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 详细处方信息以本药内容附件PDF文件（201051022514721.pdf）的“原文Priscribing Information”为准
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部分中文Ambien CR处方资料（仅供参考）

1、通用名称：酒石酸唑吡坦缓释片
   英文名称：Zolpidem Tartrate Extended Release Tablets
2、规格：（1）6.25mg （2）12.5mg
3、申报注册分类：酒石酸唑吡坦缓释片按照现行《药品注册管理办法》化学药品注册分类5类。
4、药理毒理
    药理作用：本品为咪唑并吡啶类催眠药，其化学结构与苯二氮卓类（BZ）、巴比妥类或其他类已知催眠药均不同。本品与γ氨基丁酸—苯二氮卓类（GABA—BZ）受体复合物相互作用，具有BZ类的一些药理学特性。体外试验表明，与BZ类非选择性结合并激动所有ω受体亚型的作用机制不同，本品与ω1受体的α1α5亚单位的亲和率高。ω1受体主要存在于皮质感觉运动区的IV层、黑质、小脑分子层、嗅球、腹侧丘脑复合体、脑桥、下丘和苍白球。虽然本品与ω1受体选择性结合并不是绝对的，但这种选择性可用来解释催眠剂量的本品能维持人的深睡眠和动物试验中本品几乎无肌肉松弛及抗惊厥作用的原因。
    毒理研究：遗传毒性：Ames试验、体外小鼠淋巴瘤细胞遗传毒性试验、人淋巴细胞染色体畸变试验、体外大鼠肝细胞的非程序化DNA合成试验和小鼠微核试验结果均为阴性。
生殖毒性：大鼠生殖毒性试验中，高剂量组（100mg碱/kg）大鼠出现不规律发情期和早熟间隔延长，但每天经口服给予4～100mg/kg或相当于人用推荐剂量的5～130倍（以mg/m2计算）时，对雌、雄大鼠生殖力无影响，对其他生殖参数亦无影响。20和100mg/kg的唑吡坦对孕鼠和胎鼠均有不良影响，包括与剂量相关的孕鼠嗜睡、共济失调和与剂量有关的胎鼠颅骨骨化不全。各种胎鼠骨骼的骨化不全提示了成熟延迟，此情况在使用镇静/催眠药的大鼠中常见。唑吡坦无致畸作用。唑吡坦对孕鼠和胎鼠无毒性作用的剂量是4mg碱/kg或相当于人用最大剂量的5倍（按mg/m2计算）。孕兔的所有剂量组均出现与剂量相关的镇静和体重减轻。高剂量组（16mg碱/kg）的植入后丢失和存活的胎兔胸骨节骨化不全发生率增加。胎兔的这些改变常常伴随孕兔的体重减轻。唑吡坦无明显的致畸作用。唑吡坦对胎兔的无毒性作用的剂量是4mg碱/kg或相当于人用最大剂量的7倍（按mg/m2计算）。
    由于动物生殖研究并不总能预测药物对人的作用，只有在明确需要时，本品才能用于怀孕期。
致癌性：小鼠连续2年服用唑吡坦4、18、80mg/kg/天，按mg/kg或mg/m2计算，分别相当于人用最大剂量10mg的26～520倍或2～35倍，未发现致癌作用。大鼠连续2年服用唑吡坦4、18、80mg/kg/天，按mg/kg或mg/m2计算，分别相当于人用最大剂量10mg的43～876倍或6～115倍，80mg/kg/天组发现4/100只大鼠（雄：3只，雌：1只）发生肾脂肪肉瘤，18mg/kg/天组有1只雄性大鼠发生肾脂肪瘤。由于唑吡坦组大鼠脂肪瘤和脂肪肉瘤的发生率与历史性对照相当，故认为此现象属自发性。
    药代动力学：文献报道：本品在胃肠道吸收迅速。45名健康志愿者单次口服酒石酸唑吡坦片5mg或10mg，平均Cmax分别为59（范围：29～113）ng/ml和121（范围：58～272）ng/ml,Tmax均为1.6h，平均消除半衰期为2.6（范围：1.4～4.5）h和2.5（范围：1.4～3.8）h。本品在5～20mg范围内的药动学呈线性。本品最初主要分布于腺体和脂肪组织，然后迅速消除，少量可分泌进入乳汁，在人体内的主要代谢途径为氧化苯甲基、咪唑并吡啶基生成羧酸及羟化咪唑并吡啶基，非主要代谢途径为氧化酰胺基上的甲基，代谢物均无药理活性。服药量的79～96%以代谢物的形式随胆汁、尿液和粪便排出。年轻成年人连续2周每晚服用本品20mg无蓄积。本品的血浆浓度在40～790ng/ml之间时，其血浆蛋白结合率与血浆浓度无关，本品的血浆蛋白结合率为92.5%。30名健康男性志愿者空腹或餐后20min服用本品10mg的药代动力学。结果显示：食物可以使本品的平均AUC降低15%，Cmax降低25%，平均Tmax延长60%（从1.4到2.2h），半衰期无改变。与年轻人（20～40岁）相比，老年人（>70岁）单次口服本品20mg后，平均Cmax、T1/2和AUC分别显著增加50%（255vs384ng/ml）、32%（2.2vs2.9h）和64%（955vs1，562ng·h/ml）。老年人连续1周每晚口服本品10mg,无蓄积现象。
    与健康人相比，8名慢性肝功能不全的患者单次口服本品20mg后，平均Cmax增加2倍（250vs499ng/ml）平均AUC增加了5倍（788vs4,203ng·h/ml），Tmax无改变。与正常人的平均半衰期2.2h（范围：1.6～2.4h）相比，肝硬化患者的平均半衰期9.9h（范围：4.1～25.8h）明显延长。
11名每周血液透析3次的终末期肾衰患者（平均肌酐清除率=6.5±1.5ml/min）口服本品10mg，连续14或21天。调节基值浓度后，服药的第一天和最后一天的Cmax、Tmax 、T1/2和AUC无显著差异。肾功能受损的患者服用本品的药代动力学无显著变化。
5、适应症：用于治疗入睡困难和(或)睡眠不能维持的失眠症。
6、用法用量：口服。就寝前服用。 

Ambien CR
(zolpidem tartrate) Extended-Release Tablets

DRUG DESCRIPTION
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.

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.

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INDICATIONS
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].

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DOSAGE AND ADMINISTRATION
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 [seeWARNINGS 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.

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HOW SUPPLIED
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.

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SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
•Serious anaphylactic and anaphylactoid reactions [seeWARNINGS AND PRECAUTIONS)
•Abnormal thinking, behavior changes, and complex behaviors [seeWARNINGS AND PRECAUTIONS]
•Withdrawal effects [seeWARNINGS AND PRECAUTIONS]
•CNS-depressant effects [seeWARNINGS 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.

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.

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DRUG INTERACTIONS
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 [seeWARNINGS 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 days) 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 T1/2 (–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.

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WARNINGS
Included as part of the PRECAUTIONS section.

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PRECAUTIONS
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
Prescribes 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 [see 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 was administered to mice and rats for 2 years at dietary dosages 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 or approximately 4, 20, and 100 times the MRHD on a mg/m2 basis) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals. 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. Ambien CR should be used during pregnancy only if the potential benefit justifies 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 (approximately 4, 20 and 100 times the MRHD on a mg/m2 basis) 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 (approximately 2, 8 and 30 times the MRHD on a mg/m2 basis), 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 (approximately 4, 20 and 100 times the MRHD on a mg/m2 basis) 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.

Neonatal complications
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 some 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.

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

Nursing mothers
Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Ambien CR is administered to a nursing woman.

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].

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OVERDOSE
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.

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CONTRAINDICATIONS
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 [seeWARNINGS AND PRECAUTIONS].

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