Source: Health Products Regulatory Authority (ZA) Revision Year: 2020 Publisher: sanofi-aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685, South Africa
A 2.2 Sedatives, hypnotics
Zopiclone is a hypnotic medicine, a member of the cyclopyrrolone group of compounds. Its pharmacological properties are: hypnotic, sedative, anxiolytic, anticonvulsant and musclerelaxant. These effects are related to a specific agonist action at central receptors belonging to the GABAA macromolecular complex, modulating the opening of the chloride ion channel.
Zopiclone is rapidly absorbed. Peak concentrations are reached within 1,5 to 2 hours and they are approximately 30 to 60 ng/ml after administration of 3,75 mg and 7,5 mg, respectively. Absorption is not modified by food.
Zopiclone is rapidly distributed from the vascular compartment. Plasma protein binding is weak (approximately 45%) and non-saturable. The distribution volume is 91,8 to 104,6 litres.
After repeated administration, there is no accumulation of zopiclone and its metabolites. Interindividual variations appear to be low.
Zopiclone is extensively metabolised in humans to two major metabolites, N-oxide zopiclone (pharmacologically active in animals) and N-desmethyl zopiclone (pharmacologically inactive in animals). An in vitro study indicates that cytochrome P450 (CYP) 3A4 is the major isoenzyme involved in the metabolism of zopiclone to both metabolites, and that CYP2C8 is also involved with N-desmethyl zopiclone formation.
At recommended doses, the elimination half-life of the unchanged zopiclone is approximately 5 hours.
The low renal clearance value of unchanged zopiclone (mean 8,4 ml/min) compared with the plasma clearance (232 ml/min) indicates that zopiclone clearance is mainly metabolic. Zopiclone is eliminated by the urinary route (approximately 80 ) mainly in the form of free metabolites (N-oxide and N-demethyl derivatives) and in the faeces (approximately 16).
In elderly patients, notwithstanding a slight decrease in hepatic metabolism and lengthening of elimination half-life to approximately 7 hours, various studies have not shown plasma accumulation of zopiclone on repeated dosing.
In renal insufficiency, no accumulation of zopiclone or of its metabolites has been detected after prolonged administration. Zopiclone is removed by haemodialysis; however, haemodialysis is of no value in treating overdose due to the large volume of distribution of zopiclone (see KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT).
In cirrhotic patients, the plasma clearance of zopiclone is reduced by approximately 40% in relation to the decrease of the demethylation process. Therefore, dosage will have to be modified in these patients.
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