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

Zolpidem tartrate tablets are a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep zolpidem tartrate tablets in a safe place to prevent misuse and abuse. Selling or giving away zolpidem tartrate tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.

Pregnancy Category C

There are no adequate and well-controlled studies of zolpidem in pregnant women.

Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the zolpidem maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m² basis.

Associated with Discontinuation of Treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide.

Medication Guide

Zolpidem Tartrate Tablets, USP C-IV

(ZOL-pih-dem)

Read the Medication Guide that comes with zolpidem tartrate tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about zolpidem tartrate tablets?

• •
  Do not take more zolpidem tartrate tablets than prescribed.
• •
  Do not take zolpidem tartrate tablets unless you are able to stay in bed a full night (7 to 8 hours) before you must be active again.
• •
  Take zolpidem tartrate tablets right before you get in bed, not sooner.

Zolpidem tartrate tablets may cause serious side effects, including:

• •
  After taking zolpidem tartrate tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with zolpidem tartrate tablets. Reported activities include:
  • o
    driving a car ("sleep-driving")
  • o
    making and eating food
  • o
    talking on the phone
  • o
    having sex
  • o
    sleep-walking

Call your healthcare provider right away if you find out that you have done any of the above activities after taking zolpidem tartrate tablets.

Do not take zolpidem tartrate tablets if you:

• •
  drank alcohol that evening or before bed
• •
  took another medicine to help you sleep.

What are zolpidem tartrate tablets?

Zolpidem tartrate tablets are a sedative-hypnotic (sleep) medicine. Zolpidem tartrate tablets are used in adults for the short-term treatment of a sleep problem called insomnia (trouble falling asleep).

It is not known if zolpidem tartrate tablets are safe and effective in children under the age of 18 years.

•  
  Warnings and Precautions, Severe Injuries (5.8) 10/2014

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

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

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

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

Zolpidem tartrate is a gamma-aminobutyric acid (GABA) A agonist 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 contains either 5 mg or 10 mg zolpidem tartrate with the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate, hypromellose, hydroxypropyl cellulose, polyethylene glycol, talc, titanium dioxide, carnauba wax; the 10-mg tablet also contains ferric oxide.

Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the 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. Post-marketing reports of abuse, dependence and withdrawal have been received.

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

In an 8-week study, in pediatric patients (aged 6 to 17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see WARNINGS AND PRECAUTIONS(5.4) ]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

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 reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., 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 dose of zolpidem tartrate in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see WARNINGS AND PRECAUTIONS (5.1) ].

The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.

Zolpidem tartrate tablets are contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see WARNINGS AND PRECAUTIONS (5.3)].

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

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

• •
  CNS-depressant effects and next-day impairment [see WARNINGS AND PRECAUTIONS (5.1) ]
• •
  Serious anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.3) ]
• •
  Abnormal thinking and behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS (5.4) ]
• •
  Withdrawal effects [see WARNINGS AND PRECAUTIONS (5.7) ]

• •
  CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects (5.1, 7.1)
• •
  Imipramine: Decreased alertness observed (7.1)
• •
  Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1)
• •
  Rifampin: Combination use may decrease effect (7.2)
• •
  Ketoconazole: Combination use may increase effect (7.2)

Zolpidem is excreted in human milk. Caution should be exercised when zolpidem is administered to a nursing woman.

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see WARNINGS AND PRECAUTIONS (5.1)]. The total dose of zolpidem tartrate tablets should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see WARNINGS AND PRECAUTIONS (5.1) ]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.

The pharmacokinetic profile of zolpidem is characterized by rapid absorption from the gastrointestinal 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 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 is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem 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 subjects compared the pharmacokinetics of zolpidem 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 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem should not be administered with or immediately after a meal.

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 and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, 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 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.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.

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

Zolpidem tartrate has no established use in labor and delivery [see Pregnancy (8.1) ].

Zolpidem tartrate tablets,USP are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP 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 to 5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

In post-marketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

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).

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate tablets in both of these patient populations is 5 mg once daily immediately before bedtime [see WARNINGS AND PRECAUTIONS (5.1); USE IN SPECIFIC POPULATIONS (8.5)].

NDC 63187-691-60

Zolpidem Tartrate Tablets, USP

5 mg

Rx only

PHARMACIST: Dispense the Medication Guide provided separately to each patient

60 Tablets

Zolpidem, the active moiety of zolpidem tartrate, 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 BZ receptor subtypes, zolpidem in vitro binds the BZ₁ receptor preferentially with a high affinity ratio of the α₁/α₅ subunits. This selective binding of zolpidem on the BZ₁ receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

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

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

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

• •
  CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. (5.1)
• •
  Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists after 7 to 10 days of use. (5.2)
• •
  Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.3)
• •
  "Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. (5.4)
• •
  Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. (5.5)
• •
  Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.6)
• •
  Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation (5.7, 9.3)
• •
  Severe Injuries: Drowsiness may lead to fall including severe injuries (5.8)

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

• •
  Use the lowest dose effective for the patient (2.1)
• •
  Recommended initial dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening (2.1)
• •
  Geriatric patients and patients with hepatic impairment: Recommended dose is 5 mg for men and women (2.2)
• •
  Lower doses of CNS depressants may be necessary when taken concomitantly with zolpidem tartrate tablets (2.3)
• •
  The effect of zolpidem tartrate tablets may be slowed if taken with or immediately after a meal (2.4)

Dosage adjustment may be necessary when zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects [see WARNINGS AND PRECAUTIONS (5.1)].

Zolpidem tartrate tablets, USP are available in 5 mg and 10 mg strengths for oral administration. Tablets are not scored.

Zolpidem tartrate tablets, USP 5 mg are white, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 5 on the other side.

The 10 mg tablets are yellow, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 10 on the other side.

• •
  Pregnancy: Based on animal data, may cause fetal harm (8.1)
• •
  Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder (5.4, 8.4)

See FDA-approved patient labeling (Medication Guide).

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

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

Zolpidem tartrate tablets, USP are available as follows:

5 mg, are white, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 5 on the other side.

NDC 63187-691-15, bottle of 15 tablets

NDC 63187-691-30, bottle of 30 tablets

NDC 63187-691-60, bottle of 60 tablets

NDC 63187-691-90, bottle of 90 tablets

10 mg, are yellow, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 10 on the other side.

NDC 63187-690-15, bottle of 15 tablets

NDC 63187-690-30, bottle of 30 tablets

NDC 63187-690-60, bottle of 60 tablets

NDC 63187-690-90, bottle of 90 tablets

Women clear zolpidem tartrate from the body at a lower rate than men. C_max and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of zolpidem tartrate for adult women is 5 mg, and the recommended dose for adult men is 5 or 10 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of zolpidem tartrate in geriatric patients is 5 mg regardless of gender.

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.

In controlled trials of zolpidem tartrate 10 mg taken at bedtime < 1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see USE IN SPECIFIC POPULATIONS (8.4)].

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 in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" have occurred with zolpidem tartrate alone at therapeutic doses, the co-administration of zolpidem tartrate with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem tartrate at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate 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 also occur.

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

Zolpidem tartrate, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem tartrate and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects. The use of zolpidem tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see DOSAGE AND ADMINISTRATION (2.3)].

The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem tartrate is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants; or if co-administered with other drugs that increase the blood levels of zolpidem. Patients should be cautioned against driving and other activities requiring complete mental alertness if zolpidem tartrate is taken in these circumstances [see DOSAGE AND ADMINISTRATION (2) and CLINICAL STUDIES (14.3)].

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

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of drugs on other P450 enzymes on the exposure to zolpidem is not known.

Zolpidem tartrate tablets are a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep zolpidem tartrate tablets in a safe place to prevent misuse and abuse. Selling or giving away zolpidem tartrate tablets may harm others, and is against the law. Tell your healthcare provider if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.

Pregnancy Category C

There are no adequate and well-controlled studies of zolpidem in pregnant women.

Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the zolpidem maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m² basis.

Associated with Discontinuation of Treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n =97) was discontinued after an attempted suicide.

Medication Guide

Zolpidem Tartrate Tablets, USP C-IV

(ZOL-pih-dem)

Read the Medication Guide that comes with zolpidem tartrate tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about zolpidem tartrate tablets?

• •
  Do not take more zolpidem tartrate tablets than prescribed.
• •
  Do not take zolpidem tartrate tablets unless you are able to stay in bed a full night (7 to 8 hours) before you must be active again.
• •
  Take zolpidem tartrate tablets right before you get in bed, not sooner.

Zolpidem tartrate tablets may cause serious side effects, including:

• •
  After taking zolpidem tartrate tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with zolpidem tartrate tablets. Reported activities include:
  • o
    driving a car ("sleep-driving")
  • o
    making and eating food
  • o
    talking on the phone
  • o
    having sex
  • o
    sleep-walking

Call your healthcare provider right away if you find out that you have done any of the above activities after taking zolpidem tartrate tablets.

Do not take zolpidem tartrate tablets if you:

• •
  drank alcohol that evening or before bed
• •
  took another medicine to help you sleep.

What are zolpidem tartrate tablets?

Zolpidem tartrate tablets are a sedative-hypnotic (sleep) medicine. Zolpidem tartrate tablets are used in adults for the short-term treatment of a sleep problem called insomnia (trouble falling asleep).

It is not known if zolpidem tartrate tablets are safe and effective in children under the age of 18 years.

•  
  Warnings and Precautions, Severe Injuries (5.8) 10/2014

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

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

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

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

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

Zolpidem tartrate is a gamma-aminobutyric acid (GABA) A agonist 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 contains either 5 mg or 10 mg zolpidem tartrate with the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate, hypromellose, hydroxypropyl cellulose, polyethylene glycol, talc, titanium dioxide, carnauba wax; the 10-mg tablet also contains ferric oxide.

Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the 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. Post-marketing reports of abuse, dependence and withdrawal have been received.

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

In an 8-week study, in pediatric patients (aged 6 to 17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see WARNINGS AND PRECAUTIONS(5.4) ]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

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 reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., 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 dose of zolpidem tartrate in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see WARNINGS AND PRECAUTIONS (5.1) ].

The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.

Zolpidem tartrate tablets are contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see WARNINGS AND PRECAUTIONS (5.3)].

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

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

• •
  CNS-depressant effects and next-day impairment [see WARNINGS AND PRECAUTIONS (5.1) ]
• •
  Serious anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.3) ]
• •
  Abnormal thinking and behavior changes, and complex behaviors [see WARNINGS AND PRECAUTIONS (5.4) ]
• •
  Withdrawal effects [see WARNINGS AND PRECAUTIONS (5.7) ]

• •
  CNS depressants, including alcohol: Possible adverse additive CNS-depressant effects (5.1, 7.1)
• •
  Imipramine: Decreased alertness observed (7.1)
• •
  Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1)
• •
  Rifampin: Combination use may decrease effect (7.2)
• •
  Ketoconazole: Combination use may increase effect (7.2)

Zolpidem is excreted in human milk. Caution should be exercised when zolpidem is administered to a nursing woman.

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see WARNINGS AND PRECAUTIONS (5.1)]. The total dose of zolpidem tartrate tablets should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see WARNINGS AND PRECAUTIONS (5.1) ]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.

The pharmacokinetic profile of zolpidem is characterized by rapid absorption from the gastrointestinal 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 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 is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem 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 subjects compared the pharmacokinetics of zolpidem 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 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem should not be administered with or immediately after a meal.

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 and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, 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 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.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.

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

Zolpidem tartrate has no established use in labor and delivery [see Pregnancy (8.1) ].

Zolpidem tartrate tablets,USP are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets, USP 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 to 5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

In post-marketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

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).

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate tablets in both of these patient populations is 5 mg once daily immediately before bedtime [see WARNINGS AND PRECAUTIONS (5.1); USE IN SPECIFIC POPULATIONS (8.5)].

NDC 63187-691-60

Zolpidem Tartrate Tablets, USP

5 mg

Rx only

PHARMACIST: Dispense the Medication Guide provided separately to each patient

60 Tablets

Zolpidem, the active moiety of zolpidem tartrate, 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 BZ receptor subtypes, zolpidem in vitro binds the BZ₁ receptor preferentially with a high affinity ratio of the α₁/α₅ subunits. This selective binding of zolpidem on the BZ₁ receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

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

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

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

• •
  CNS depressant effects: Impairs alertness and motor coordination. Instruct patients on correct use. (5.1)
• •
  Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists after 7 to 10 days of use. (5.2)
• •
  Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.3)
• •
  "Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes. (5.4)
• •
  Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose. (5.5)
• •
  Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.6)
• •
  Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation (5.7, 9.3)
• •
  Severe Injuries: Drowsiness may lead to fall including severe injuries (5.8)

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

• •
  Use the lowest dose effective for the patient (2.1)
• •
  Recommended initial dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening (2.1)
• •
  Geriatric patients and patients with hepatic impairment: Recommended dose is 5 mg for men and women (2.2)
• •
  Lower doses of CNS depressants may be necessary when taken concomitantly with zolpidem tartrate tablets (2.3)
• •
  The effect of zolpidem tartrate tablets may be slowed if taken with or immediately after a meal (2.4)

Dosage adjustment may be necessary when zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects [see WARNINGS AND PRECAUTIONS (5.1)].

Zolpidem tartrate tablets, USP are available in 5 mg and 10 mg strengths for oral administration. Tablets are not scored.

Zolpidem tartrate tablets, USP 5 mg are white, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 5 on the other side.

The 10 mg tablets are yellow, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 10 on the other side.

• •
  Pregnancy: Based on animal data, may cause fetal harm (8.1)
• •
  Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder (5.4, 8.4)

See FDA-approved patient labeling (Medication Guide).

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

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

Zolpidem tartrate tablets, USP are available as follows:

5 mg, are white, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 5 on the other side.

NDC 63187-691-15, bottle of 15 tablets

NDC 63187-691-30, bottle of 30 tablets

NDC 63187-691-60, bottle of 60 tablets

NDC 63187-691-90, bottle of 90 tablets

10 mg, are yellow, round-shaped, biconvex, film coated tablets, with ZLP debossed on one side and 10 on the other side.

NDC 63187-690-15, bottle of 15 tablets

NDC 63187-690-30, bottle of 30 tablets

NDC 63187-690-60, bottle of 60 tablets

NDC 63187-690-90, bottle of 90 tablets

Women clear zolpidem tartrate from the body at a lower rate than men. C_max and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of zolpidem tartrate for adult women is 5 mg, and the recommended dose for adult men is 5 or 10 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of zolpidem tartrate in geriatric patients is 5 mg regardless of gender.

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including zolpidem tartrate. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.

In controlled trials of zolpidem tartrate 10 mg taken at bedtime < 1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see USE IN SPECIFIC POPULATIONS (8.4)].

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 in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" have occurred with zolpidem tartrate alone at therapeutic doses, the co-administration of zolpidem tartrate with alcohol and other CNS depressants increases the risk of such behaviors, as does the use of zolpidem tartrate at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate 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 also occur.

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

Zolpidem tartrate, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of zolpidem tartrate and of other concomitant CNS depressants may be necessary when zolpidem tartrate is administered with such agents because of the potentially additive effects. The use of zolpidem tartrate with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see DOSAGE AND ADMINISTRATION (2.3)].

The risk of next-day psychomotor impairment, including impaired driving, is increased if zolpidem tartrate is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants; or if co-administered with other drugs that increase the blood levels of zolpidem. Patients should be cautioned against driving and other activities requiring complete mental alertness if zolpidem tartrate is taken in these circumstances [see DOSAGE AND ADMINISTRATION (2) and CLINICAL STUDIES (14.3)].

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

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of drugs on other P450 enzymes on the exposure to zolpidem is not known.