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Gerard Laboratories

Unit 35/36, Baldoyle Industrial Estate, Grange Road, Baldoyle, Dublin 13, Ireland
Telephone: +353 1 8393788
Fax: +353 1 8390040
Medical Information Direct Line:
Medical Information e-mail: sales@gerard-laboratories.ie


Summary of Product Characteristics last updated on medicines.ie: 08/12/2011
SPC Zimoclone 7.5 mg Film-Coated Tablets



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1. NAME OF THE MEDICINAL PRODUCT

Zimoclone 7.5mg Film-coated Tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 7.5mg of the active ingredient zopiclone.

Excipients: 30.8mg lactose anhydrous/film-coated tablet

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Film-coated tablet.

White, film coated, oval tablet having a breakline, with 'ZZ' on one side and '7.5' on the other.

The tablet can be divided into equal halves.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Zopiclone Tablets 7.5mg 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.


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4.2 Posology and method of administration

Administration:

Zopiclone Tablets 7.5mg 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. (see warnings on dependence and tolerance in section 4.4)

Dosage

Adults:

The recommended dose for adults is 1 tablet (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. (See section 4.4).

Children and adolescents:

Zopiclone should not be used in children or adolescents younger than 18 years of age.


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4.3 Contraindications

Zopiclone is contraindicated in patients with any of the following:

history of hypersensitivity to zopiclone or to any of the 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.


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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:

Zopiclone does not constitute a treatment for depression. Any underlying cause of the insomnia should also be addressed before symptomatic treatment to avoid under treating potentially serious effects of depression.

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.

Somnambulism and associated behaviours:

Sleepwalking and other associated behaviours such as 'sleep driving', preparing and eating food or making phone calls with amnesia for the event, have been reported in patients who have taken zopiclone and were not fully awake. It appears that there is an increased risk of such behaviour with the concomitant use of alcohol, other CNS depressants or the use of zopiclone at doses exceeding the maximum recommended dose. If such behaviours are reported, administration of zopiclone should be discontinued (see Section 4.5).

Specific patient groups:

For the elderly: Hypnotics should be avoided in the elderly who are at risk of becoming ataxic and confused and so liable to fall and injure themselves. If, based on clinical need, a decision to treat is nevertheless taken, treatment should be initiated at a lower dose (see section 4.2) and co-administration of zopiclone with CYP3A4 inhibitors should be avoided (see section 4.5).

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:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.


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4.5 Interaction 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 co-administration 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)

Since zopiclone is metabolised by CYPP4503A4 isoenzyme, plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors, such as erythromycin, clarithromycin, ketoconazole, itraconazole, fluconazole, tacrolimus and ritonavir. This may result in an increased risk of adverse effects, particularly in the elderly. Consequently, co-administration of zopiclone with CYP3A4 inhibitors should be avoided in the elderly (see section 4.4); for all other patients a dose reduction may be considered.

Conversely, plasma levels of zopiclone may be decreased, therefore reducing the sedative effects of zopiclone when co-administered with CYP3A4 inducers, such as rifampicin, nefazodone, phenobarbital, phenytoin and St John's wort. When co-administered with CYP3A4 inducers or inhibitors a dose adjustment may be considered.

A single dose study has indicated that when zopiclone and carbamazepine are taken in combination, their sedative effects are additive. However, as carbamazepine is a potent inducer of CYP3A4, it is predicted that long term use of carbamazepine could result in a reduction of zopiclone plasma levels and reduce its hypnotic effects accordingly.

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.

Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.


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4.6 Pregnancy and lactation

Insufficient data are available on zopiclone to assess its safety during pregnancy and lactation in humans.

Zopiclone should not be used during pregnancy unless clearly necessary.

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, for compelling medical reasons 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. Infants born to mothers who took benzodiazepines or benzodiazepine-like agents chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

To date zopiclone has not produced injurious effects in animal studies except at very high maternally toxic doses.

Zopiclone should not be used in nursing mothers since zopiclone and its metabolites are excreted in breast milk.

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.


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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 drive 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.


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4.8 Undesirable effects

The following undesirable effects have been reported at the approximate frequencies shown: very common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Immune system disorders

Rare:

Allergic reactions including skin reactions

Very rare:

Anaphylactic reactions and/or angioedema

Psychiatric disorders

Rare:

Confusion, numbed emotions, depression, restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, sleepwalking and other adverse behaviour

Very rare:

Changes in libido

Not known:

Dependency

See below under 'Depression', 'Psychiatric and paradoxical reactions', 'Somnambulism and associated behaviours' and 'Dependency'.

Nervous system disorders

Common:

Drowsiness during the following day, reduced alertness, headaches, dizziness

Rare:

Amnesia, ataxia (predominantly at the start of therapy and usually disappears with repeated administration)

See below under 'Amnesia'.

Eye disorders

Rare:

Double vision (predominantly at the start of therapy and usually disappears with repeated administration)

Gastrointestinal disorders

Very common:

Bitter taste

Common:

Other gastrointestinal complaints

Musculoskeletal and connective tissue disorders

Rare:

Muscle weakness

General disorders and administration site conditions

Uncommon:

Fatigue

Investigations

Rare:

Mild to moderate increases in serum transaminases and/or alkaline phosphatase

Amnesia:

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour (see Section 4.4).

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 are more likely to occur in children and the elderly.

Somnambulism and associated behaviours:

There is an increased risk of sleepwalking and other associated behaviours with amnesia for the event in patients who have taken zopiclone and were not fully awake. It appears that there is an increased risk of such behaviour with the concomitant use of alcohol, other CNS depressants and the use of zopiclone at doses exceeding the maximum recommended dose (see Section 4.4)

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 Section 4.4). Psychological dependence may occur. Abuse has been reported.


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4.9 Overdose

Symptoms of central nervous system depression which can range from drowsiness to coma are the main reactions to overdose of zopiclone. The effects of overdose may be magnified if combined with alcohol or any other CNS depressants and in severe cases may be life-threatening.

Treatment of overdose should be symptomatic and supportive paying particular attention to respiratory and cardiac functions. If overdose is detected soon after ingestion, gastric lavage may be useful. If CNS depression is severe consider the use of flumazenil. It has a short half-life (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A 'DIAGNOSTIC' TEST. Haemodialysis does not have any therapeutic effect in cases of zopiclone overdose.

For current practice, refer to local poison centre (or equivalent information sources) regarding management of overdose.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

ATC code: N05C F01. Hypnotic and sedatives; benzodiazepine related drugs

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.

Pharmacological properties are: anxiolysis, sedation, hypnosis, anticonvulsion and muscle relaxation


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5.2 Pharmacokinetic properties

Absorption:

Zopiclone is swiftly absorbed. Maximum plasma concentrations are achieved after 1½ - 2 hours and are approximately 30 and 60ng/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 eliminated 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.


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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.

Foetal developmental retardations and foetotoxic effects in rats and rabbits were observed only at doses well above the maximum human dosage. There was no evidence of a teratogenic potential.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Lactose anhydrous

Calcium hydrogen phosphate, anhydrous

Maize starch

Povidone

Magnesium Stearate

Hypromellose

Titanium dioxide (E171)

Macrogol 400


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6.2 Incompatibilities

Not applicable


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6.3 Shelf life

2 Years.


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6.4 Special precautions for storage

Do not store above 25°C

Store in the original package


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6.5 Nature and contents of container

Cartons containing PVC/PVdC/Aluminium blister strips of 5 or 7 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.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Generics [UK] Limited

Station Close

Potters Bar

Hertfordshire EN6 1TL

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 405/44/1


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28th April 2000

Date of latest renewal: 8th December 2008


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10. DATE OF REVISION OF THE TEXT

September 2011



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Active Ingredients

 
   Zopiclone