Zolpidem Tartrate (Page 3 of 5)

7 DRUG INTERACTIONS

7.1 CNS active drugs

Zolpidem tartrate tablets were evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem 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 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 was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)].

A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem 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 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), 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 zolpidem tartrate tablets 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.

7.2 Drugs that affect drug metabolism via cytochrome P450

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 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, placebo-controlled, crossover interaction study in eight healthy female volunteers between 5 consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (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.

7.3 Other drugs

A study involving cimetidine/zolpidem and ranitidine/zolpidem 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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 zolpidem tartrate tablets 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 zolpidem tartrate tablets 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 zolpidem tartrate tablets 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 zolpidem tartrate tablets 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 zolpidem tartrate tablets on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Zolpidem tartrate tablets 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.

8.2 Labor and delivery

Zolpidem tartrate tablets have no established use in labor and delivery.

8.3 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 zolpidem tartrate tablets in nursing mothers is not recommended.

8.4 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 (5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse event.

8.5 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).

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 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 recommended dose of zolpidem tartrate tablets is 5 mg in elderly to decrease the possibility of side effects [see Dosage and Administration (2) and Warnings and Precautions (5)].

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