DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Zolpimist (Zolpidem Tartrate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Zolpimist (zolpidem tartrate) is a gamma-aminobutyric acid (GABA) A agonist of the imidazopyridine class. Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide l-(+)-tartrate (2:1). It has the following structure:

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.89.

Zolpimist is available as an oral solution designed to be sprayed directly into the mouth over the tongue. Each metered actuation of Zolpimist delivers 5 mg of zolpidem tartrate in 100 μL. Two actuations deliver 10 mg of zolpidem tartrate. Zolpimist includes the following inactive ingredients: artificial cherry flavor, benzoic acid, citric acid monohydrate, hydrochloric acid, neotame, propylene glycol, and purified water.

CLINICAL PHARMACOLOGY

Mechanism of Action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the α15 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

Pharmacokinetics

Zolpimist (zolpidem tartrate) Oral Spray is bioequivalent to Ambien® tablets (Sanofi-Aventis). The pharmacokinetic profile of Zolpimist is characterized by rapid absorption from the oral mucosa and gastrointestinal tract, and a short elimination t1/2 in healthy subjects.

In a single-dose crossover study in 10 healthy young (18-40 years of age) male subjects administered 2.5, 5, and 10 mg Zolpimist, the results demonstrated a linear relationship to dose for mean Cmax and AUC0-∞ over the range of doses administered in the study.

In a single-dose crossover study in 43 healthy young (18-45 years of age) subjects administered 5 and 10 mg Zolpimist, the means for Cmax were 114 (range: 19 to 197) and 210 ng/mL (range: 77 to 401), respectively, occurring at a mean time to maximum concentration (Tmax) of approximately 0.9 hours for both. The mean zolpidem t1/2 was 2.7 (range: 1.7 to 5.0) and 3.0 hours (range: 1.7 to 8.4), for 5 and 10 mg Zolpimist, respectively. In the same study, the means for Cmax were 123 (range: 53 to 221) and 219 ng/mL (range: 101 to 446) for 5 and 10 mg Ambien® tablets, respectively, occurring at a mean Tmax of 0.9 and 1.0 hours, respectively. The mean zolpidem t1/2 was 2.8 (range: 1.5 to 6.0) and 3.1 hours (range: 1.1 to 8.6) for the 5 and 10 mg Ambien® tablets, respectively.

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion. Total protein binding for zolpidem was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate for 2 weeks.

A food-effect crossover study in 14 healthy young (18-45 years of age) male subjects compared the pharmacokinetics of Zolpimist 10 mg when administered while fasting at least 8 hours or 5 minutes after eating a standard high-fat meal. Results demonstrated that with food, mean AUC0-∞ and Cmax were decreased by 27% and 58%, respectively, while mean Tmax was prolonged by 225% (from 0.8 to 2.6 hours). These results suggest that, for faster sleep onset, as with all zolpidem products, Zolpimist should not be administered with or immediately after a meal.

Special Populations:

Elderly: In the elderly, the dose for zolpidem tartrate should be 5 mg [see Warnings and Precautions ( 5 ) and Dosage and Administration ( 2 )]. This recommendation is based on several studies in which the mean Cmax, t1/2, and AUC were significantly increased when compared to results in young adults administered zolpidem tartrate. In a pharmacokinetic study of 24 elderly (≥65 years of age) subjects administered 5 mg Zolpimist, the means for Cmax and AUC were 134 ng/mL and 493 ng∙hr/mL respectively, following administration of a single 5 mg oral dose of Zolpimist. Zolpidem tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic impairment: The pharmacokinetics of zolpidem in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 ng∙hr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean t1/2 in cirrhotic patients of 9.9 hours (range: 4.1 to 25.8 hours) was greater than that observed in normal subjects of 2.2 hours (range: 1.6 to 2.4 hours). Dosing should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration ].

Renal impairment: The pharmacokinetics of zolpidem were studied in 11 patients with end-stage renal failure (mean Cl Cr=6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, t1/2, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function.

Drug interactions:

CNS-depressants: Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs. 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.

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions].

Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 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.

A single-dose interaction study with zolpidem tartrate 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 were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem t1/2 (17%) was observed. There was no evidence of an additive effect in psychomotor performance.

Drugs that affect drug metabolism via cytochrome P450: Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady state levels in male volunteers resulted in a 34% increase in AUC0-∞ of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects 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 tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem.

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination t1/2 (30%) along with an increase in the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

Other drugs with no interactions with zolpidem: 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 tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in healthy subjects.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2.5, 10, and 50 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) on mg/m2 basis. In rats, these doses are approximately 5, 20, and 100 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/day) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested. The no-effect dose for these findings is approximately 24 times the MRHD on a mg/m2 basis. There was no impairment of fertility at any dose tested.

CLINICAL STUDIES

Transient Insomnia

Normal adults experiencing transient insomnia (n=462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo on objective (polysomnographic) measures of sleep latency, sleep duration, and number of awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n=35) during the first two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15, and 20 mg) and placebo. All zolpidem doses were superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).

Chronic Insomnia

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n=75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem.

Studies Pertinent to Safety Concerns for Sedative-hypnotic Drugs

Next-day residual effects: Next-day residual effects of zolpidem tartrate were evaluated in seven studies involving normal subjects. In three studies in adults (including one study in a phase advance model of transient insomnia) and in one study in elderly subjects, a small but statistically significant decrease in performance was observed in the Digit Symbol Substitution Test (DSST) when compared to placebo. Studies of zolpidem tartrate in non-elderly patients with insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep Latency Test (MSLT), and patient ratings of alertness.

Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg.

Memory impairment: Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration of zolpidem tartrate. However, in one study involving zolpidem doses of 10 and 20 mg, there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post-dose) (i.e., these subjects experienced anterograde amnesia). There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of zolpidem tartrate, predominantly at doses above 10 mg.

Effects on sleep stages: In studies that measured the percentage of sleep time spent in each sleep stage, zolpidem tartrate has generally been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor changes in REM (paradoxical) sleep at the recommended dose.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017