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Pharmacotherapeutic Group: Hypnotic.
Pharmacology: Pharmacodynamics: Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Zopiclone belongs to a novel chemical class which is structurally unrelated to existing hypnotics. However, the pharmacological profile of zopiclone is similar to that of the benzodiazepines.
In sleep laboratory studies of one to 21-day duration in man, zopiclone reduced sleep latency, increased the duration of sleep and decreased the number of nocturnal awakenings. Zopiclone delayed the onset of REM sleep but did not reduce consistently the total duration of REM periods. The duration of stage 1 sleep was shortened, and the time spent in stage 2 sleep increased. In most studies, stage 3 and 4 sleep tended to be increased, but no change and actual decreases have also been observed. The effect of zopiclone on stage 3 and 4 sleep differs from that of the benzodiazepines which suppress slow wave sleep. The clinical significance of this finding is not known.
With hypnotic drugs, the duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) and beta (elimination) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absence. If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e. in relation 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 rapidly eliminated benzodiazepines or benzodiazepines-like hypnotics: increased wakefulness during the last third of the night and; the appearance of increased day-time anxiety (see Warnings).
During nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepines or benzodiazepine-like hypnotics may develop. However, in two sleep laboratory studies involving 17 patients, there was an absence of tolerance with zopiclone for treatment periods of more than 4 weeks.
Rebound Insomnia: A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic treatment.
Some manifestations of rebound insomnia have been reported both in sleep laboratory and clinical studies following the withdrawal of zopiclone.
Zopiclone treatment was associated with dose-related residual effects (see Precautions).
Pharmacokinetics: Absorption: Zopiclone is rapidly and well absorbed. Bioavailability is more than 75%, indicating the absence of a significant first-pass effect. After the administration of 3.75 and 7.5mg doses, peak plasma concentrations of 30 and 60 ng/mL, respectively were reached in less than 2 hours. Absorption was similar in males and females.
Repeated daily administration of 1 7.5 mg oral dose for 14 days did not change the pharmacokinetic characteristics of zopiclone and did not lead to accumulation.
Distribution: Zopiclone is rapidly distributed from the vascular compartment (distribution half-life (t½: 1.2 hours) while the elimination half-life is approximately 5 hours (range: 3.8 to 6.5 hours). Plasma protein binding is low (approximately 45% in the 25 - 100 ng/mL concentration range) and non saturable. The risk of drug interaction arising from displacement of bound drug is low.
Metabolism: Zopiclone is extensively metabolized by three major pathways; only about 4 to 5% of the drug is excreted unchanged in the urine. The principal metabolites are the N-oxide derivative (X12%) which has weak pharmacological activity in animals, and the N-desmethyl metabolite (X16%) which is pharmacologically inactive. Their apparent half-lives evaluated from the urinary date are approximately 4.5 and 7.4 hours, respectively.
Both metabolites are excreted renally. Other metabolites resulting from oxidative decarboxylation are partly eliminated via the lung as carbon dioxide. In animals, zopiclone did not induce hepatic microsomal enzymes.
Excretion: Excretion studies, using C14 - zopiclone have shown that more than 90% of the administered dose was excreted over a period of 5 days, 75% being eliminated in the urine and 16% in the feces.
The low renal clearance of unchanged zopiclone (mean 8.4 mL/min) compared with that of plasma (232 mL/min) indicates that zopiclone clearance is mainly metabolic.
Special Patient Population: Elderly Subjects: The absolute bioavailability of zopiclone was increased (94% vs 77% in young subjects) and the elimination half-life prolonged (~7 hours). Accumulation has not been observed on repeated dosing.
Patients with Hepatic insufficiency: Elimination half-life was substantially prolonged (11.9 hours) and time to peak plasma levels delayed (3.5 hours). Consequently, lower doses are recommended (see Dosage & Administration).
Patients with Mild to Moderate Renal Insufficiency: The pharmacokinetics of zopiclone were not affected. Hemodialysis did not appear to increase the plasma clearance of the drug.
Lactating Women: Zopiclone was present in the milk, its concentration paralleled plasma levels but was about 50% lower.
