2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for women and either 6.25 or 12.5 mg for men, taken only once per night immediately before bedtime with at least 7–8 hours remaining before the planned time of awakening. If the 6.25 mg dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning blood levels following use of the 12.5 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.2)]. The total dose of AMBIEN CR should not exceed 12.5 mg once daily immediately before bedtime. AMBIEN CR should be taken as a single dose and should not be readministered during the same night.

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

Treatment with AMBIEN CR should be as short as possible. Extended treatment should not take place without re-evaluation of the patient's status, since the risk of abuse and dependence increases with duration of treatment [see Drug Abuse and Dependence (9.3)].

2.2 Special Populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime [see Warnings and Precautions (5.2), Use in Specific Populations (8.5)].

Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects. The recommended dose of AMBIEN CR in these patients is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Warnings and Precautions (5.8), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.3 Use with CNS Depressants

Dosage adjustment may be necessary when AMBIEN CR is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.2, 5.7)].

2.4 Administration

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

5.1 Complex Sleep Behaviors

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of AMBIEN CR. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Postmarketing reports have shown that complex sleep behaviors may occur with AMBIEN CR alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)]. Discontinue AMBIEN CR immediately if a patient experiences a complex sleep behavior [see Contraindications (4)].

5.2 CNS-Depressant Effects and Next-Day Impairment

AMBIEN CR is a CNS depressant and can impair daytime function in some patients even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of AMBIEN CR may develop, patients using AMBIEN CR should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.

Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use [see Drug Interactions (7.1)]. Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered [see Dosage and Administration (2.3)].

The use of AMBIEN CR with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended.

The risk of next-day psychomotor impairment is increased if AMBIEN CR is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants or alcohol; or coadministered with other drugs that increase the blood levels of zolpidem. Patients should be warned against driving and other activities requiring complete mental alertness if AMBIEN CR is taken in these circumstances [see Dosage and Administration (2), Clinical Studies (14.2)].

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness, and impaired driving the morning after therapy. In order to minimize this risk a full night of sleep (7–8 hours) is recommended.

Because AMBIEN CR can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.

5.3 Need to Evaluate for Comorbid Diagnoses

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

5.4 Severe Anaphylactic and Anaphylactoid Reactions

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.

5.5 Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR. 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, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with Ambien 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)]. There have been postmarketing reports of delirium with zolpidem use [see Adverse Reactions (6.2)].

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.

5.6 Use in Patients with Depression

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.

5.7 Respiratory Depression

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 AMBIEN CR is prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. Postmarketing reports of respiratory insufficiency in patients receiving10 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 AMBIEN CR in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use [see Dosage and Administration (2.3), Drug Interactions (7.1)].

5.8 Precipitation of Hepatic Encephalopathy

Drugs affecting GABA receptors, such as zolpidem tartrate, have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

5.9 Withdrawal Effects

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, 9.3)].

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AMBIEN CR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 × ULN, alkaline phosphatase ≥2 × ULN, transaminase ≥5 × ULN).

Psychiatric disorders: delirium

7.1 CNS-Active Drugs

7.2 Drugs that Affect Drug Metabolism via Cytochrome P450

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

AMBIEN CR 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 6–17 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 (5.5)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

FDA has not required pediatric studies of AMBIEN CR in the pediatric population based on these efficacy and safety findings.

8.5 Geriatric Use

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

The dose of AMBIEN CR in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.2)].

8.6 Gender Difference in Pharmacokinetics

Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC parameters of zolpidem from AMBIEN CR were, respectively, approximately 50% and 75% higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and 12 hours after dosing, zolpidem concentrations were 2 to 3 fold higher in adult female compared to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended initial dose of AMBIEN CR for adult women is 6.25 mg, and the recommended dose for adult men is 6.25 or 12.5 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of AMBIEN CR in geriatric patients is 6.25 mg regardless of gender.

8.7 Hepatic Impairment

The recommended dose of AMBIEN CR in patients with mild to moderate hepatic impairment is 6.25 mg once daily immediately before bedtime. Avoid AMBIEN CR use in patients with severe hepatic impairment as it may contribute to encephalopathy [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].

9.1 Controlled Substance

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

9.2 Abuse

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 effects were 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.

9.3 Dependence

Use of Ambien CR may lead to development of physical and/or psychological dependence. This risk of dependence increases with dose and duration of treatment. The risk of abuse and dependence is also greater in patients with history of alcohol or drug abuse. AMBIEN CR should be used with extreme caution in patients with current or past alcohol or drug abuse.

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, convulsions, and delirium.

The following adverse events, which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during AMBIEN CR 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. There have been postmarketing reports of abuse, dependence and withdrawal with zolpidem.

10.1 Signs and Symptoms

In postmarketing 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.

10.2 Recommended Treatment

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.

12.1 Mechanism of Action

Zolpidem is a GABA A receptor positive modulator presumed 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 resulting in the inhibition of neuronal excitation.

12.2 Pharmacodynamics

Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3 subunit containing receptors. Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors.

12.3 Pharmacokinetics

AMBIEN CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of AMBIEN CR 12.5 mg and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with AMBIEN CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration-time profiles are shown in Figure 1.

Figure 1: Mean Plasma Concentration-Time Profiles for AMBIEN CR (12.5 mg) and Immediate-Release Zolpidem Tartrate (10 mg)

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Controlled Clinical Trials

AMBIEN CR was evaluated in three placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV™).

Adult outpatients (18–64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 12.5 mg and placebo. AMBIEN CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. AMBIEN CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment. AMBIEN CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

Elderly outpatients (≥65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing AMBIEN CR 6.25 mg and placebo. AMBIEN CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. AMBIEN CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing LPS) during the first 2 nights of treatment and after 2 weeks on treatment. AMBIEN CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

In both studies, in patients treated with AMBIEN CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.

In a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18–64 years) with primary insomnia (N=1025), AMBIEN CR 12.5 mg administered as needed (3 to 7 nights per week) was superior to placebo over 24 weeks, on patient global impression regarding aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep maintenance with no significant increased frequency of drug intake observed over time.

14.2 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Store between 15°C–25°C (59°F–77°F). Limited excursions permissible up to 30°C (86°F).

Complex Sleep Behaviors

Instruct patients and their families that AMBIEN CR may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue AMBIEN CR and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions (5.1)].

CNS-Depressant Effects and Next-Day Impairment

Tell patients that AMBIEN CR can cause next-day impairment even when used as prescribed, and that this risk is increased if dosing instructions are not carefully followed. Caution patients against driving and other activities requiring complete mental alertness the day after use. Inform patients that impairment can be present despite feeling fully awake. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.2)].

Severe Anaphylactic and Anaphylactoid Reactions

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur [see Warnings and Precautions (5.4)].

Suicide

Tell patients to immediately report any suicidal thoughts.

Alcohol and other Drugs

Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use AMBIEN CR if they drank alcohol that evening or before bed.

Concomitant Use with Opioids

Inform patients and caregivers that potentially serious additive effects may occur if AMBIEN CR is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [Warnings and Precautions (5.2, 5.7), Drug Interactions (7.1)].

Tolerance, Abuse, and Dependence

Tell patients not to increase the dose of AMBIEN CR on their own, and to inform you if they believe the drug "does not work."

Administration Instructions

Patients should be counseled to take AMBIEN CR right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. AMBIEN CR tablets should not be taken with or immediately after a meal. Advise patients NOT to take AMBIEN CR if they drank alcohol that evening.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with AMBIEN CR. Advise patients that use of AMBIEN CR late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used AMBIEN CR during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding mothers using AMBIEN CR to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after AMBIEN CR administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].