"The U.S. Food and Drug Administration today announced it is requiring the manufacturers of Ambien, Ambien CR, Edluar and Zolpimist, widely used sleep drugs that contain the active ingredient zolpidem, to lower current recommended doses. Ambi"...
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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 (zolpidem tartrate) alone at therapeutic doses, the use of alcohol and other CNS depressants with Ambien CR (zolpidem tartrate) appears to increase the risk of such behaviors, as does the use of Ambien CR (zolpidem tartrate) at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Ambien CR (zolpidem tartrate) 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.
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 (zolpidem tartrate) , like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Ambien CR (zolpidem tartrate) 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 (zolpidem tartrate) . Ambien CR (zolpidem tartrate) 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 (zolpidem tartrate) is administered with such agents because of the potentially additive effects.
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 (zolpidem tartrate) 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 (zolpidem tartrate) 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 (zolpidem tartrate) 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 (zolpidem tartrate) 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 (zolpidem tartrate) 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 (zolpidem tartrate) 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 (zolpidem tartrate) 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.
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 (zolpidem tartrate) 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 (zolpidem tartrate) when drinking alcohol.
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 Category C
There are no adequate and well-controlled studies of Ambien CR (zolpidem tartrate) in pregnant women. Ambien CR (zolpidem tartrate) 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 (zolpidem tartrate) 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.
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 (zolpidem tartrate) has no established use in labor and delivery [see Pregnancy].
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 (zolpidem tartrate) is administered to a nursing woman.
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 (zolpidem tartrate) in the pediatric population based on these efficacy and safety findings.
A total of 99 elderly ( ≥ 65 years of age) received daily doses of 6.25 mg Ambien CR (zolpidem tartrate) in a 3-week placebo-controlled study. The adverse reaction profile of Ambien CR (zolpidem tartrate) 6.25 mg in this population was similar to that of Ambien CR (zolpidem tartrate) 12.5 mg in younger adults ( ≤ 64 years of age). Dizziness was reported in 8% of Ambien CR (zolpidem tartrate) -treated patients compared with 3% of those treated with placebo.
The dose of Ambien CR (zolpidem tartrate) in elderly patients is 6.25 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 5/10/2010
This monograph has been modified to include the generic and brand name in many instances.
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