receiving 10-mg doses of zolpidem tartrate, most of whom had preexisting respiratory impairment.1,89 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 and in patients receiving concomitant opiates or other CNS depressants.1,89 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 or in those receiving concomitant opiates or other CNS depressants.1,89

Precipitation of Hepatic Encephalopathy

Precipitation of hepatic encephalopathy has been reported in patients with hepatic insufficiency receiving drugs affecting GABA receptors (e.g., zolpidem tartrate).1,89 In addition, zolpidem is eliminated more slowly in patients with hepatic insufficiency.1,89 Avoid use of zolpidem conventional or extended-release tablets in patients with severe hepatic impairment.1,89

Tolerance, Dependence, and Abuse

Use of zolpidem may lead to the development of physical and/or psychological dependence.1,89 The risk of dependence increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse.1,89

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.1,89 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, seizures, and delirium.1,89 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.1,89 These adverse events occurred in 1% or less of patients.1,89 Available data cannot provide a reliable estimate of the frequency, if any, of dependency during therapy with recommended dosages of zolpidem.1,89 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.1,89 Because patients with a current or past history of addiction to or abuse of drugs or alcohol are at increased risk for misuse or abuse of or addiction to zolpidem, the drug should be used with extreme caution in such patients.1,89 Patients should be advised not to increase the dosage of zolpidem and to inform their clinician if the drug is not effective.1,89 Long-term use of zolpidem is not recommended; treatment duration should be as short as possible.1,89 Extended treatment should not take place without reevaluation of the patient's status; risk of abuse and dependence increases with the duration of treatment.1,89

Specific Populations

Pregnancy

Published data from observational studies, birth registries, and case reports do not report a clear association between use of zolpidem and major birth defects.1,89,93 There are limited postmarketing reports of moderate to severe neonatal respiratory depression requiring artificial ventilation or intratracheal intubation when zolpidem was used late in the third trimester of pregnancy; the majority of neonates recovered within hours to a few weeks after birth once treated.1,89,93

Zolpidem crosses the placenta and may cause respiratory depression and sedation in neonates.1,89,93 Neonates exposed to zolpidem during pregnancy and labor should be monitored for signs of excess sedation, hypotonia, and respiratory depression and treated as clinically appropriate.1,89,93

Reproduction studies in animals were performed using zolpidem rather than zolpidem tartrate; dosages are expressed in terms of the base.1,89 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.1 When zolpidem was administered at oral dosages of 4, 20, and 100 mg/kg daily to pregnant rats during the period of organogenesis, delayed fetal development (incomplete 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/m2 basis).1,89,93 In addition, administration of zolpidem to rats at oral dosages of 4, 20, and 100 mg/kg daily from day 15 of gestation through lactation delayed offspring growth and decreased survival at all but the lowest dosage.1,89,93 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.1,89,93 No risk of adverse effects on fetal development was observed following oral administration of zolpidem to pregnant rats and rabbits at clinically relevant doses.1,89,93

Lactation

Zolpidem is distributed into milk in small amounts in humans.1,84,89,93,94,100 Excess sedation has been reported in nursing infants exposed to zolpidem through breast milk.1,89,93 The effects of zolpidem on milk production are not known.1,89,93

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for zolpidem and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1,89,93 Infants exposed to zolpidem through breast milk should be monitored for excess sedation, hypotonia, and respiratory depression.1,89,93 Nursing women may consider interrupting breast-feeding and pumping and discarding breast milk during treatment and for 23 hours after administration of zolpidem to minimize drug exposure to a breast-fed infant.1,89,93

Pediatric Use

Zolpidem tartrate is not recommended for use in pediatric patients.1,89,93,94 Safety and efficacy of the drug have not been established in pediatric patients younger than 18 years of age.1,89,93,94 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.1,89 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%).1,89

Geriatric Use

Safety and efficacy of zolpidem for the treatment of insomnia in geriatric patients have been evaluated in controlled, double-blind studies.1,89 Geriatric or debilitated patients may be particularly sensitive to the effects of zolpidem.1,89 Adverse effects of the drug tend to be dose-related,1,2,4,9,82,89 particularly in geriatric patients.1,2,9 In addition, peak plasma zolpidem concentrations, elimination half-life, and AUC are increased substantially in geriatric patients compared with younger adults receiving zolpidem tartrate as conventional tablets.1

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.1 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.89 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).1 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).1

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.1,89,93,94 Sedatives may cause confusion and oversedation in geriatric patients; geriatric patients should be observed closely.94 Geriatric patients are at a higher risk of falls related to drowsiness and CNS depression caused by zolpidem.1,89,93,94

Hepatic Impairment

Elimination of zolpidem tartrate is prolonged in patients with hepatic impairment; dosage should be reduced in patients with mild or moderate hepatic impairment.1,81,89

Avoid use of zolpidem conventional or extended-release tablets in patients with severe hepatic impairment since the drug may contribute to hepatic encephalopathy.1,89

Renal Impairment

Pharmacokinetic alterations are possible in patients with renal impairment.2,3,81 Manufacturers state that dosage adjustment of zolpidem is not necessary;1,89,93,94 however, some clinicians recommend that dosage reduction be considered.2,3,81

Common Adverse Effects !!navigator!!

Zolpidem tartrate conventional tablets generally are well tolerated at recommended doses (i.e., up to 10 mg).1,2,9 Adverse effects of the drug tend to be dose-related,1,2,4,9,82 particularly in geriatric patients1,2,9 and at doses exceeding those recommended.2,3,4,9 The most common adverse reactions with zolpidem conventional tablets when used in the short-term (<10 nights) include drowsiness, dizziness, and diarrhea; common adverse reactions reported with long-term use (28-35 nights) of the conventional tablets include dizziness and drugged feeling.1

Adverse effects of zolpidem tartrate as extended-release tablets tend to be dose-related, particularly for certain adverse nervous system and GI effects.89 The most common adverse effects of zolpidem tartrate as extended-release tablets (occurring in >10% of adult patients) include headache, next-day somnolence, and dizziness.89

The incidence of adverse effects in patients receiving zolpidem tartrate as 1.75- or 3.5-mg sublingual tablets were headache, fatigue, and nausea.94

Drug Interactions ⬆ ⬇

[Section Outline]

Zolpidem is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP1A2 and CYP2D6.88

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Some drugs that inhibit CYP3A may increase systemic exposure to zolpidem.1,89 Because of possible increased hypnotic effects, a lower dose of zolpidem should be considered when used concomitantly with a potent CYP3A4 inhibitor.1,89 The effect of inhibitors of other CYP isoenzymes on the pharmacokinetics (e.g., systemic exposure) of zolpidem is not known.1,89

Some drugs that induce CYP3A may decrease systemic exposure to zolpidem.1,89 Concomitant use of zolpidem with potent CYP3A4 inducers is not recommended.1,89 The effect of other CYP inducers on the pharmacokinetics (e.g., systemic exposure) of zolpidem is not known.1,89

CNS Depressants !!navigator!!

Concomitant use of zolpidem with other CNS depressants (e.g., alcohol, benzodiazepines, opiates, sedating antihistamines, tricyclic antidepressants) increases the risk of CNS depression.1,89,200 Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability.1,89

Concomitant use of alcohol with zolpidem results in an additive adverse effect on psychomotor performance.1,89 Patients should be advised of the importance of not taking zolpidem after consuming alcohol in the evening or before bedtime.1,89,93,94

Concomitant use of zolpidem with opiates may increase the risk of respiratory depression.1,89 Dosage and duration of concomitant use of zolpidem and opiates should be limited.1,89

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.1,89,93,94 Concomitant use of zolpidem with other sedative and hypnotic drugs (including other zolpidem-containing preparations and OTC preparations used to treat insomnia [e.g., diphenhydramine, doxylamine succinate]) at bedtime or in the middle of the night is not recommended.1,89,200

Chlorpromazine !!navigator!!

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.1,89

Cimetidine !!navigator!!

Cimetidine does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem.1,89

Ciprofloxacin !!navigator!!

Concomitant use of ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) is likely to inhibit metabolism of zolpidem, potentially leading to an increase in zolpidem exposure.1,89

Digoxin !!navigator!!

Zolpidem had no effect on digoxin pharmacokinetics in healthy individuals.1,89

Fluoxetine !!navigator!!

Clinically important pharmacokinetic or pharmacodynamic interactions have not been observed when zolpidem was used concomitantly with fluoxetine in healthy individuals.1,89,102,103 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.1,89,103 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.1,89,102

Fluvoxamine !!navigator!!

Concomitant use of fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2C9) is likely to inhibit metabolism of zolpidem, potentially leading to an increase in zolpidem exposure.1,89

Haloperidol !!navigator!!

Haloperidol does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem.1,89 However, the lack of an interaction following single-dose administration does not predict the absence of an effect following chronic administration.1,89

Imipramine !!navigator!!

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.1,89

Itraconazole !!navigator!!

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 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.1,89,104

Ketoconazole !!navigator!!

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.1,89 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.1,89

Ranitidine !!navigator!!

Ranitidine does not appear to affect the pharmacokinetics or pharmacodynamics of zolpidem.1,89

Rifampin !!navigator!!

Rifampin, a potent CYP3A4 inducer, substantially reduces systemic exposure to and pharmacodynamic effects of zolpidem.1,89,101 Concomitant use with rifampin may decrease the hypnotic efficacy of zolpidem and is not recommended.1,89,101 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.89,101

Sertraline !!navigator!!

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.1,89,93,105 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%.1,89,105 Zolpidem did not appear to have clinically important effects on the pharmacokinetics of sertraline or N -desmethylsertraline.1,89,105

St. John's Wort !!navigator!!

Concomitant use of St. John's wort ( Hypericum perforatum ), a CYP3A4 inducer, with zolpidem may decrease concentrations of zolpidem and is not recommended.1,89

Warfarin !!navigator!!

Zolpidem did not appear to affect prothrombin time (PT) when used concomitantly with warfarin in healthy individuals.1,89

Other Information ⬆ ⬇

Description

Zolpidem tartrate, a type A γ-aminobutyric acid (GABAA)-receptor positive modulator of the imidazopyridine class, is a sedative and hypnotic agent.1,2,3,4,89,93 Although zolpidem is structurally unrelated to the benzodiazepines and other sedative and hypnotic agents, it shares some of the pharmacologic properties of benzodiazepines and has been shown to interact with the CNS GABA-benzodiazepine-chloride ionophore receptor complex.1,2,3,89,93,94 Zolpidem is thought to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening and resulting in the inhibition of neuronal excitation.1,89,93 Unlike some benzodiazepines, which nonselectively bind to and activate central type 1 (BZ1) and 2 (BZ2) benzodiazepine receptors, as well as peripheral type 3 (BZ3) receptors, resulting in nonspecific pharmacologic actions,1,2,3 zolpidem binds preferentially to BZ1 receptors with a greater affinity for the α1 subunit relative to the α2 and α3 subunits; zolpidem has no appreciable binding affinity for the α5 subunit.1,2,3,17,89 Such selectivity of zolpidem for the BZ1 receptor is not absolute, but may account for the decreased muscle relaxant, anxiolytic, and anticonvulsant effects compared with benzodiazepines observed in certain animals1,2,3,4,6,7,89,93,94 and also may explain the preservation of deep (stages 3 and 4) sleep at hypnotic doses in humans.4,94 Such selectivity reportedly also may result in reduced abuse potential and tolerance development as well as in only minor effects on duration of sleep stages compared with benzodiazepines.2,3,4,7,18 However, some in vivo data from an animal (mouse) model have not confirmed such selectivity,16 and other data suggest that pharmacologic and toxicologic selectivity of zolpidem may be dose5,6 and species5,8 dependent. In addition, changes in sleep EEG observed with zolpidem are similar to those associated with benzodiazepines.4,12 Although some evidence suggests that the risk of residual daytime sedative effects and impairment of psychomotor and mental performance is minimal with zolpidem at usual dosages,1,2,3,4,9,10,11,12,13,89 blood concentrations of the drug may be high enough in some patients on the morning after use to impair performance of activities that require alertness, including driving.95 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.95 Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5-HT2, adrenergic, histaminergic or muscarinic receptors.1,89,93

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Zolpidem is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

Zolpidem Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

6.25 mg*

Ambien CR® (C-IV)

Sanofi-Aventis

Zolpidem Tartrate Extended-release Tablets (C-IV)

12.5 mg*

Ambien CR® (C-IV)

Sanofi-Aventis

Zolpidem Tartrate Extended-release Tablets (C-IV)

Tablets, film-coated

5 mg*

Ambien® (C-IV)

Sanofi-Aventis

Zolpidem Tartrate Tablets (C-IV)

10 mg*

Ambien® (C-IV)

Sanofi-Aventis

Zolpidem Tartrate Tablets (C-IV)

Sublingual

Tablets

1.75 mg*

Zolpidem Tartrate Sublingual Tablets (C-IV)

3.5 mg*

Zolpidem Tartrate Sublingual Tablets (C-IV)

5 mg*

Edluar® (C-IV)

Meda

Zolpidem Tartrate Sublingual Tablets (C-IV)

10 mg*

Edluar® (C-IV)

Meda

Zolpidem Tartrate Sublingual Tablets (C-IV)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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