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Ambien CR (Zolpidem Tartrate) - Description and Clinical Pharmacology

 
 



Ambien CR™    CIV
(zolpidem tartrate extended-release tablets)

DESCRIPTION

Ambien CR contains zolpidem tartrate, a non-benzodiazepine hypnotic of the imidazopyridine class. Ambien CR (zolpidem tartrate extended-release tablets) is available in 6.25-mg and 12.5-mg strength tablets for oral administration.

Chemically, zolpidem tartrate 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 764.88.

Ambien CR consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The 6.25-mg Ambien CR tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium dioxide. The 12.5-mg Ambien CR tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Subunit modulation of the GABAA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABAA receptor complex is located on its alpha (α) subunit and is referred to as the benzodiazepine (BZ) receptor.

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines, or other drugs with known hypnotic properties. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The BZ1 receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. 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

Ambien CR exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond three hours after administration. A study in 24 healthy male subjects was conducted to compare mean zolpidem plasma concentration-time profiles obtained after single oral administration of Ambien CR (12.5 mg) and of an immediate-release formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with Ambien CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10 mg). The mean plasma concentration time profiles for Ambien CR (12.5 mg) and for zolpidem tartrate (10 mg) are shown below:

In adult and elderly patients treated with Ambien CR, there was no evidence of accumulation after repeated once-daily dosing for up to two weeks.

Absorption

Following administration of Ambien CR, administered as a single 12.5-mg dose in healthy male adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to 197 ng/ml) occurring at a median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740 ng∙hr/mL (range: 295 to 1359 ng∙hr/mL).

A food-effect study in 45 healthy subjects compared the pharmacokinetics of Ambien CR 12.5 mg when administered while fasting or within 30 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while median Tmax was increased from 2 hours to 4 hours. The half-life was not changed. These results suggest that, for faster sleep onset, Ambien CR should not be administered with or immediately after a meal.

Distribution

Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.

Metabolism

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.

Elimination

Ambien CR administered as a single 12.5 mg dose in healthy male adult subjects, the mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).

Special Populations

Elderly

In 24 elderly (≥65 years) healthy subjects administered a single 6.25-mg dose of Ambien CR, the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring at a median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 ng∙hr/mL (range: 124 to 1190 ng∙hr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).

Hepatic Impairment

Ambien CR was not studied in patients with hepatic impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate 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 half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency (see Precautions and Dosage and Administration ).

Renal Impairment

Ambien CR was not studied in patients with renal impairment. The pharmacokinetics of an immediate-release formulation of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 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, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On day 1, T1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng∙hr/mL after the first dose and 818± 170 ng∙hr/mL after repeated dosing. 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. However, as a general precaution, these patients should be closely monitored.

Controlled trials supporting safety and efficacy

Ambien CR was evaluated in two placebo-controlled studies for the treatment of patients with chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV).

Adult outpatients (18–64 years) with primary insomnia (N=212) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 12.5 mg and placebo. Ambien CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during the first 2 nights and for the first 5 hours after 2 weeks of treatment. Ambien CR 12.5 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks of treatment. Ambien CR 12.5 mg was also superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

Elderly outpatients (≥65 years) with primary insomnia (N=205) were evaluated in a double-blind, randomized, parallel-group, 3-week trial comparing Ambien CR 6.25 mg and placebo. Ambien CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during the first 2 nights and the first 4 hours after 2 weeks of treatment. Ambien CR 6.25 mg was superior to placebo on objective measures (polysomnography recordings) of sleep induction (by decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2 weeks on treatment. Ambien CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.

In both studies, in patients treated with Ambien CR, polysomnography showed increased wakefulness at the end of the night compared to placebo-treated patients.

Studies Pertinent To Safety Concerns For Sedative/Hypnotic Drugs

Next-day residual effects

In five clinical studies; three controlled studies in adults (18–64 years of age) administered Ambien CR 12.5 mg and two controlled studies in the elderly (≥ 65 years of age) administered Ambien CR 6.25 mg or 12.5 mg, the effect of Ambien CR on vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies, no significant decrease in performance was observed eight hours after a nighttime dose. In addition, no evidence of next-day residual effects were detected with Ambien CR 12.5 mg and 6.25 mg using self-ratings of sedation.

Next day somnolence was reported by 15% of the adult patients who received 12.5 mg Ambien CR versus 2% of the placebo group. Next day somnolence was reported by 6% of the elderly patients who received 6.25 mg Ambien CR versus 5% of the placebo group. (See Adverse Reactions.)

Rebound effects

Rebound insomnia, defined as a dose-dependent worsening in sleep parameters (latency, sleep efficiency, and number of awakenings) compared with baseline following discontinuation of treatment, is observed with short- and intermediate-acting hypnotics. In the two placebo-controlled studies in patients with primary insomnia, a rebound effect was only observed on the first night after abrupt discontinuation of Ambien CR. On the second night, there was no worsening compared to baseline in the Ambien CR group.

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