Zolpidem tartrate tablets for oral administration

Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets have been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14)].

The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

The dose of zolpidem tartrate tablets should be individualized.

The recommended dose for adults is 10 mg immediately before bedtime.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate tablets . Patients with hepatic insufficiency do not clear the drug as rapidly as normals. An initial 5 mg dose is recommended in these patients [see Warnings and Precautions (5)].

Downward dosage adjustment may be necessary when zolpidem tartrate tablets is administered with agents having known CNS-depressant effects because of the potentially additive effects [see Warnings and Precautions (5)].

The total zolpidem tartrate tablets dose should not exceed 10 mg per day.

Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration.

Zolpidem tartrate tablets 5-mg are white round film-coated tablets engraved with “CST 8”. Zolpidem tartrate tablets 10-mg are white round film-coated tablets engraved with “B”. Tablets are not scored.

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

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.

Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem tartrate tablets. Because some of the important adverse effects of zolpidem tartrate tablets appear to be dose related [see Dosage and Administration (2)], it is important to use the smallest possible effective dose, especially in the elderly.

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem tartrate tablets. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem tartrate tablets should not be rechallenged with the drug.

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

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

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

Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS depressant drugs [see Drug Abuse and Dependence (9)].

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

Serious adverse reactions including severe anaphylactic and anaphylactoid reactions, abnormal thinking and behavior, complex behaviors, withdrawal effects, amnesia, anxiety, other neuropsychiatric symptoms and CNS-depressant effects have been reported with zolpidem [see Warnings and Precautions (5)].

Zolpidem tartrate tablets were evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)].

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

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

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

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC_0-∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized, placebo-controlled, crossover interaction study in eight healthy female volunteers between 5 consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%), C_max (–58%), and T_1/2 (–36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.

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

Zolpidem tartrate tablets have no established use in labor and delivery.

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

In addition, in a rat study, zolpidem inhibited the secretion of milk. The no-effect dose was 4 mg base/kg or 6 times the recommended human dose in mg/m².

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

Safety and effectiveness of zolpidem have not been established in pediatric patients.

In an 8-week controlled study, 201 pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics), were treated with an oral solution of zolpidem, 0.25 mg/kg/day, up to a maximum of 10 mg/day (n=136), or placebo (n = 65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse events observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions: Special Populations (5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse event.

A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received zolpidem were ≥60 years of age. For a pool of U.S. patients receiving zolpidem at doses of ≤10 mg or placebo, there were three adverse events occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (ie, they could be considered drug related).

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30 (93%) who were ≥70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses >10 mg.

The recommended dose of zolpidem tartrate tablets is 5 mg in elderly to decrease the possibility of side effects [see Dosage and Administration (2) and Warnings and Precautions (5)].

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate tablets 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The U.S. clinical trial experience from zolpidem does not reveal any clear evidence for withdrawal syndrome. Nevertheless, the following adverse events included in DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Rare post-marketing reports of abuse, dependence and withdrawal have been received.

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk of habituation and dependence, they should be under careful surveillance when receiving zolpidem or any other hypnotic.

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

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

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

Zolpidem tartrate is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.

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

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

Each zolpidem tartrate tablet includes the following inactive ingredients: lactose, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol, and titanium dioxide.

Subunit modulation of the GABA_A receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA_A receptor complex is located on its alpha (α) subunit and is referred to as the benzodiazepine (BZ) or omega (ω) receptor. At least three subtypes of the (ω) receptor have been identified.

While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all (ω) receptor subtypes, zolpidem in vitro binds the (ω₁) receptor preferentially with a high affinity ratio of the α₁/ α₅ subunits. The (ω₁) receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (parsreticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the (ω₁) receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

The pharmacokinetic profile of zolpidem tartrate tablets is characterized by rapid absorption from the GI tract and a short elimination half-life (T_1/2) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (C_max) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (T_max) of 1.6 hours for both. The mean zolpidem tartrate tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.

A food-effect study in 30 healthy male volunteers compared the pharmacokinetics of zolpidem tartrate tablets 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and C_max were decreased by 15% and 25%, respectively, while mean T_max was prolonged by 60% (from 1.4 to 2.2hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem tartrate tablets should not be administered with or immediately after a meal.

In the elderly, the dose for zolpidem tartrate tablets should be 5 mg [see Warnings and Precautions (5) and Dosage and Administration (2)]. This recommendation is based on several studies in which the mean C_max, T_1/2, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for C_max, T_1/2, and AUC significantly increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate tablets do not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

The pharmacokinetics of zolpidem tartrate tablets in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem dose, mean C_max and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 ng·hr/mL) higher, respectively, in hepatically compromised patients. T_max did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see Warnings and Precautions (5) and Dosage and Administration (2)].

The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean Cl_Cr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for C_max, T_max, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, C_max was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, C_max was 203± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, T_max was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing T_max was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On day 1, T_1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T_1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng·hr/mL after the first dose and 818 ± 170 ng·hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem tartrate pharmacokinetics was not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. As a general precaution, these patients should be closely monitored.

Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo on objective (polysomnographic) measures of sleep latency, sleep duration, and number of awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n = 35) during the first two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n= 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate (10 and 15 mg) and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 15 mg was superior to placebo for all 5 weeks; zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem (10 and 15 mg) and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week. Zolpidem 15 mg was superior to placebo on a subjective measure of total sleep latency for the first 3 weeks, on a subjective measure of total sleep time for the first week, and on number of awakenings and sleep quality for the first 2 weeks.

Zolpidem tartrate tablets 5-mg are white round film-coated tablets engraved with “CST 8”

NDC Number        Size

063126-231-30             Bottle of 30

063126-231-01             Bottle of 1,000

Zolpidem tartrate tablets 10-mg are white round film-coated tablets engraved with “B”

NDC Number        Size

063126-232-30             Bottle of 30

063126-232-01             Bottle of 1,000

Store at controlled room temperature 20° to 25°C (68° to 77°F)

Rx only

Manufactured by:

Yung Shin Pharmaceutical Industrial Co., Ltd.
Tachia, Taichung
Taiwan, ROC

Revision: April 2007

Patient information is printed at the end of this insert. To assure safe and effective use of zolpidem tartrate tablets, this information and instructions provided in the patient information section should be discussed with patients.

Your doctor has prescribed zolpidem tartrate tablets to help you sleep. The following information is intended to guide you in the safe use of this medicine. It is not meant to take the place of your doctor's instructions. If you have any questions about zolpidem tartrate tablets be sure to ask your doctor or pharmacist.

Zolpidem tartrate tablets are used to treat different types of sleep problems in adults, such as:

• trouble falling asleep
• waking up too early in the morning
• waking up often during the night

Some people may have more than one of these problems.

Zolpidem tartrate tablets belong to a group of medicines known as the “sedative/hypnotics,” or simply, sleep medicines. There are many different sleep medicines available to help people sleep better. Sleep problems are usually temporary, requiring treatment for only a short time, usually 1 or 2 days up to 1 or 2 weeks. Some people have chronic sleep problems that may require more prolonged use of sleep medicine. However, you should not use these medicines for long periods without talking with your doctor about the risks and benefits of prolonged use.