WARNINGS AND 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 tartrate.
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 tartrate. 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 Edluar 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 tartrate 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 (8.4) ].
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 tartrate. 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 Edluar alone at therapeutic doses, the use of alcohol and other CNS depressants with Edluar appears to increase the risk of such behaviors, as does the use of Edluar at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Edluar 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), 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 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 (9) ].
CNS depressant effects
Edluar, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Edluar should 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 Edluar. 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 of Edluar may be necessary when Edluar 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 Edluar dosage is 5 mg in the elderly and/or debilitated patients [ see Dosage and Administration (2.2) and Geriatric Use (8.5) ] to decrease the possibility of side effects. These patients should be closely monitored.
Use in patients with concomitant illness:
Clinical experience with zolpidem tartrate in patients with concomitant systemic illness is limited. Caution is advisable in using Edluar 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 zolpidem tartrate (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if Edluar is prescribed to patients with compromised respiratory function. Edluar should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Post-marketing reports of respiratory insufficiency following treatment with 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 zolpidem tartrate did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment of Edluar in renally impaired patients is required; however, these patients should be closely monitored [ see Clinical Pharmacology (12.3) ].
A study in subjects with hepatic impairment treated with zolpidem tartrate did reveal prolonged elimination in this group; therefore, treatment with Edluar should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [ see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ].
Use in patients with depression:
As with other sedative/hypnotic drugs, Edluar 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.
Edluar is not recommended for use in children. Safety and effectiveness of Edluar have not been established in pediatric patients below the age of 18. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD, an oral solution of 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 (8.4) ].
USE IN SPECIFIC POPULATIONS
Pregnancy Category C:
There are no adequate and well-controlled studies of Edluar in pregnant women. Edluar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. There is a published case report documenting the presence of zolpidem in human umbilical cord blood. Children born to 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 to mothers who received sedative-hypnotic drugs during pregnancy.
Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 10 mg/day (8 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 5, 24, and 120 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 5 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 2.5, 10, and 40 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 10 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 5, 24, and 120 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 5 times the MRHD on a mg/m2 basis.
Labor and delivery
Edluar has no established use in labor and delivery [ see Pregnancy (8.1) ].
Zolpidem is excreted into human milk. Studies in lactating mothers indicate that the T1/2 of zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hours). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Edluar is administered to a nursing mother.
Safety and effectiveness of Edluar have not been established in pediatric patients below the age of 18.
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 (5.6) ]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥60 years of age. For a pool of U.S. patients receiving zolpidem tartrate 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 (i.e., they could be considered drug-related).
| Adverse Event || Zolpidem || Placebo |
|Dizziness ||3% ||0% |
|Drowsiness ||5% ||2% |
|Diarrhea ||3% ||1% |
A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem tartrate 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 (78%) were receiving zolpidem doses >10 mg.
The dose of Edluar in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [ see Dosage and Administration (2), Warnings and Precautions (5) Clinical Pharmacology (12) and Clinical Studies (14) ].