Ambien CR

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, biconvex, debossed with A~ on one side and supplied as:

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

*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 A SANOFI COMPANY. Revised: Dec 2016

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.

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. 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.

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.

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.

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.

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.

AMBIEN CR is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

CNS Depressant Effects And Next-Day Impairment

AMBIEN CR is a central nervous system (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. Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered.

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 co-administered with other CNS depressants or alcohol; or co-administered 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.

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.

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

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

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.

Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” have occurred with AMBIEN CR alone at therapeutic doses, the co-administration of alcohol and other CNS depressants increases 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 also occur.

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

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.

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. Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risk of respiratory depression should be considered prior to prescribing AMBIEN CR in patients with respiratory impairment including sleep apnea and myasthenia gravis.

Precipitation Of Hepatic Encephalopathy

GABA agonists 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.

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.

Severe Injuries

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

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Medication Guide). Inform patients and their families about the benefits and risks of treatment with AMBIEN CR. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with AMBIEN CR and with each prescription refill. Review the AMBIEN CR Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that AMBIEN CR should be taken only as prescribed.

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.

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

Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.

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.

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg. In mice, these doses are approximately 2, 9, and 40 times the maximum recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) on mg/m² basis. In rats, these doses are approximately 4, 18, and 80 times the MRHD on a mg/m² basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid-and high doses.

Mutagenesis

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment Of fertility

Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg/day) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested. The no-effect dose for these findings is approximately 20 times the MRHD on a mg/m² basis. There was no impairment of fertility at any dose tested.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of AMBIEN CR in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. AMBIEN CR should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the AMBIEN CR maximum recommended human dose (MRHD) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis.

Labor And Delivery

AMBIEN CR has no established use in labor and delivery.

Nursing Mothers

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

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. 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 3week 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.

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.

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.

CNS-depressants

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression. Zolpidem tartrate was evaluated in healthy volunteers 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 the absence of an effect following chronic administration.

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated.

Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 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.

A single-dose interaction study with zolpidem tartrate 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 were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.

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 on the pharmacokinetics of zolpidem is unknown.

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC0-∞of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T½ (-36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem.

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30 %) along with an increase in the pharmacodynamic effects of zolpidem.

Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) are also likely to inhibit zolpidem's metabolic pathways, potentially leading to an increase in zolpidem exposure.

Other Drugs With No Interactions With Zolpidem

A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.

Pregnancy Category C

There are no adequate and well-controlled studies of AMBIEN CR in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. AMBIEN CR should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the AMBIEN CR maximum recommended human dose (MRHD) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the MRHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 4 times the MRHD on a mg/m² basis.

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

• CNS-depressant effects and next-day impairment
• Serious anaphylactic and anaphylactoid reactions
• Abnormal thinking and behavior changes, and complex behaviors
• Withdrawal effects

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)

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

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, respiratory depression, 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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 > 2x ULN, alkaline phosphatase ≥ 2x ULN, transaminase ≥ 5x ULN).

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-todate information on the management of hypnotic drug product overdosage.

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.