Zopiclone 3.75mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zopiclone 3.75mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 3.75mg of the active ingredient zopiclone.
For excipients see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Blue, F/C, round tablet, ‘ZE3’ on one side and ‘G’ on the reverse.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Zopiclone 3.75mg Tablets are indicated for the short-term treatment of insomnia.
Benzodiazepines and benzodiazepine-like agents are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.
4.2. Posology and method of administration
Administration:
Zopiclone 3.75mg tablets are for oral use only. Treatment with zopiclone should be as short as possible. Generally the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off, of four weeks.
In certain cases an extension beyond the maximum treatment period may be necessary; if so it should take place after re-evaluation of the patient’s status.
Dosage
Adults.
The recommended dose for adults is 2 tablets (7.5mg Zopiclone). This dose should not be exceeded. The tablet should be taken just before retiring.
Impaired renal function:
Although accumulation of zopiclone and/or its metabolites has not been shown in patients with impaired renal function, a starting dose of 3.75mg is recommended in these patients.
Impaired hepatic function and chronic respiratory insufficiency:
A dose of 3.75mg is recommended in patients with impaired hepatic function since elimination of zopiclone may be reduced in these patients. The dosage may be increased to 7.5mg with caution if considered clinically necessary, depending on patient acceptability.
Elderly.
A starting dose of 3.75mg is recommended, this dose may consequently be increased to 7.5mg if considered necessary depending on patient acceptability.
Children and adolescents:
Zopiclone should not be used in children or adolescents younger than 18 years of age.
4.3. Contraindications
Zopiclone is contraindicated in patients with any of the following:
history of hypersensitivity to zopiclone or to any other excipients
myasthenia gravis
severe hepatic impairment
sleep apnoea syndrome
respiratory failure
Zopiclone should not be given to children or adolescents younger than 18 years of age.
4.4. Special warnings and precautions for use
Risk of dependence:
As with the benzodiazepines and other benzodiazepine-like drugs, there is a risk of physical and psychological dependence. This risk increases with dose and length of treatment. Patients with a history of alcohol and/or drug abuse or those with personality disorders are more at risk of dependence and this should be considered when prescribing zopiclone. If a patient does become dependent, abrupt cessation of treatment may result in withdrawal symptoms including: anxiety, headaches, muscle pain, tension, confusion and restlessness and irritability. In severe cases symptoms may also include personality disturbances, derealisation, numbness of the extremities, hypersensitivity to noise, light and physical contact, hallucinations or epileptic seizures.
Rebound insomnia:
On cessation of treatment with zopiclone, there may be a transient, and often enhanced, recurrence of insomnia which may be accompanied by some of the withdrawal symptoms described above. Abrupt discontinuation of treatment should be avoided, instead, the dosage should be reduced gradually.
Depression:
Benzodiazepines and benzodiazepine-like agents should not be used as the only treatment of depression or anxiety associated with depression (suicide may be precipitated in such patients).
Tolerance:
Some loss of efficacy to the hypnotic effects of benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks. However with Zopiclone no marked tolerance occurred during treatment periods of up to four weeks.
Amnesia:
If sleep is interrupted or retiring to bed is delayed after taking the tablet, the patient may suffer anterograde amnesia, situations when this might occur should therefore be avoided.
Psychiatric and ‘Paradoxical’ reactions:
It is known that reactions such as restlessness, agitation, irritability, aggression, delusion, outbursts of rage, nightmares, hallucinations, psychoses, unsuitable behaviour and other behavioural disturbances may occur during the use of benzodiazepines and benzodiazepine-like substances. If this is the case administration of the medicinal product should be discontinued.
Specific patient groups:
For the elderly: see Posology and method of administration. A lower dose is advised for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines and benzodiazepine-like substances are not suitable for the treatment of patients with severe hepatic insufficiency, since they may promote the occurrence of encephalopathy. Benzodiazepines and benzodiazepine-like substances are not recommended as the primary treatment of psychoses. Benzodiazepines and benzodiazepine-like substances should not be used as the sole treatment of depression or anxiety linked with depression (suicide may be triggered in such patients). Benzodiazepines and benzodiazepine-like substances should be administered with extreme caution to patients with a previous history of alcohol and drug abuse.
Before starting treatment with zopiclone any underlying cause of insomnia should be addressed carefully.
Period of treatment:
The period of treatment should be as short as possible (see Posology and method of administration) but not longer than 4 weeks including the tapering off process. This period should only be exceeded after re-evaluation of the patient’s condition. It may be of benefit to inform the patient at the beginning of treatment that the treatment will be of short duration, and to explain precisely how to reduce the dose gradually. It is also important to point out to the patient the possibility of the occurrence of rebound phenomena in order to keep to a minimum any worries about the occurrence of such symptoms during the tapering off period of the treatment. In the case of benzodiazepines and benzodiazepine-like substances with a short period of action, there are indications that withdrawal symptoms may occur within the dosage interval, especially if the dose is high.
Excipients of known effect
Lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ponceau 4R Aluminium Lake (E124):
May cause allergic reactions.
4.5. Interactions with other medicinal products and other forms of interaction
Alcohol may enhance the sedative effect of zopiclone, this may persist to the following morning and could affect the patient’s ability to drive or use machinery.
Central depressive effects may be enhanced when zopiclone is used in combination with CNS depressants. Therefore, the therapeutic benefit of coadministration with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines should therefore be carefully considered.
Use of benzodiazepine-like drugs in combination with narcotic analgesics may enhance their euphoric effects, which may in turn increase the risk of dependency.
The activity of zopiclone may be increased when used in combination with drugs which inhibit hepatic enzymes (in particular cytochrome P450)
The interaction between erythromycin and zopiclone results in accelerated absorption which may lead to a faster hypnotic effect. Metoclopramide increases and atropine decreases concentration of zopiclone in plasma.
The effects of zopiclone are considerably reduced by rifampicin because of enhanced metabolism of zopiclone. It is likely that zopiclone also shows a reduced hypnotic effect when used concomitantly with other potent inducers of CYP3A4, such as phenytoin and carbamazepine.
Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.
4.6. Pregnancy and lactation
Insufficient data are available on zopiclone to assess its safety during pregnancy and lactation in humans.
To date zopiclone has not produced injurious effects in animal studies except at very high maternally toxic doses.
Any woman of child-bearing potential prescribed zopiclone, should be advised to consult her physician about discontinuing use of zopiclone in the event that she wishes to, or suspects that she has, become pregnant.
If zopiclone is administered during the late phase of pregnancy or during labour, effects on the neonate such as hypothermia, hypotonia, moderate respiratory depression, decreased muscle tone and suckling reflex (“floppy infant syndrome”) can be expected.
Zopiclone should not be used in nursing mothers since zopiclone has been found to be excreted in breast milk. Infants born to mothers who took benzodiazapines or benzodiazapine-like agents chronically during the later stages may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
4.7. Effects on ability to drive and use machines
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. Therefore, patients should not drive or use machinery after taking a dose.
Patients should be advised not to drink alcoholic beverages or operate machinery the day after treatment until it is established that their performance is unimpaired.
Use of zopiclone with alcohol may enhance the sedative effect and affect the patient’s ability to drive and use machinery the following morning.
4.8. Undesirable effects
Drowsiness during the following day, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision occur predominantly at the start of therapy and usually disappear with repeated administration. Other side effects like gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally. Bitter taste is the most common side effect observed with Zopiclone.
Amnesia:
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour (see Warnings and precautions).
Depression:
Pre-existing depression may be unmasked during use of benzodiazepines or benzodiazepine-like agents.
Psychiatric and “paradoxical” reactions:
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like products. They may be quite severe with this product, but long experience is still lacking. They are more likely to occur in children and the elderly.
Dependence:
Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see Warnings and precautions). Psychic dependence may occur. Abuse has been reported.
4.9 Overdose
Fatal dose not known.
Symptoms:
In the cases of overdosage reported the main effects are drowsiness, lethargy and ataxia. Rarely, A-V block has occurred.
Management:
Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg within 1 hour. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose. If CNS depression is severe consider the use of flumazenil. It has a short halflife (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC” TEST. Management should include general symptomatic and supportive measures including a clear airway and monitoring cardiac and vital signs until stable.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Zopiclone is a hypnotic agent belonging to the cyclopyrrolone class of psychotherapeutic agents. Although structurally unrelated to the benzodiazepines, zopiclone binds with high affinity and specificity to the GABAA-benzodiazepine chloride channel macromolecular receptor complex. Zopiclone binds to a site different to the benzodiazepines and induces different conformational changes to the receptor complex thus modifying the activity of the chloride ion channel.
ATC code: NO5C FOI.
Pharmacological properties are: anxiolysis, sedation, hypnosis, anticonvulsion and muscle relaxation
5.2. Pharmacokinetic Properties
Absorption:
Zopiclone is swiftly absorbed. Maximum plasma concentrations are achieved after 1/2 - 2 hours and are approximately 30 and 60mg/ml after administration of 3.75mg and 7.5mg respectively. Absorption is the same in men and women and is not affected by simultaneous ingestion of food or repetition of doses.
Distribution:
Zopiclone is swiftly distributed from the vascular compartment. The plasma protein binding is at least 45% and is not saturable.
The decrease in plasma level does not depend on the dose between 3.75 and 15mg.
The elimination half-life is approximately 5 hours at the recommended doses.
No accumulation occurs after repeated administration and individual differences appear slight.
Less than 1.0% of the dose ingested by the mother is eliminated in breast milk. Metabolism:
The most important metabolites are the N-oxide derivative (pharmacologically active in animals) and the N-desmethyl metabolite (pharmacologically inactive in animals). Their apparent half-life times are approximately 4.5 hours and 7.4 hours respectively. No significant accumulation of the compound as seen following repeat dosing. (15mg) for 14 days.
Elimination:
The low renal clearance of zopiclone (on average 8.4ml/min compared to the plasma clearance (232ml/min) shows that zopiclone is cleared chiefly by metabolism. Zopiclone is eliminated in the urine (approximately 80%) in the form of unconjugated metabolites (N-oxide and N-desmethyl derivatives) and in the faeces (approximately 16%).
Special patient groups:
In various trials with elderly patients, no accumulation of zopiclone was observed in the plasma after repeated doses, in spite of a slight reduction in the renal function and extension of the elimination half-life to approximately 7 hours.
In renal insufficiency, no accumulation of zopiclone or its metabolites have been detected after prolonged administration. Zopiclone crosses the dialysing membrane.
In patients with cirrhosis of the liver the slow demethylating process causes the plasma clearance of zopiclone to be delayed by approximately 40%. For this reason the dosage should be adjusted for these patients.
5.3. Preclinical Safety Data
Hepatotoxic effects were observed in repeat dose toxicity studies conducted in rats and dogs. In dogs anaemia was observed in some studies.
Zopiclone is not mutagenic in either in-vitro or in vivo tests.
Increased incidence of mammary carcinomas in female rats at high multiples of the maximum plasma concentration from therapeutic doses in humans has been attributed to increased 17-beta-estradiol serum levels. Increased incidence of thyroid tumours in rats has been associated with increased TSH serum levels. In humans zopiclone has no effects on thyroid hormones.
Fertility was impaired in two rat studies.
Zopiclone had no adverse effects on fertility in rabbits.
Double-blind long-term studies (7.5mg zopiclone for 84 days) in healthy volunteers revealed no changes in ejaculate volume, sperm concentration, sperm motility or morphology.
6. PHARMACEUTICAL PARTICULARS 6.1. List of Excipients
Lactose anhydrous
Calcium hydrogen phosphate, anhydrous
Maize starch
Povidone
Magnesium Stearate Hypromellose Titanium dioxide (E 171)
Macrogol 400
Indigo Carmine Aluminium Lake (E132) Ponceau 4R Aluminium Lake (E124) Quinoline Yellow Aluminium Lake (E104)
6.2. Incompatibilities
Not applicable
6.3. Shelf Life
2 Years.
6.4. Special Precautions for Storage
Do not store above 25°C
Blister packs: Keep container in the outer carton.
6.5.
Nature and Content of Container
Blister packs comprising 60g/m PVdC coated PVC sealed on to 20pm hard temper aluminium foil in strips of 5, 7 or 14 tablets, available in packs of 5, 7 10, 14, 20, 21, 28, 30, 56, 60, 84, 90 and 100 tablets.
Also available in bulk packs of 100 tablets in a polypropylene container.
6.6. Instruction for Use, Handling and Disposal
None.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd t/a Mylan
Station Close
Potters Bar
Herts
EN6 1TL
8. MARKETING AUTHORISATION NUMBER
PL 04569/0450
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/09/2010
10 DATE OF REVISION OF THE TEXT
20/09/2010