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General

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 Ambien. Because some of the important adverse effects of Ambien appear to be dose related [see DOSAGE AND ADMINISTRATION], it is important to use the smallest possible effective dose, especially in the elderly.

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 Ambien. 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 Ambien 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 (eg, 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.]

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. 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 alone at therapeutic doses, the use of alcohol and other CNS depressants with Ambien appears to increase the risk of such behaviors, as does the use of Ambien at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Ambien 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 thinking, has 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, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien should only be ingested 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. Ambien 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 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 dosage is 5 mg in such patients [see DOSAGE AND ADMINISTRATION] to decrease the possibility of side effects. These patients should be closely monitored.

Use in patients with concomitant illness

Clinical experience with Ambien (zolpidem tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using Ambien 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 Ambien 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 Ambien (10 mg) when compared to placebo. However, precautions should be observed if Ambien is prescribed to patients with compromised respiratory function, since sedative/hypnotics have the capacity to depress respiratory drive. Ambien should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Post-marketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. Data in end-stage renal failure patients repeatedly treated with Ambien 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 Pharmacokinetics ]. A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored.

Use in depression

As with other sedative/hypnotic drugs, Ambien 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 over-dosage 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.

Pediatric patients

Safety and effectiveness of zolpidem have not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD, 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: Pediatric Use ].

Laboratory tests

Monitoring

There are no specific laboratory tests recommended to monitor zolpidem levels.

Interference with laboratory tests

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.

Non Clinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Zolpidem was administered to rats and mice for 2 years at dietary dosages of 4, 18, and 80 mg/kg/day. In mice, these doses are 26 to 520 times or 2 to 35 times the maximum 10 mg human dose on a mg/kg or mg/m² basis, respectively. In rats these doses are 43 to 876 times or 6 to 115 times the maximum 10 mg human dose on a mg/kg or mg/m² basis, respectively. No evidence of carcinogenic potential was observed in mice. Renal liposarcomas were seen in 4/100 rats (3 males, 1 female) receiving 80 mg/kg/day and a renal lipoma was observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma for zolpidem were comparable to those seen in historical controls and the tumor findings are thought to be a spontaneous occurrence.

Mutagenesis

Zolpidem did not have mutagenic activity in several tests including the Ames test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human lymphocytes, unscheduled DNA synthesis in rat hepatocytes in vitro, and the micronucleus test in mice.

Impairment of fertility

In a rat reproduction study, the high dose (100 mg base/kg) of zolpidem resulted in irregular estrus cycles and prolonged precoital intervals, but there was no effect on male or female fertility after daily oral doses of 4 to 100 mg base/kg or 5 to 130 times the recommended human dose in mg/m². No effects on any other fertility parameters were noted.

Use In Specific Populations

Pregnancy Teratogenic effects

Pregnancy Category C

Zolpidem tartrate was administered to pregnant Sprague-Dawley rats by oral gavage during the period of organogenesis at doses of 4, 20, or 100 mg based/kg/day. Adverse maternal and embryo/fetal effects occurred at doses of 20 mg base/kg and higher, manifesting as dose-related lethargy and ataxia in pregnant rats while examination of fetal skull bones revealed a dose-related trend toward incomplete ossification. Teratogenicity was not observed at any dose level. The no-effect dose of zolpidem for maternal and embryofetal toxicity was 4 mg base/kg/day (between 4 to 5 times the MRHD of Ambien on a mg/m² basis).

Administration of zolpidem tartrate to pregnant Himalayan Albino rabbits at doses of 1, 4, or 16 mg base/kg/day by oral gavage (over 35 times the MRHD of Ambien on a mg/m² basis) during the period of organogenesis produced dose-related maternal sedation and decreased maternal body weight gain at all doses. At the high dose of 16 mg base/kg, there was an increase in postimplantation fetal loss and under-ossification of sternebrae in viable fetuses. Teratogenicity was not observed at any dose level. The no-effect dose of zolpidem for maternal toxicity was below 1 mg base/kg/day (< 2-times the MRHD of Ambien on a mg/m² basis). The no-effect dose for embryofetal toxicity was 4 mg base/kg/day (between 9 and 10 times the MRHD of Ambien on a mg/m² basis).

Administration of zolpidem tartrate at doses of 4, 20, or 100 mg base/kg/day to pregnant Sprague-Dawley rats starting on Day 15 of gestation and continuing through Day 21 of the postnatal lactation period produced dose-dependent lethargy and ataxia in dams at doses of 20 mg base/kg and higher. Decreased maternal body weight gain as well as evidence on non-secreting mammary glands and a single incidence of maternal death was observed at 100 mg base/kg. Effects observed on rat pups included decreased body weight with maternal doses of 20 mg base/kg and higher and decreased pup survival at maternal doses of 100 mg base/kg. The no-effect dose for maternal and offspring toxicity was 4 mg base/kg (between 4 to 5 times the MRHD of Ambien on a mg/m² basis).

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

Nonteratogenic effects. Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. However, 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 (zolpidem tartrate) has no established use in labor and delivery.

Nursing mothers

Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young normal volunteers (2.6 ± 0.3 hr). Between 0.004 and 0.019% of the total administered dose is excreted into milk, but the effect of zolpidem on the infant is unknown.

In addition, in a rat study, zolpidem inhibited the secretion of milk. The no-effect dose was 4 mg base/kg or 6 times the recommended human dose in mg/m².

The use of Ambien in nursing mothers is not recommended.

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, 0.25 mg/kg/day, up to a maximum of 10 mg/day (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 events 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: Special Populations]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse event.

Geriatric use

A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received zolpidem were ≥60 years of age. For a pool of U.S. patients receiving zolpidem at doses of≤ 10 mg or placebo, there were three adverse events occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (ie, they could be considered drug related).

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30 (93%) who were ≥70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were 70 years of age. Of these 18 patients, 14 (7≥8%) were receiving zolpidem doses >10 mg.

The recommended dose of Ambien is 5 mg in elderly to decrease the possibility of side effects [see DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS ].

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