Ambien CR contains zolpidem tartrate, a non-benzodiazepine hypnotic of the imidazopyridine class. Ambien CR (zolpidem tartrate extended-release tablets) is available in 6.25 mg and 12.5 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.

Ambien CR consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The 6.25 mg Ambien CR tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5 mg Ambien CR tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.

Last updated on RxList: 1/17/2008

Ambien CR (zolpidem tartrate extended-release tablets) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by wake time after sleep onset).

The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-reported assessment in adult patients only) in duration [see Clinical Studies] .

The dose of Ambien CR should be individualized.

Dosage in adults

The recommended dose of Ambien CR for adults is 12.5 mg once daily immediately before bedtime. The total Ambien CR dose should not exceed 12.5 mg per day.

Special populations

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 normals. The recommended dose of Ambien CR in both of these patient populations is 6.25 mg once daily immediately before bedtime [see WARNINGS and PRECAUTIONS].

Use with CNS depressants

Dosage adjustments may be necessary when Ambien CR is combined with other CNS depressant drugs because of the potentially additive effects [see WARNINGS and PRECAUTIONS] .

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.

Dosage Forms And Strengths

Ambien CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem tartrate for oral administration. Tablets are not scored.

Ambien CR 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.

Ambien CR 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.

Storage And Handling

Ambien CR 6.25 mg tablets are composed of two layers* and are coated, pink, round, bi-convex, debossed with A~ on one side and supplied as:

NDC Number	Size
0024-5501-31	bottle of 100
0024-5501-50	bottle of 500
0024-5501-10	carton of 30 unit dose
0024-5501-34	carton of 100 unit dose

Ambien CR 12.5 mg tablets are composed of two layers* and are coated, blue, round, bi-convex, debossed with A~ on one side and supplied as:

NDC Number	Size
0024-5521-31	bottle of 100
0024-5521-50	bottle of 500
0024-5521-10	carton of 30 unit dose
0024-5521-34	carton of 100 unit dose
*Layers are covered by the coating and are indistinguishable.

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

Sanofi-Aventis U.S. LLC Bridgewater, NJ 08807., December 2007. FDA rev date: 12/20/2007

Last updated on RxList: 1/17/2008

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

• Serious anaphylactic and anaphylactoid reactions [see WARNINGS and PRECAUTIONS]
• Abnormal thinking, behavior changes, and complex behaviors [ WARNINGS and PRECAUTIONS]
• Withdrawal effects [see WARNINGS and PRECAUTIONS]
• CNS-depressant effects [see WARNINGS and PRECAUTIONS]

Clinical trials experience

Associated with discontinuation of treatment: In 3-week clinical trials in adults and elderly patients ( > 65 years), 3.5% (7/201) patients receiving Ambien CR 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with Ambien CR was somnolence (1%).

In a 6-month study in adult patients (18-64 years of age), 8.5% (57/669) of patients receiving Ambien CR 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of Ambien CR included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

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.

Most commonly observed adverse reactions in controlled trials: During treatment with Ambien CR in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of Ambien CR were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating Ambien CR 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for Ambien CR versus 2.6% for placebo).

Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received Ambien CR in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following tables were derived from results of two placebo-controlled efficacy trials involving Ambien CR. These trials involved patients with primary insomnia who were treated for 3 weeks with Ambien CR at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively. The tables include only adverse reactions occurring at an incidence of at least 1% for Ambien CR patients and with an incidence greater than that seen in the placebo patients.

Table 1. Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting)

Body System/Adverse Reaction *	Ambien CR 12.5 mg (N = 102)	Placebo (N =110)
Infections and infestations
Influenza	3	0
Gastroenteritis	1	0
Labyrinthitis	1	0
Metabolism and nutrition disorders
Appetite disorder	1	0
Psychiatric disorders
Hallucinations **	4	0
Disorientation	3	2
Anxiety	2	0
Depression	2	0
Psychomotor retardation	2	0
Binge eating	1	0
Depersonalization	1	0
Disinhibition	1	0
Euphoric mood	1	0
Mood swings	1	0
Stress symptoms	1	0
Nervous system disorders
Headache	19	16
Somnolence	15	2
Dizziness	12	5
Memory disorders ***	3	0
Balance disorder	2	0
Disturbance in attention	2	0
Hypoesthesia	2	1
Ataxia	1	0
Paresthesia	1	0
Eye disorders
Visual disturbance	3	0
Eye redness	2	0
Vision blurred	2	1
Altered visual depth	1	0
perception
Asthenopia	1	0
Ear and labyrinth disorders
Vertigo	2	0
Tinnitus	1	0
Respiratory, thoracic and mediastinal disorders
Throat irritation	1	0
Gastrointestinal disorders
Nausea	7	4
Constipation	2	0
Abdominal discomfort	1	0
Abdominal tenderness	1	0
Frequent bowel movements	1	0
Gastroesophageal reflux	1	0
disease
Vomiting	1	0
Skin and subcutaneous tissue disorders
Rash	1	0
Skin wrinkling	1	0
Urticaria	1	0
Musculoskeletal and connective tissue disorders
Back pain	4	3
Myalgia	4	0
Neck pain	1	0
Reproductive system and breast disorders
Menorrhagia	1	0
General disorders and administration site conditions
Fatigue	3	2
Asthenia	1	0
Chest discomfort	1	0
Investigations
Blood pressure increased	1	0
Body temperature increased	1	0
Injury, poisoning and procedural complications
Contusion	1	0
Social circumstances
Exposure to poisonous plant	1	0
*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group. **Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations. ***Memory disorders include: memory impairment, amnesia, anterograde amnesia.

Table 2. Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting)

Body System/Adverse Reaction *	Ambien CR 6.25 mg (N=99)	Placebo (N=106)
Infections and infestations
Nasopharyngitis	6	4
Lower respiratory tract	1	0
infection
Otitis externa	1	0
Upper respiratory tract infection	1	0
Psychiatric disorders
Anxiety	3	2
Psychomotor retardation	2	0
Apathy	1	0
Depressed mood	1	0
Nervous system disorders
Headache	14	11
Dizziness	8	3
Somnolence	6	5
Burning sensation	1	0
Dizziness postural	1	0
Memory disorders **	1	0
Muscle contractions involuntary	1	0
Paresthesia	1	0
Tremor	1	0
Cardiac disorders
Palpitations	2	0
Respiratory, thoracic and mediastinal disorders
Dry throat	1	0
Gastrointestinal disorders
Flatulence	1	0
Vomiting	1	0
Skin and subcutaneoustissue disorders
Rash	1	0
Urticaria	1	0
Musculoskeletal and connective tissue disorders
Arthralgia	2	0
Muscle cramp	2	1
Neck pain	2	0
Renal and urinary disorders
Dysuria	1	0
Reproductive system and breast disorders
Vulvovaginal dryness	1	0
General disorders and administration site conditions
Influenza like illness	1	0
Pyrexia	1	0
Injury, poisoning and procedural complications
Neck injury	1	0
*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group. **Memory disorders include: memory impairment, amnesia, anterograde amnesia.

Dose relationship for adverse reactions: There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Other adverse reactions observed during the premarketing evaluation of Ambien CR: Other treatment-emergent adverse reactions associated with participation in Ambien CR studies (those reported at frequencies of < 1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.

Adverse Events Observed During the Premarketing Evaluation of Immediate-Release Zolpidem Tartrate: Immediate-release zolpidem tartrate was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Ambien, they were not necessarily caused by it.

Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system: Frequent: dry mouth. Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: chest pain, edema, falling, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.

Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system: Frequent: ataxia, confusion, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. Infrequent: agitation, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system: Frequent: diarrhea, dyspepsia, hiccup. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.

Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.

Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.

Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system: Frequent: sinusitis. Infrequent: bronchitis, coughing, dyspnea. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

CNS-active drugs

Since the systematic evaluations of zolpidem 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.

An immediate-release formulation of zolpidem tartrate was evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. 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. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. 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] .

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 Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Drugs that affect drug metabolism via cytochrome P450

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 d ays) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ 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 subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of an immediate-release formulation of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (-73%), Cmax (-58%), and T½ (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.

A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of immediate-release zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem alone and prolonged the elimination half-life by approximately 30% along with an increase in the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given with zolpidem and consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of Ambien CR with ketoconazole may enhance the sedative effects.

Other drugs with no interaction with 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 pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.

Drug-laboratory test interactions

Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

Drug Abuse And Dependence

Controlled substance

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

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.

Dependence

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.

Last updated on RxList: 1/17/2008

Included as part of the PRECAUTIONS section.

Need to evaluate for co-morbid 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.

Severe anaphylactic and anaphylactoid reactions

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. 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.

Abnormal thinking and behavioral changes

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 (e.g. 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 reported hallucinations [see Use in Specific Populations] .

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 with sedative-hypnotics, including zolpidem. 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 Ambien CR alone at therapeutic doses, the use of alcohol and other CNS depressants with Ambien CR appears to increase the risk of such behaviors, as does the use of Ambien CR at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Ambien CR 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 thoughts and actions including completed suicides), have 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 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.

Withdrawal effects

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] .

CNS depressant effects

Ambien CR, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien CR should only be taken 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 Ambien CR. Ambien CR 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 Ambien CR is administered with such agents because of the potentially additive effects.

Special populations

Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Ambien CR dosage is 6.25 mg in such patients to decrease the possibility of side effects [see DOSAGE AND ADMINISTRATION] . These patients should be closely monitored.

Use in patients with concomitant illness: Clinical experience with Ambien CR (zolpidem tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using Ambien CR in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normals 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 an immediate-release formulation of zolpidem tartrate (10 mg) when 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. Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received.

Ambien CR should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

Data in end-stage renal failure patients repeatedly treated with an immediate-release formulation of zolpidem tartrate (10 mg) did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored [see CLINICAL PHARMACOLOGY] .

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with Ambien CR 6.25 mg in patients with hepatic compromise, and they should be closely monitored [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] .

Use in patients with depression: As with other sedative/hypnotic drugs, Ambien CR should be administered with caution to patients exhibiting signs or symptoms of depression. 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 least amount of drug that is feasible should be prescribed for the patient at any one time.

Use in pediatric patients: Safety and effectiveness of zolpidem has not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD given an immediate-release oral solution of zolpidem tartrate, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations] .

Patient Counseling Information

Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics, should counsel them in its appropriate use, and should instruct them to read the accompanying Medication Guide .

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.

Sleep-driving and other complex behaviors

There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Ambien CR is taken with alcohol or other central nervous system depressants [see WARNINGS and PRECAUTIONS] . 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.

In addition, patients should be advised to report all concomitant medications to the prescriber. Patients should be instructed to report events such as “sleep-driving” and other complex behaviors immediately to the prescriber.

Administration instructions

Patients should be counseled to take Ambien 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 crushed, divided, or chewed, and should not be taken with or immediately after a meal. Advise patients NOT to take Ambien CR when drinking alcohol.

Nonclinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Zolpidem tartrate was administered to CD-1 mice and Sprague-Dawley rats for two years at dietary dosages of 4, 18, and 80 mg/kg/day. No evidence of carcinogenic potential was observed in either mice or rats at doses up to 80 mg base/kg/day (40 and 80 times the maximum recommended human dose [MRHD] of Ambien CR 12.5 mg [10 mg zolpidem base], respectively, on a mg/m² basis).

Mutagenesis

Zolpidem did not have mutagenic activity in several tests including an in vitro bacterial reverse mutation (Ames) assay, an in vitro mammalian gene forward mutation assay in mouse lymphoma cells, and an in vitro unscheduled DNA synthesis in rat hepatocytes. Zolpidem was not clastogenic in an in vitro chromosomal aberration assay in human lymphocytes or in an in vivo micronucleus test in mice.

Impairment of fertility

Zolpidem tartrate was administered by oral gavage to Sprague-Dawley rats at doses of 4, 20, or 100 mg base/kg/day. Treatment of males began 71 days prior to mating and continued through mating while treatment of females began 14 days prior to mating and continued through mating, gestation, and weaning which occurred on post partum Day 25. Zolpidem administered at 100 mg base/kg was associated with irregular estrus cycles and prolonged pre-coital intervals, but did not produce a decline in fertility. The no-effect dose was 20 mg base/kg/day (20 times the MRHD of Ambien CR on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Ambien CR in pregnant women. Ambien CR should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Oral studies of zolpidem in pregnant rats and rabbits showed adverse effects on the development of offspring only at doses greater than the maximum recommended human dose (MRHD of 12.5 mg/day). These doses were also maternally toxic in animals. A teratogenic effect was not observed in these studies. Administration to pregnant rats during the period of organogenesis produced dose-related maternal toxicity and decreases in fetal skull ossification at doses 20 to 100 times the MRHD. The no-effect dose for embryo-fetal toxicity was 4 times the MRHD. Treatment of pregnant rabbits during organogenesis resulted in maternal toxicity at all doses studied and increased post-implantation embryo-fetal loss and under-ossification of fetal sternebrae at the highest dose (30 times the MRHD). The no-effect level for embryo-fetal toxicity was approximately 8 times the MRHD. Administration to rats during the latter part of pregnancy and throughout lactation produced maternal toxicity and decreased pup growth and survival at doses approximately 20 to 100 times the MRHD. The no-effect dose for offspring toxicity was approximately 4 times the MRHD.

Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. There is a published case report documenting the presence of zolpidem in human umbilical cord blood. Children born of mothers taking sedative/hypnotic drugs may be at some risk for withdrawal symptoms from the drug during the postnatal period. In addition, neonatal flaccidity has been reported in infants born of mothers who received sedative/hypnotic drugs during pregnancy.

Labor and delivery

Ambien CR has no established use in labor and delivery [see Pregnancy].

Nursing mothers

Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young normal subjects (2.6 ± 0.3 hr). Between 0.004% and 0.019% of the total administered dose is excreted into milk. The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Ambien CR is administered to a nursing mother.

Pediatric use

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 (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 reactions 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] . 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.

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] .

Last updated on RxList: 1/17/2008

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.

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.

Ambien CR is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see WARNINGS and PRECAUTIONS].

Last updated on RxList: 1/17/2008

Mechanism of action

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) receptor.

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ₁ receptor preferentially with a high affinity ratio of the alpha₁/alpha₅ subunits. The BZ₁ receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. 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 at hypnotic doses.

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.

Absorption

Following administration of Ambien CR, administered as a single 12.5 mg dose in healthy male adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at a median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740 ng·hr/mL (range: 295 to 1359 ng·hr/mL).

A food-effect study in 45 healthy subjects compared the pharmacokinetics of Ambien CR 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median Tmax was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, Ambien CR should not be administered with or immediately after a meal.

Distribution

Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.

Metabolism

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.

Elimination

When Ambien CR was administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).

Special Populations

Elderly

In 24 elderly ( ≥ 65 years) healthy subjects administered a single 6.25 mg dose of Ambien CR, the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring at a median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 ng·hr/mL (range: 124 to 1190 ng·hr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).

Hepatic Impairment

Ambien CR was not studied in patients with hepatic impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20-mg oral zolpidem tartrate dose, mean Cmax 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. Tmax 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 normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see DOSAGE AND ADMINISTRATION, WARNINGS and PRECAUTIONS] .

Renal Impairment

Ambien CR was not studied in patients with renal impairment. The pharmacokinetics of an immediate-release formulation 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 tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax 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, T½ was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T½ 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 pharmacokinetics were not significantly different in renally-impaired patients. No dosage adjustment is necessary in patients with compromised renal function. However, as a general precaution, these patients should be closely monitored.

Clinical Studies

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.

Studies pertinent to safety concerns for sedative/hypnotic drugs

Next-day residual effects: In five clinical studies [three controlled studies in adults (18-64 years of age) administered Ambien CR 12.5 mg and two controlled studies in the elderly ( 65 years of age) administered Ambien CR 6.25 mg or 12.5 mg], the effect of Ambien CR on vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies, no significant decrease in performance was observed eight hours after a nighttime dose. In addition, no evidence of next-day residual effects was detected with Ambien CR 12.5 mg and 6.25 mg using self-ratings of sedation.

During the 3-week studies, next-day somnolence was reported by 15% of the adult patients who received 12.5 mg Ambien CR versus 2% of the placebo group; next-day somnolence was reported by 6% of the elderly patients who received 6.25 mg Ambien CR versus 5% of the placebo group [see ADVERSE REACTIONS] . In a 6-month study, the overall incidence of next-day somnolence was 5.7% in the Ambien CR group as compared to 2% in the placebo group.

Rebound effects: Rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics.n the two 3-week placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of Ambien CR. On the second night, there was no worsening compared to baseline in the Ambien CR group.

In a 6-month placebo-controlled study in which Ambien CR was taken as needed (3 to 7 nights per week), within the first month a rebound effect was observed for Total Sleep Time (not for WASO) during the first night off medication. After this first month period, no further rebound insomnia was observed. After final treatment discontinuation no rebound was observed.

Last updated on RxList: 1/17/2008

Medication Guide

AMBIEN CR^®
( m'b - n see ahr) (zolpidem tartrate extended-release tablets )

Read the Medication Guide that comes with AMBIEN CR 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 doctor about your medical condition or treatment.

What is the most important information I should know about AMBIEN CR?

After taking AMBIEN CR, 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 AMBIEN CR. Reported activities include:

• driving a car ("sleep-driving")
• making and eating food
• talking on the phone
• having sex
• sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking AMBIEN CR.

Important

1. Take AMBIEN CR exactly as prescribed
   • Do not take more AMBIEN CR than prescribed.
   • Take AMBIEN CR right before you get in bed, not sooner.
2. Do not take AMBIEN CR if you:
   • drink alcohol
   • take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take AMBIEN CR with your other medicines.
   • cannot get a full night's sleep

What is AMBIEN CR?

AMBIEN CR is a sedative-hypnotic (sleep) medicine. AMBIEN CR is used in adults for the treatment of a sleep problem called insomnia. Symptoms of insomnia include:

• trouble falling asleep
• waking up often during the night

AMBIEN CR is not for children.

Who should not take AMBIEN CR?

Do not take AMBIEN CR if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in AMBIEN CR.

AMBIEN CR may not be right for you. Before starting AMBIEN CR, tell your doctor about all of your health conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take AMBIEN CR with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take AMBIEN CR?

• Take AMBIEN CR exactly as prescribed. Do not take more AMBIEN CR than prescribed for you.
• Take AMBIEN CR right before you get into bed.
• Do not take AMBIEN CR unless you are able to stay in bed a full night (7-8 hours) before you must be active again.
• Swallow AMBIEN CR Tablets whole. Do not chew or break the tablets. Tell your doctor if you cannot swallow tablets whole.
• For faster sleep onset, AMBIEN CR should NOT be taken with or immediately after a meal.
• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problems.
• If you take too much AMBIEN CR or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of AMBIEN CR?

Serious side effects of AMBIEN CR include:

• getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See “What is the most important information I should know about AMBIEN CR?)
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking AMBIEN CR.

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using AMBIEN CR.

The most common side effects of AMBIEN CR are:

• headache
• sleepiness
• dizziness
• You may still feel drowsy the next day after taking AMBIEN CR. Do not drive or do other dangerous activities after taking AMBIEN CR until you feel fully awake.

After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as: trouble sleeping, nausea, flushing, lightheadedness, uncontrolled crying, vomiting, stomach cramps, panic attack, nervousness, and stomach area pain.

These are not all the side effects of AMBIEN CR. Ask your doctor or pharmacist for more information.

How should I store AMBIEN CR?

• Store AMBIEN CR at room temperature, 59° to 77°F (15° to 25° C).
• Keep AMBIEN CR and all medicines out of reach of children.

General Information about AMBIEN CR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use AMBIEN CR for a condition for which it was not prescribed.

Do not share AMBIEN CR with other people, even if you think they have the same symptoms that you have. It may harm them and it is against the law. This Medication Guide summarizes the most important information about AMBIEN CR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AMBIEN CR that is written for healthcare professionals. For more information about AMBIEN CR, call 1-800-633-1610 or visit www.ambiencr.com.

What are the ingredients in AMBIEN CR?

Active Ingredient: Zolpidem tartrate

Inactive Ingredients: The 6.25 mg tablets contain: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5 mg tablets contain: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last updated on RxList: 1/17/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ZOLPIDEM EXTENDED-RELEASE - ORAL

(ZOHL-pee-dem)

COMMON BRAND NAME(S): Ambien CR

USES: Zolpidem is used to treat sleep problems (insomnia). It may help you fall asleep faster, stay asleep longer, and reduce the number of times you awaken during the night. Zolpidem belongs to a class of drugs called sedative/hypnotics. It acts on your brain to produce a calming effect.

HOW TO USE: Read the Medication Guide and Patient Information Leaflet provided by your pharmacist before you start using zolpidem and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth, usually once nightly immediately before bedtime on an empty stomach, or as directed by your doctor. Do not take it with food because the effect of the medication will be delayed.

Swallow this medication whole. Do not crush, chew, or break this medication. Doing so can destroy the long action of the drug and may increase side effects.

Dosage is based on your medical condition, age, and response to therapy.

Although unlikely, this drug can infrequently cause temporary memory loss. To avoid this effect, do not take a dose of this drug unless you have time for a full night's sleep that lasts at least 7-8 hours. For example, do not take zolpidem during an overnight plane flight of less than 8 hours.

This medication may cause dependence, especially if it has been used regularly for an extended period of time, or if it has been used in high doses. In such cases, if you suddenly stop this drug, withdrawal reactions may occur. Such reactions can include nausea, vomiting, flushing, stomach cramps, nervousness, or shakiness. Report any such reactions to your doctor immediately. When stopping extended, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Though it is very unlikely to occur, this medication can also result in abnormal drug-seeking behavior (addiction/habit-forming). Do not increase your dose, take it more frequently or use it for a longer period of time than prescribed. Properly stop the medication when so directed. This will lessen the chances of becoming addicted.

When used for an extended period, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

You may have trouble sleeping the first few nights after you stop taking this medication. This is called rebound insomnia and it is normal. It will usually go away after 1-2 nights. If this effect continues, contact your doctor.

Inform your doctor if your condition persists or worsens after 7-10 days.

SIDE EFFECTS: Dizziness, lightheadedness, headache, upset stomach, diarrhea, and dry mouth may occur. To minimize the risk of falls, remember to get up slowly when rising from a seated or lying position. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

This medication may make you sleepy during the day. Tell your doctor if you have daytime drowsiness. Your dose may need to be adjusted.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/pounding heartbeat, unusual tiredness, mental/mood changes (e.g., new or worsening depression, rare thoughts of suicide, hallucinations, aggressive behavior, anxiety), memory loss, unsteadiness.

Tell your doctor immediately if any of these rare but very serious side effects occur: chest pain.

Rarely, after taking this drug, people have gotten out of bed and driven vehicles while not fully awake ("sleep-driving"). People have also sleepwalked, prepared/eaten food, made phone calls, or had sex while not fully awake. Often, these people do not remember these events. If you discover that you have experienced any of these events, tell your doctor immediately.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling (especially of the face, lips, tongue, or throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking zolpidem, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, mental/mood problems (e.g., depression), personal or family history of regular use/abuse of drugs/alcohol/other substances, lung/breathing problems (e.g., chronic obstructive pulmonary disease-COPD, sleep apnea), a certain muscle disease (myasthenia gravis).

This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Avoid alcoholic beverages because they may increase the risk of this drug's side effects.

Caution is advised when using this drug in children because they may be more likely to experience hallucinations, especially if they have attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD).

The elderly may be more sensitive to the effects of this drug, especially dizziness and excessive drowsiness.

This medication should be used only when clearly needed during pregnancy. Infants born to mothers who have taken sedative/hypnotic drugs near the time of delivery may have undesirable effects such as withdrawal symptoms. Discuss the risks and benefits with your doctor.

A small amount of this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because a very serious interaction may occur: sodium oxybate.

If you are currently using this medication listed above, tell your doctor or pharmacist before starting zolpidem.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove zolpidem from your body (such as azole antifungals-including ketoconazole, HIV protease inhibitors-including ritonavir, rifamycins-including rifampin).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for anxiety (e.g., alprazolam, diazepam), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include slowed breathing or a deep sleep from which you cannot be awakened.

NOTES: Do not share this medication with others. It is against the law.

Usually, insomnia is temporary and requires sleep medication only for a short time. If you require treatment for more than 2 weeks, laboratory and/or medical tests should be performed to find the cause of your sleep problem.

As you get older, your sleep pattern may naturally change and your sleep may be interrupted several times during the night. Consult your doctor or pharmacist for ways to improve your sleep without medication, such as avoiding caffeine and alcohol close to bedtime, avoiding daytime naps, and going to bed at the same time each night.

MISSED DOSE: If you miss a dose, take it as soon as you remember if it is still near bedtime and you have trouble falling asleep. If it is already the next day, resume your usual dosing schedule that night at bedtime. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C). Brief storage up to 86 degrees F (30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.