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Insopin
DESCRIPTION A yellow colour,
oval shaped tablet with marking '861' &'DUO'
COMPOSITION Each tablet
contains Zopiclone BP 7.5 mg
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. The pharmacological profile of zopiclone is similar to
that of the benzodiazepines. PHARMACOLOGY: In sleep laboratory
studies of 1 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.
PHARMACOKINETICS
Absorption, Distribution and Bioavailability: Zopiclone is rapidly
absorbed and distributed after oral administration, the time of maximum
observed plasma concentration being about 1.75 hours. A study of 16 healthy
volunteers receiving a single dose of 7.5 mg of zopiclone intravenously
demonstrated the apparent volume of distribution of zopiclone to be 104 ±
15.5 L.
Autoradiographic studies in the rat showed rapid distribution into the blood
and peak tissue levels at 0.5 hours in the liver, small intestines, stomach,
kidneys and the adrenals. After twenty four hours the total residual
radioactivity in the body of the rat was 8%.
The bioavailability of the 7.5 mg tablets in man is 76.3 ± 9.6%, a hepatic
first pass effect has been demonstrated. In fresh human plasma, zopiclone is
approximately 45% protein bound in the 25-100 ng/mL concentration range.
Metabolism: Zopiclone is extensively and rapidly metabolised by the
liver. A large number of metabolites have been isolated and characterised,
with the two major ones being the N-oxide, produced by oxidation of the
piperazine nitrogen and the N-desmethyl produced by oxidative demethylation
of the N-methyl piperazine.
Only the N-oxide analogue has weak pharmacological activity.
Elimination and Excretion: Zopiclone is rapidly eliminated, mainly by
means of hepatic metabolism. The elimination half-life after a single oral
dose is 5.26 ± 0.76 hours. The elimination half-life for the N-oxide
metabolite is 7.28 ± 0.49 hours and that for the N-desmethyl metabolite is
7.28 ± 0.49 hours. Renal clearance is 13.9 ± 7.0 mL/min which further shows
that the major elimination pathway is by hepatic metabolism. The amount of
renal excretion is also low, unchanged zopiclone 3.6%, the N-oxide
metabolites 11.4% and the N-desmethyl metabolite 13.4%.
Elderly: In elderly patients, the absolute bioavailability is
increased (94% vs 77% in young subjects), and the elimination half-life
prolonged (approximately 7 hours).
Hepatic insufficiency: In patients with hepatic insufficiency,
elimination half-life is prolonged (11.9) and time to peak plasma levels
delayed (3.5 hours).
Renal insufficiency: In patients with mild to moderate renal
insufficiency, the pharmacokinetics of zopiclone are not altered.
Haemodialysis does not appear to increase the plasma clearance of the drug.
INDICATIONS
Short term
treatment of insomnia (2 to 4 weeks).
RECOMMENDED DOSAGE
Adults: 7.5 mg by oral administration shortly before retiring for a
maximum of 2-4 weeks. This dose should not be exceeded. Depending on
clinical response, the dose may be lowered to 3.75 mg.
Zopiclone is not recommended for long term use (i.e. periods of more than 4
weeks). If used for long periods, treatment should be withdrawn gradually
(see Warnings).
Elderly patients: In the elderly and/or debilitated patient an
initial dose of 3.75 mg is recommended. The dose may be increased to a
maximum of 7.5 mg if the starting dose does not offer adequate therapeutic
effect, but in clinical trials, 25% of elderly patients treated with
zopiclone experienced CNS side effects at the higher dose. Zopiclone should
be used with caution in these patients.
Paediatric: Zopiclone is contraindicated in children. Dosage has not
been established.
Hepatic Insufficiency: The recommended dose is 3.75 mg depending on
acceptability and efficacy. Up to 7.5 mg may be used with caution in
appropriate cases.
Alternative therapy: For long term treatment of insomnia, alternative
non-pharmacological methods should be considered. Effective practical
management of insomnia must respond to the presenting characteristics of the
complaint. Giving accurate information is a form of treatment; there is
benefit in discussing some simple facts with the patient and relating them
to the problem, thereby assisting the patient to place the sleep problem in
its context. Sleep hygiene such as reduction of caffeine intake, should be
exercised. Programmes designed to establish an optimal sleeping pattern for
the patient may also be useful as are relaxation techniques designed to
assist the patient deal with tension and intrusive thoughts in bed.
CONTRAINDICATIONS Patients
with known hypersensitivity to zopiclone or any of the excipients,
myasthenia gravis, severe impairments of respiratory function, acute
cerebrovascular accident, sleep apnoea syndrome. Zopiclone is
contraindicated in children.
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