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Ambien CR (Zolpidem Tartrate) - Warnings and Precautions

 
 



WARNINGS

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. Because some of the important adverse effects of zolpidem appear to be dose related (see Precautions and Dosage and Administration ), it is important to use the smallest possible effective dose, especially in the elderly.

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. Complex behaviorssuch as “sleep-driving” (i.e., driving while not fully awake after ingesting 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 zolpidem alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem appears to increase the risk of such behaviors, as does the use of zolpidem at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem 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.

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 ).

Zolpidem, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien CR 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 CR. Zolpidem 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.

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 tongue, 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.

PRECAUTIONS

General

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 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 zolpidem 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 tartrate in normal 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 an immediate-release formulation of zolpidem tartrate (10 mg) when compared to placebo. However, precautions should be observed if Ambien CR is prescribed to patients with compromised respiratory function, since sedative/hypnotics have the capacity to depress respiratory drive. Ambien CR should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Post-marketing reports of respiratory insufficiency in patients receiving immediate-release zolpidem tartrate, most of which involved patients with pre-existing respiratory impairment, have been received. Data in end-stage renal failure patients repeatedly treated with immediate-release zolpidem tartrate 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 Ambien CR 6.25 mg in patients with hepatic compromise, and they should be closely monitored.

Use in depression

Sedative/hypnotic drugs 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.

Information for Patients

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

“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 ). 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.

Patients should be instructed NOT to take Ambien CR or other sedative-hypnotics when drinking alcohol. In addition, patients should be advised to report all concomitant medications to the prescriber. Patients should be counseled to take Ambien CR right before they get in bed and only when they are able to stay in bed a full night (7-8 hours). Patients should be instructed to report events such as sleep-driving and other complex behaviors immediately to the prescriber.

A patient Medication Guide is available for Ambien CR. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss contents of the Medication Guide and obtain answers to any questions they may have. The Medication Guide is printed at the end of this document.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug interactions

CNS-active drugs

An immediate-release formulation of zolpidem tartrate was evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. A study involving haloperidol and zolpidem tartrate revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem tartrate 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 tartrate produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. 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 tartrate was demonstrated.

A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state levels in male subjects did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem tartrate 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 tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female subjects), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Since the systematic evaluations of Ambien CR 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.

Drugs that affect drug metabolism via cytochrome P450

Compounds that inhibit cytochrome P450 may enhance the activity of zolpidem.

A randomized, double-blind, crossover interaction study in ten healthy subjects between itraconazole (200 mg once daily for 4 days) and a single dose of an immediate-release formulation of zolpidem tartrate (10 mg) given five 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 double blind crossover interaction study in twelve healthy subjects showed that co-administration of 5 mg of immediate-release zolpidem tartrate with ketoconazole (200 mg twice daily), a potent CYP3A4 inhibitor, increased the total AUC of zolpidem by a factor 1.83 compared to zolpidem alone, prolonged the elimination half life and decreased oral clearance to 64% along with an increase in the pharmacodynamic effects of zolpidem. A routine dosage adjustment is not considered necessary, however, patients should be advised that use of Ambien CR with ketoconazole may enhance the sedative effects.

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.

Other drugs

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 had no effect on digoxin kinetics and did not affect prothrombin time when given with warfarin in normal subjects. Zolpidem's sedative/hypnotic effect was reversed by flumazenil; however, no significant alterations in zolpidem pharmacokinetics were found.

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.

Carcinogenesis, Mutagenesis, and 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 [MHRD] 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 theMRHD of Ambien CR on a mg/m2 basis).

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 base/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 embryo/fetal toxicity was 4 mg base/kg/day (4 times the MRHD of Ambien CR 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 (up to 30 times the MRHD of Ambien CR, 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 CR, on a mg/m2 basis). The no-effect dose for embryofetal toxicity was 4 mg base/kg/day (8 times the MRHD of Ambien CR 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 (4 times the MRHD of Ambien CR on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Ambien CR 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 CR has no established use in labor and delivery. (See also 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, 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 CR in nursing mothers is not recommended.

Pediatric Use

Safety and effectiveness of Ambien CR in patients below the age of 18 have not been established.

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 event 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.

Page last updated: 2007-09-27

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