Monograph: |
Zopiclone
A white or slightly yellow powder. Practically insoluble in
water and in alcohol; sparingly soluble in acetone; freely sol-
uble in dichloromethane. It dissolves in dilute mineral acids.
Protect from light.
Dependence and Withdrawal, Adverse
Effects, Treatment, and Precautions
As for Diazepam.
A bitter or metallic taste in the mouth has been re-
ported.
Zopiclone is contra-indicated in severe hepatic in-
sufficiency.
In a French postmarketing survey of 20 513 patients treated
with zopiclone the most commonly reported adverse events
were bitter taste (3.6%), dry mouth (1.6%). difficulty arising
in the morning (1.3%), sleepiness (0.5%). nausea (0.5%) and
nightmares (0.5%). The UK Committee on Safety of Medi-
cines (CSM) had received 122 reports of adverse reactions to
zopiclone over a period of about one year since the products
introduction in November 1989. A fifth of these were wu-
ropsychiatric reactions, a proportion similar to that found
with other hypnotics. Many of these reactions were potential-
ly serious and involved hallucinations (3 auditory and 2 visu-
al), amnesia (4) and behavioural disturbances (10, including
3 cases of aggression). Most reactions started immediately or
shortly after the first dose and improved rapidly on stopping
the drug. Three patients had difficulty in stopping treatment.
2 because of withdrawal symptoms and one due to repeated
rebound insomnia. The CSM considered that. although differ-
ing structurally from the benzodiazepines. zopiclone has the
same potential for adverse psychiatric reactions, including
dependence. Like benzodiazepines it should be reserved for
patients with severe sleep disturbance and its duration of use
limited to 28 days. As with all hypnotics, care should be taken
in the elderly, those who have a history of previous psychiat-
ric illness, or who are prone to drug abuse.
Administration. Results in 9 healthy subjects given zopi-
clone indicated a significant delay in onset of action when the
drug was taken in the supine, as opposed lo the standing,
position: this was associated with a prolongation of more than
20 minutes in the lag time before absorption began. In order
io obtain a rapid and complete hypnotic effect from zopiclone
the tablet should be swallowed in the standing position.
Dependence. Reports of zopiclone dependence and asso-
ciated withdrawal symptoms on dosage reduction or cessation
of use are there in literature.
Driving. There are increased risk of road-traffic
accidents for drivers taking zopiclone.
Hepatic impairment. A study of the pharmacokinetics of
zopidone in cirrhosis. Zopiclone was given in a dose of
7.5 mg to 7 cirrhotic patients and 8 healthy subjects; a further
2 cirrhotic patients received 3.75 mg. Mean peak plasma con-
centrations were similar in healthy subjects and those with
hepatic impairment following equivalent doses but lime to
peak plasma concentration was significantly delayed in cir-
rhotics at 4 hours as compared with 2 hours in the healthy
subjects. Elimination was greatly prolonged in cirrhotic pa-
tients. in whom the mean plasma half-life was 8,53 compared
with 3.50 hours. The CNS-depressant effects of zopiclone
were delayed in the cirrhotic patients in a way consistent with
the pharmacokinetic changes. There was also some evidence
of an increased response in these patients. Caution should be
exercised in administering zopiclone to patients with severe
hepatic disease.
0verdosage. Consciousness was rapidly regained after in-
travenous flumazenil administration in a patient who had tak-
en an overdosage of zopiclone.
Interactions
As for Diazepam.
Erythromycin. In a study in healthy subjects erythromycin
increased the rate of absorption of zopiclone and prolonged
its elimination.
Rifampicin. Concomitant administration of rifampicin or
other potent inducers of the cytochrome P450 isozyme
CYP3A4 such as carbamazepine or phenytoin is likely to re-
duce the effects of zopiclone. In a study in 8 healthy
subjects
concomitant administration of rifampicin was associated with
an 82% reduction in the area under the curve for zopiclone.
The peak plasma concentration of zopiclone was reduced
from 76.9 to 22.5 ng per mL and the elimination half-life
from 3.8 to 2.3 hours.
Pharmacokinetics
Zopiclone is rapidly absorbed following administra-
tion by mouth and widely distributed. It has an elim-
ination half-life of 3.5 to 6.5 hours and is reported to
be about 45 to 80% bound to plasma proteins. Zop-
iclone is extensively metabolised in the liver; the 2
major metabolites, the less active zopiclone N-oxide
and the inactive N-desmethylzopiclone are excreted
mainly in the urine. About 50% of a dose is convert-
ed by decarboxylation to inactive metabolites which
are partly eliminated via the lungs as carbon diox-
ide. Only about 5% of a dose appears unchanged in
the urine and about 16% appears in the faeces. Ex-
cretion of zopiclone in the saliva may explain re-
ports of a bitter taste. It is also distributed into breast
milk.
Distribution Into breast milk. Zopiclone was distributed
into breast milk in 12 lactating women in concentrations ap-
proximately half those in plasma.' The calculated dose that
would be received by a neonate was 1.5 ng per kg body-
weight. corresponding to 1.2% of the maternal dose.
Uses and Administration
Zopiclone is a cyclopyrrolone which is reported to
have similar sedative, anxiolytic, muscle relaxant.
amnesic. and anticonvulsant properties to those of
the benzodiazepines . Like di-
azepam. its actions are mediated by enhancement of
the activity of aminobutyric acid (GABA) in the
brain. Zopiclone is reported to bind to the benzodi-
azepine receptor component of the GABA receptor
complex but at a different site to the benzodi-
azepines.
Zopiclone is used as a hypnotic in the short-term
management of insomnia . The usual dose is
7.5 mg by mouth at night. In elderly patients and in
those with renal insufficiency or mild to moderate
hepatic insufficiency, treatment should be initiated
with a dose of 3.75 mg at night.
Zopiclone has a similar pharmacological and pharmacokinet-
ic profile to the short-acting benzodiazepines. It is claimed to
initiate sleep rapidly, without reduction of total rapid-eye-
movement ( REM ) sleep, and then sustain It with preservation
of normal slow-wave sleep, It is generally considered to be an
effective as an hypnotic in the benzodiazepines. Rebound
insomnia has occurred but does not appear to be common.
Residual effects the next day may be less pronounced after
zopiclone than after short-acting benzodiazepines but there
appears to be little evidence that zopiclone offers any
clinical
advantage in terms of its potential to induce tolerance, with-
drawal symptoms, or dependence. For recommendations of
the UK Committee on Safety of Medicines concerning its use
as a hypnotic, see under Dependence and Withdrawal. Ad-
verse Effects, Treatment, and Precautions, above.
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