Insomnia: Zolpidem Extended-Release for the Treatment of Sleep Induction and Sleep Maintenance Symptoms

Paul P. Doghramji, MD, FAAFP

Disclosures

January 17, 2007

Development of an Extended-Release Formulation of Zolpidem

Original zolpidem is effective for sleep onset, but has not consistently been shown to improve sleep maintenance.[17,18,19] This has led to the development of an extended-release formulation of zolpidem, to maintain plasma concentrations through the middle of the night. Unlike the original zolpidem formulation, zolpidem extended-release does not have any recommended limitations on duration of use; therefore, it can be prescribed as long as medically necessary.

Zolpidem extended-release is a 2-layer, biphasic tablet: One layer releases approximately 60% of the dose immediately, whereas the second layer releases the remainder of the drug content at a slower rate. As a result, plasma concentrations are maintained for a longer period of time. This is confirmed by an increase in plasma levels beyond 3 hours post dose compared with the immediate-release zolpidem formulation.[20] Pharmacokinetic and pharmacodynamic analyses have also demonstrated that zolpidem extended-release has a rapid onset of action and elimination half-life of 2.8 hours in adults and 2.9 hours in elderly individuals, which is similar to the pharmacokinetic properties of original zolpidem. Consistent with these elimination characteristics, at 8 hours post dose no differences were observed between zolpidem extended-release and placebo-treated subjects on measures of psychomotor and cognitive performance, indicating a lack of morning residual sedation in healthy volunteers.[21,22]

The improved hypnotic profile of zolpidem extended-release is supported by studies in healthy volunteers with models of insomnia. In a traffic noise model of sleep disturbance, which involves exposing the subject to audible traffic noise throughout the entire night to disturb sleep, zolpidem extended-release 12.5 mg significantly reduced the number of awakenings (wakeful events lasting ≥ 15 seconds) up to 5 hours post dose compared with placebo. In contrast, original zolpidem 10 mg only provided efficacy for reduced awakenings up to 3 hours in the same study (Figure 1).[23,24]

Figure 1.

Number of awakenings by hour (manual reading, 30-second cutoff) in healthy subjects, placebo vs zolpidem extended-release 12.5 mg and original zolpidem 10 mg. Key: *P < .05 vs placebo, P < .05 zolpidem extended-release vs original zolpidem, and P = .0542 zolpidem extended-release vs original zolpidem. With permission from CNS Drugs.[24] Copyright 2006, Adis International.

In a model of sleep maintenance disturbance involving scheduled nocturnal awakenings at 3, 4, or 5 hours post dose (separate treatment nights) and a presentation of noise to disturb the return to sleep, zolpidem extended-release 12.5 mg significantly decreased the time to return to persistent sleep compared with original zolpidem 10 mg at both 4 and 5 hours post dose. This is consistent with the sustained plasma concentration of zolpidem extended-release 12.5 mg beyond 3 hours post dose.[25]

Zolpidem extended-release has a safety profile comparable to original zolpidem. In healthy adult (12.5 mg) and elderly (≥ 65 years; 6.25 mg and 12.5 mg [double the recommended dose in the elderly]) subjects, zolpidem extended-release did not significantly affect psychomotor and cognitive performance 8 hours post dose compared with placebo, on the basis of neurocognitive tests of vigilance and motor and memory.[21,22]

The impact of zolpidem extended-release 12.5 mg on next-day cognitive and psychomotor performance was compared with immediate-release zolpidem and placebo in a separate, crossover study. Zolpidem extended-release 12.5 mg had no significant effect on psychomotor and cognitive tests at 8 and 9 hours post dose compared with both placebo and zolpidem (Figure 2 and Table ).[23]

Figure 2.

Digit Symbol Substitution Test (DSST) (performed 8 hours post dose) -- a measure of attention and sedation. Subjects are presented with rows of blank squares paired with randomly assigned numbers. In a defined time period, they are required to substitute digits with a different, corresponding nonsense symbol, the key to which is provided: no significant difference in DSST scores between groups (SEM = standard error of the mean). With permission from Pharmacotherapy.[23] Copyright 2005, Pharmacotherapy Publications.

Zolpidem extended-release has also demonstrated efficacy in inducing and maintaining sleep in studies of adult and elderly patients with primary insomnia. In two 3-week studies, zolpidem extended-release 12.5 mg improved sleep maintenance by significantly reducing wake time after sleep onset (a sleep maintenance assessment of the amount of time spent awake after initially falling asleep, measured by polysomnography) during the first 6 hours of sleep in both young and elderly adults with insomnia.[26,27] Compared with placebo, zolpidem extended-release also significantly reduced latency to persistent sleep, both at the start and after 2 weeks of double-blind therapy in young adult and elderly patients. Furthermore, in a long-term study (24 weeks) in patients with chronic primary Insomnia, zolpidem extended-release taken up to 7 nights per week demonstrated sustained improvements in sleep onset and sleep maintenance, as measured by patient and clinical global impression scales.[28]

There are a minimal number of drug-drug interactions with zolpidem extended-release, and, although they are well characterized, the pharmacology of any central nervous system-active drug should be considered prior to administration.

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