Ambien

Ambien

Ambien
(zolpidem tartrate tablets)

DESCRIPTION

Ambien (zolpidem tartrate) is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.

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 764.88.

Each Ambien tablet includes the following inactive ingredients: hydroxypropyl methylcellulose, lactose, magnesium stearate, micro-crystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide; the 5 mg tablet also contains FD&C Red No. 40, iron oxide colorant, and polysorbate 80.

 

Ambien

CLINICAL PHARMACOLOGY

Mechanism of action

Subunit modulation of the GABA_A receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA_A receptor complex is located on its alpha (α) subunit and is referred to as the benzodiazepine (BZ) or omega (ω) receptor. At least three subtypes of the (ω) receptor have been identified. While zolpidem 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 omega receptor subtypes, zolpidem in vitro binds the (ω₁) receptor preferentially with a high affinity ratio of the alpha1/alpha₅ subunits. The (ω₁) receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (parsreticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the (ω₁) 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

The pharmacokinetic profile of Ambien is characterized by rapid absorption from the GI tract and a short elimination half-life (T½) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Ambien is converted to inactive metabolites that are eliminated primarily by renal excretion. Ambien demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding 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 tablets for 2 weeks.

A food-effect study in 30 healthy male volunteers compared the pharmacokinetics of Ambien 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, Ambien should not be administered with or immediately after a meal.

In the elderly, the dose for Ambien should be 5 mg [see WARNINGS and PRECAUTIONS and DOSAGE AND ADMINISTRATION ]. This recommendation is based on several studies in which the mean Cmax, T½, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for Cmax, T½, and AUC significantly increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng•hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Ambien did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

The pharmacokinetics of Ambien in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem 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 com-promised 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 normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see WARNINGS and PRECAUTIONS and DOSAGE AND ADMINISTRATION ].

The pharmacokinetics 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 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, T½ was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T½ 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. Ambien (zolpidem tartrate) pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. As a general precaution, these patients should be closely monitored.

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Postulated relationship between elimination rate of hypnotics and their profile of common untoward effects

The type and duration of hypnotic effects and the profile of unwanted effects during administration of hypnotic drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. When half-lives are long, drug or metabolites may accumulate during periods of nightly administration and be associated with impairment of cognitive and/or motor performance during waking•hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives, including•half-lives of active metabolites, are short, drug and metabolites will be cleared before the next dose is ingested, and carryover effects related to excessive sedation or CNS depression should be minimal or absent. Ambien has a short half-life and no active metabolites. During nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the interval between each night’s use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of other rapidly eliminated hypnotics, namely, increased wakefulness during the last third of the night, and the appearance of increased signs of daytime anxiety. Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with Ambien.

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 (10 and 15 mg) and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 15 mg was superior to placebo for all 5 weeks; 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 (10 and 15 mg) 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. Zolpidem 15 mg was superior to placebo on a subjective measure of total sleep latency for the first 3 weeks, on a subjective measure of total sleep time for the first week, and on number of awakenings and sleep quality for the first 2 weeks.

Studies Pertinent To Safety Concerns For Sedative/Hypnotic Drugs

Next-day residual effects

Next-day residual effects of Ambien were evaluated in seven studies involving normal volunteers. 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 Ambien 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 Ambien (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 Ambien. 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), ie, these subjects experienced anterograde amnesia. There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of Ambien, predominantly at doses above 10 mg.

Effects on sleep stages

In studies that measured the percentage of sleep time spent in each sleep stage, Ambien 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.