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Apo-zopiclone
Zopiclone Tablets 7.5 mg
PHARMACOLOGY
Zopiclone, a cyclopyrrolone derivative, is a shortacting 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 differs from that of the benzodiazepines which
suppresses 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 halt-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, the drug and metabolites will be cleared before the next dose is
ingested, and carry-over effects related to sedation or CNS depression
should be minimal or absent. 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 benzodiazepine-like hypnotics : 1) increased wakefulness
during the last third of the night and 2) the appearance of increased
daytime anxiety.
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.
Pharmacokinetics
Absorption : Zopiclone is rapidly and well absorbed. Bio-availability is
more than 75%, indicating the absence of a significant first-pass effect.
After the administration of 3.75 and 7.5 mg 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 a 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
[t½a] : 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 (~12%) which has weak pharmacological activity in
animals, and the N-desmethyl metabolite (~16%) which is pharmacologically
inactive. Their apparent halt-lives evaluated from the urinary data 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.
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.
INDICATIONS
Sleep disturbance may be the presenting manifestation of a physical and/or
psychiatric disorder. Consequently, a decision to initiate symptomatic
treatment of insomnia should only be made after the patient has been
carefully evaluated.
APO-ZOPICLONE (zopiclone) is indicated for the symptomatic relief of
transient and short-term insomnia characterized by difficulty in falling
asleep, frequent nocturnal awakenings and/or early morning awakenings.
Treatment with APO-ZOPICLONE should usually not exceed 7-10 consecutive
days. Use for more than 2-3 consecutive weeks requires complete reevaluation
of the patient.
Prescriptions for APO-ZOPICLONE should be written for short-term use (7 - 10
days) and it should not be prescribed in quantities exceeding a 1-month
supply.
The use of hypnotics should be restricted for insomnia where disturbed sleep
results in impaired daytime functioning.
ADVERSE EFFECTS
The most common adverse reaction seen with zopiclone is taste alteration
(bitter taste). Severe drowsiness and/or impaired coordination are signs of
drug intolerance or excessive doses.
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