(and dosage form):
Zopiclone 7,5 mg
A 2.2 Sedatives, hypnotics
Zopiclone is a hypnotic agent, a member of the cyclopyrrolone group of compounds which is reported to have hypnotic, sedative, anxiolytic, muscle relaxant and anticonvulsant properties.
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. There is very little risk of drug interactions due to protein binding.
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.
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 derivates) and in the faeces (approximately 16%).
In elderly patients, not withstanding a slight decrease in hepatic metabolism and lengthening of elimination half-life to approximately 7 hours, various studies have not shown plasma accumulation of the substance 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.
In cirrhotic patients, the plasma clearance of zopiclone is reduced by approximately 40% in relation with the decrease of the demethylation process. Therefore dosage will have to be modified in these patients.
Zopiclone is only indicated when the disorder is severe, disabling or subjecting the individual to extreme stress.
Zopiclone is used in the short term treatment of insomnia in adults.
Safety in long term treatment has not been demonstrated.
Hypersensitivity to zopiclone.
Zopiclone should not be used in children under the age of 18.
The safety in pregnancy and lactation has not been established.
Zopiclone should be avoided in patients with pre-existing central nervous system depression or coma, acute pulmonary insufficiency, or sleep apnoea.
Drowsiness and incoordination on waking can occur.
Patients should be cautioned about driving motor vehicles or operating machinery until it has been established that their performance is not affected.
DOSAGE AND DIRECTIONS FOR USE
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded. The treatment should be as short as possible. Generally the duration of treatment varies from a few days to two weeks, with a maximum, including tapering off process, of four weeks. In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patients status.
Adults - One tablet orally, shortly before retiring.
Elderly patients - A lower dose of 3,75 mg (half a tablet) should be employed initially and depending on the effectiveness and tolerance, the dose can be increased to 7,5 mg.
Patients with hepatic insufficiency - Treatment should be initiated with a dose of 3,75 mg (half a tablet) at night. See Special Precautions.
Renal insufficiency - It is recommended that patients with impaired renal function should start treatment with 3,75 mg.
Paediatric dosage - Not to be used in children.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The side-effect most commonly recorded is bitter or metallic aftertaste.
Drowsiness, sedation and ataxia are also frequent side-effects. They generally decrease on continued administration and are a consequence of central nervous system depression.
Less frequent effects include vertigo, headache, confusion, mental depression, slurred speech or dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation and amnesia.
Some patients may experience a paradoxical excitation which may lead to hostility, aggression and disinhibition.
Jaundice, blood disorders and hypersensitivity reactions have been reported rarely.
Respiratory depression and hypotension occasionally occur with high dosage.
Rebound insomnia may be the result of tolerance to the effect of zopiclone or part of a withdrawal syndrome (see Dependence under Special Precautions).
Zopiclone is not recommended for the primary treatment of psychotic illness. Zopiclone should not be used alone to treat depression or anxiety with depression (suicide may be precipitated in such patients). Zopiclone should be used with extreme caution in patients with a history of alcohol or drug abuse.
Use with care in patients with chronic pulmonary insufficiency.
Zopiclone should be given with care to elderly or debilitated patients who may be more prone to adverse effects.
Caution is required in patients with muscle weakness, or impaired liver or kidney function.
Severe hepatic insufficiency (serum albumin less than 30 g/L or presence of gross oedema) may significantly interfere with the elimination of zopiclone and the lower dosage level (half a tablet) is recommended in such patients. The standard one tablet dose may be cautiously prescribed to patients with moderate (compensated) hepatic or renal insufficiency, but higher doses are not recommended in these patients. Zopiclone is removed by dialysis.
Caution is required in patients with organic brain changes, particularly arteriosclerosis.
Zopiclone has less frequently provoked seizures in epileptic patients; seizures may also occur on abrupt withdrawal of therapy.
A transient syndrome whereby the symptoms that led to treatment with zopiclone recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety and restlessness. Since risk of withdrawal phenomena / rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
There is a potential for abuse and the development of physical and psychic dependence, especially with prolonged use and high doses. The risk of dependence is also greater in patients with a history of alcohol or drug abuse. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability.
In severe cases the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.
Duration of treatment
The duration of treatment should be as short as possible (see dosage), but should not exceed 4 weeks for insomnia, including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation. It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms, should they occur while zopiclone is being discontinued.
Sedation or respiratory and cardiovascular depression may be enhanced by other medicines with central nervous system depressant properties; these include alcohol, antidepressants, antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives and opioid analgesics.
Erythromycin increases the rate of absorption of zopiclone and prolongs its elimination.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdose is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma according to the quantity ingested. Drowsiness, lethargy and ataxia have been the principal effects reported. Overdose may be life-threatening especially when combined with other central nervous system depressants (including alcohol).
Treatment is symptomatic and supportive.
Flumazenil may be useful as an antidote.
White to off white, oval, biconvex, film-coated tablets with breakline.
Blister packs containing 30 tablets.
Store below 25°C in well closed containers, protected from light.
KEEP OUT OF THE REACH OF CHILDREN.
NAME AND BUSINESS ADDRESS OF THE APPLICANT
Rolab (Pty) Limited 72 Steel Road
Spartan Kempton Park
Marketed by: Hexal Pharma (SA) (Pty) Ltd
10 Fangio Road Mahogany Ridge Westmead Pinetown
DATE OF PUBLICATION OF THIS PACKAGE INSERT
1 August 2001
New addition to this site: April 2005
Source: Pharmaceutical Industry
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