National Geographic : 2005 May
Ambien® Drugs that affect drug metabolism via cytochromeP450:A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once i eit daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of (zolpidem tartrate) itraconazole resulted in a 34% increase in AUC. of zolpidem. There were no significant BRIEFSUMMARY pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psy INDICATIONSANDUSAGE chomotor performance. Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia. Ambien A randomized, placebo-controlled, crossover interaction study in eight healthy female has been shown to decrease sleep latency and increasethe duration of sleepfor up to volunteers between 5 consecutive daily doses of rifampin 600 mg) and a single dose of 35 days in controlled clinicalstudies. zolpidem(20 mg) given 17 hours afterthe lastdose of rifampin showed significant reduc Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation of the tions of the AUC (-73%), C,, (-58%),and T10 -36%) of zolpidem together with significant patient is recommended ifthey are to be taken for more than 2 to 3 weeks. Ambien should reductions in the pharmacodynamic effects of zolpidem. not be prescribed in quantities exceeding a 1-month supply (see Warnings). Other drugs: A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations CONTRAINDICATIONS revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpi None known. dem. Zolpidem had no effect on digoxin kinetics and did not affect prothrombin time when WARNek . given with warfarin innormal subjects. Zolpidem's sedative/hypnotic effect was reversed by WARNINGS iflumazenil; however, no significant alterations in zolpidem pharmacokinetics were found. Sincesleep disturbances maybethe presenting manifestationofa physicaland/or psychic DrugLaboratory test interactions:Zolpidemis not knownto interfere with commonly atric disorder, symptomatic treatment of insomnia should be initiated only after a careful Drug/Laboratorytest interactions: Zolpidem is not known to interfere with commonly evaluation of the patient. The failure of insomnia to remit after 7 to 10 days oftreatment may employss-read c with labenzodiazepitests. In addition, barbiturnicaldates, coindicaine, cannabinolpids, or amphet indicate the presence of a primary psychiatric and/or medical illness which should be eval- amines intwo nzodiazepines, opiates, barbiturates,cocaine, cannabinoids, or amphet uated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities ames n standard urinedrug screens. may be the consequence of an unrecognized psychiatric or physical disorder. Such findings Carcingenesis, mutagenesis, impairment of ferti iy have emerged during the course of treatment with sedative/hypnotic drugs, including Carcinogenesis:Zolpidem was administered to rats and mice for 2 years at dietary dosages Ambien. Becausesome of the importantadverse effectsof Ambienappear to be dose of4, 18,and80 mg/kg/day.Inmice,thesedosesare26to52imesor2to35timesthe max related(see Precautionsand DosageandAdministration),it is importantto usethe smallest imum 10-mghuman doseon amg/kg or mg/m 2 basis,respectively.In rats these dosesare possible effective dose, especially in the elderly. 43 to 876 times or 6 to 115 times the maximum 10-mg human dose on a mg/kg or mg/ma Avariety of abnormal thinking and behaviorchanges have been reported to occur in asso- basis, respectively. No evidence of carcinogenic potential was observed in mice. Renal ciation with the use of sedative/hypnotics. Some of these changes may be characterized by liposarcomas were seen in4/100 rats (3 males, 1 female) receiving 80 mg/kg/day and a renal decreased inhibition leg, aggressiveness and extroversion that seemed out of character), lipoma was observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma similar to effects produced by alcohol and other CNS depressants. Other reported behav- and liposarcoma for zolpidem were comparable to those seen in historical controls and the ioral changes have included bizarre behavior, agitation, hallucinations, and depersonaliza- tumor findings are thought to be a spontaneous occurrence. tion. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily Mtagenesis: Zolpidem did not have mutagenic activity in several tests including the Ames depressed patients, worsening of depression, including suicidal thinking, has been reported test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured in association with the useof sedative/hypnotics. human lymphocytes, unscheduled DNA synthesis in rat hepatocytes in vitro, and the It can rarely be determined with certainty whether a particular instance of the abnormal micronucleus test in mice. behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying Impairment of fertility: In a rat reproduction study, the high dose (100 mg base/kg) of psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or zolpidem resulted in irregular estrus cycles and prolonged precoital intervals, but there symptom of concern requires careful and immediate evaluation, was no effect on male or female fertilityafter daily oral doses of 4 to 100 mg base/kg or 5 to Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there 130times the recommended human dose in mg/m 2 . No effects on any other fertilityparam have been reports of signs and symptoms similar to those associated with withdrawal from eters were noted. other CNS-depressant drugs (see DrugAbuse and Dependence). Pregnancy Ambien, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid Teratogenic effects: Category B. Studies to assess the effects of zolpidem on human repro onset of action, Ambien should only be ingested immediately prior to going to bed. Patients duction and development have not been conducted. should be cautioned against engaging inhazardous occupations requiring complete mental Teratology studies were conducted in rats and rabbits. alertness or motor coordination such as operating machinery or driving a motor vehicle In rats, adverse maternal and fetal effects occurred at 20 and 100 mg base/kg and after ingesting the drug, including potential impairment of the performance of such activi- included dose-related maternal lethargy and ataxia and a dose-related trend to incomplete ties that may occur the day following ingestion of Ambien. Ambien showed additive effects ossification of fetal skull bones. when combined with alcohol and should not be taken with alcohol. Patients should also be In rabbits, dose-related maternal sedation and decreased weight gain occurred at all cautioned about possible combined effects with other CNS-depressant drugs. Dosage doses tested. At the high dose, 16 mg base/kg, there was an increase in postimplantation adjustments may be necessary when Ambien is administered with such agents because of fetal loss and underossification of sternebrae in viable fetuses. the potentially additive effects. This drug should be used during pregnancy only if clearly needed. PRECAUTIONS Nonteratogenic effects: Studies to assess the effects on children whose mothers took zolpi General dem during pregnancy have not been conducted. However, children born of mothers taking Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance sedative/hypnotic drugs may be at some risk for withdrawal symptoms from the drug dur after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in ing the postnatal period. In addition, neonatal flaccidity has been reported in infants born of the treatment of elderly and/or debilitated patients. Therefore, the recommended Ambien mothers who received sedative/hypnotic drugs during pregnancy. dosage is 5 mg in such patients (see Dosage and Administration) to decrease the Laborand delivery:Ambien has no established use in labor and delivery. possibility of side effects. These patients should be closely monitored. Nursing mothers: Studies in lactating mothers indicate that between 0.004 and 0.019% of Use in patients with concomitant illness:Clinicalexperience with Ambien in patients with the total administered dose is excreted into milk, but the effect of zolpidem on the infant is concomitant systemic illness is limited. Caution is advisable in using Ambien in patients unknown. with diseases or conditions that could affect metabolism or hemodynamic responses. The use of Ambien in nursing mothers is not recommended. Although studies did not reveal respiratory depressant effects at hypnotic doses of Ambien Pediatric use: Safety and effectiveness in pediatric patients below the age of 18 have not in normals or in patients with mild to moderate chronic obstructive pulmonary disease been established. (COPD),a reduction in the Total Arousal Index together with a reduction in lowest oxygen Geriatricuse: A total of 154 patients in U.S.controlled clinical trials and 897 patients in non saturation and increase in the times of oxygen desaturation below 80% and 90% was U.S .clinical trials who received zolpidem were 60 years of age. For a pool of U.S. patients observed in patients with mild-to-moderate sleep apnea when treated with Ambien (10 mg) receiving zolpidem at doses of s10 mg or placebo, there were three adverse events occur when compared to placebo. However, precautions should be observed if Ambien is ring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was prescribed to patients with compromised respiratory function, since sedative/hypnotics at least twice the placebo incidence (ie, they could be considered drug related). have the capacity to depress respiratory drive. Post-marketing reports of respiratory insuffi- Averse Event Zolpidem Placebo ciency, most of which involved patients with pre-existing respiratory impairment, have been nvre vedn dem aen received. Data in end-stage renal failure patients repeatedly treated with Ambien did not izziness 3% 0% demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage Drowsiness 5% 2% adjustment in renally impaired patients is required; however, these patients should be Diarrhea 3% 1% closely monitored (see Pharmacokinetics).A study in subjects with hepatic impairment did A total of 30/1,959 (1.5%)non-U.S . patients receiving zolpidem reported falls,including 28/30 reveal prolonged elimination in this group; therefore, treatment should be initiated with (93%)who were a70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem 5 mg in patients with hepatic compromise, and they should be closely monitored, doses >10 mg. A total of 24/1,959 (1.2%) non-U.S . patients receiving zolpidem reported Use in depression: As with other sedative/hypnotic drugs, Ambien should be administered confusion, including 18/24(75%) who were a70years of age. Of these 18 patients, 14 (78%) with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies were receiving zolpidem doses >10 mg. may be present insuch patients and protective measures may be required. Intentional over- ADVERSEREACTIONS dosage is more common in this group of patients; therefore, the least amount of drug that Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who is feasible should be prescribed for the patient at any one time. received zolpidem at all doses (1.25 to 90 mg) in U.S.premarketing clinical trials discontin Informationforpatients: Patient information is printed in the complete prescribing information, ued treatment because of an adverse clinical event. Events most commonly associated with Laboratorytests: There are no specific laboratory tests recommended, discontinuation from U.S. trials were daytime drowsiness (0.5%),dizziness (0.4%), headache Drug interactions (0.5%),nausea (0.6%),and vomiting (0.5%). CNS-active drugs: Ambien was evaluated in healthy volunteers in single-dose interaction Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) studies for several CNS drugs. A study involving haloperidol and zolpidem revealed no in similar foreign trials discontinued treatment because of an adverse event. Events effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. most commonly associated with discontinuation from these trials were daytime Imipramine in combination with zolpidem produced no pharmacokinetic interaction other drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache than a 20% decrease in peak levels of imipramine, but there was an additive effect of (0.4%),and falls (0.4%). decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI)treated pharmacokinetic interaction, but there was an additive effect of decreased alertness and patients were given zolpidem revealed that four of the seven discontinuations during psychomotor performance. The lack of a drug interaction following single-dose administra- double-blind treatment with zolpidem (n=95) were associated with impaired concentration, tion does not predict a lack following chronic administration, continuing or aggravated depression, and manic reaction; one patient treated with placebo An additive effect on psychomotor performance between alcohol and zolpidem was (n=97) was discontinued after an attempted suicide. demonstrated. Incidencein controlled clinical trials Asingle-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state Most commonly observed adverse events in controlled trials: During short-term treatment levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed adverse pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady- events associated with the use of zolpidem and seen at statistically significant differences state concentrations were evaluated in healthy females, the only significant change was a from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizzi 17% increase in the zolpidem half-life. There was no evidence of an additive effect in ness 1%), and diarrhea (1%). During longer-term treatment (28to 35 nights) with zolpidem psychomotor performance. at doses up to 10 mg, the most commonly observed adverse events associated with the use Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline of zolpidem and seen at statistically significant differences from placebo-treated patients 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem C,,, were dizziness (5%)and drugged feelings (3%). was significantly higher (43%) and T,,,, was significantly decreased (53%).Pharmacokinetics Treatment-emergent adverse experiences in placebo-controlled clinical trials: The follow of sertraline and N-desmethylsertraline were unaffected by zolpidem. ing are treatment-emergent adverse events from U.S.placebo-controlled clinical trials. Data Since the systematic evaluations of Ambien in combination with other CNS-active drugs are limited to data from doses up to and including 10 mg. In short-term trials, events seen have been limited, careful consideration should be given to the pharmacology of any in zolpidem patients (n=685) at an incidence equal to 1% or greater compared to placebo CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could (n=4731were: headache (7% vs 6% for placebo), drowsiness (2% vs 0%), dizziness (1% vs potentially enhance the CNS-depressant effects of zolpidem.