SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Zopiclone Tablets 3.75mg.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

"Zopiclone Tablets 3.75mg" contain 3.75 mg of Zopiclone BP per tablet.

3.    PHARMACEUTICAL FORM

Tablets.

4    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

Zopiclone is indicated for the short term treatment of insomnia.

4.2.    Posology and Method of Administration

The usual dose of Zopiclone in healthy adults is 7.5 mg, taken by oral administration in an upright position 30 to 60 minutes before retiring.

Use in children:

No studies have been carried out in children, and consequently the administration of Zopiclone in children is not recommended.

Use in elderly patients:

In elderly patients an initial dose of 3.75 mg is recommended. This can be increased, if necessary, to 7.5 mg per day.

Use in patients with a diminished renal and/or hepatic function:

In general, in patients who have a decrease in the renal and/or hepatic function the dose should be kept to a minimum.

In patients with mild hepatic and mild to moderate renal insufficiency a standard dose of 7.5 mg may be given with caution.

In patients with severe hepatic and renal insufficiency a daily dose of 3.75 mg should not be exceeded.

A single treatment should not continue for longer than 4 weeks including any tapering off. Long term continuous use in not recommended.

4.3. Contra-Indications

-    Hypersensitivity to Zopiclone or any other component of the tablet.

-    Myasthenia gravis.

-    Severe sleep apnoea.

4.4. Special Warnings and Special Precautions for Use

In patients with chronic respiratory insufficiency there is a chance for depression of respiration, especially at night. Administration of Zopiclone in these patients should be considered carefully and a daily dose of 7.5 mg should not be exceeded.

Caution should be taken in patients who are prone to drug abuse. A number of investigations have been conducted without showing evidence of a significant propensity for drug dependence. Nonetheless any drugs of this type may produce dependence in some individuals.

Risk of dependence: The risk of dependence is minimal when the duration of treatment is limited to not more than 4 weeks.

Withdrawal: The termination of treatment with Zopiclone is unlikely to be associated with withdrawal effects when duration is limited to 4 weeks. Patients may benefit from tapering off the dose before discontinuation.

Depression: As with other hypnotics, Zopiclone does not constitute a treatment for depression.

Tolerance: With Zopiclone therapy there is an absence of any marked tolerance during treatment periods of up to 4 weeks.

Rebound insomnia: To avoid the risk of possible rebound insomnia a course of treatment should not continue for longer than 4 weeks including any tapering off.

4.5. Interactions with other Medicinal Products and other forms of Interaction

Concomitant use of central nervous system depressants including antidepressant agents, neuroleptic agents, hypnotics, anxiolytics, narcotic analgesics and antihistamines may result in an accentuation of the central depressant effect. There is also a possibility of abnormal changes in mood or behaviour. Therefore, administration of Zopiclone in combination with these drugs is not recommended.

Concomitant use with alcohol is not recommended, as this could affect the patients ability to drive or use machines the next day.

4.6. Pregnancy and Lactation

Insufficient data exist on the use of Zopiclone during pregnancy in humans. Animal studies have shown that Zopiclone only partially crosses the placenta and does not cause any teratogenic effects.

Zopiclone should not be used in pregnancy.

If Zopiclone is used during the last three months of pregnancy or during labour, effects on the neonate, such as hypothermia, hypnotic and respiratory depression can be expected.

Zopiclone and its metabolites are excreted in breast milk. Calculations have shown that the dose that would be received by the neonate was corresponding to 1.4 % of the maternal dose. The short elimination half-life of Zopiclone suggests that there would be little accumulation of the drug in breast milk during repeated daily administration. However, when possible the use of Zopiclone in nursing mothers should be avoided.

4.7. Effects on Ability to Drive and Use Machines

Due to its effects Zopiclone may affect the ability to drive and use machines during the first hours after administration.

After normal use the residual effects the next morning are small, especially when dosages of 3.75 mg are taken. Patients should be advised not to drive or operate machinery the day after treatment until it is established that their performance is unimpaired.

4.8. Undesirable Effects

Zopiclone is generally well tolerated. Undesirable effects include morning drowsiness or in-coordination, headache, dizziness, bitter or metallic taste, dry mouth, blurring of vision, occasional irritability, depression of mood and nervousness. Some cases of gastrointestinal disturbances including nausea and vomiting, amnesia, automatism, confusion, nightmare and "hangover" have also occurred. Allergic and allied manifestations (urticaria and various rashes) have only very rarely been observed.

In a few cases, withdrawal symptoms and rebound effects have occurred after stopping a prolonged treatment.

4.9. Overdose

In general, Zopiclone has demonstrated to be a safe substance. No serious effects were seen in the few recorded cases of accidental overdose with Zopiclone. Central nervous system depression (drowsiness, lethargy and ataxia) was the most frequently reported event and no particular medical treatment was necessary, apart from clinical monitoring of vital functions and emesis. Emesis is only useful when performed soon after ingestion.

Flumazenil may be a useful antidote.

Overdose should not be life-threatening unless combined with other CNS depressants, including alcohol.

5 PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Zopiclone is a cyclopyrrolone which possesses similar sedative, anxiolytic, muscle relaxant and anticonvulsant properties as the benzodiazepines. Zopiclone recognises specifically and with high affinity the central receptors of the GABA_A-benzodiazepine chloride channel macromolecular receptor

complex in the central nervous system. After binding of Zopiclone to this receptor complex (at a site distinct from, but closely related to the benzodiazepine binding site), the affinity of the receptor complex for GABA increases. Binding of GABA to the complex induces opening of the chloride channels, through which hyperpolarisation of the cell membrane and inhibition of the neurons takes place.

Zopiclone has no affinity for peripheral benzodiazepine receptors.

Significant improvements in sleep onset time, sleep quality, number of awakenings and total sleep time were observed after administration of a single Zopiclone dose. The influence of Zopiclone on sleep architecture is minimal.

5.2. Pharmacokinetic Properties

Zopiclone is rapidly absorbed following oral administration. The oral administration of 7.5 mg Zopiclone resulted in mean peak plasma concentrations of 54 to 86 pg/L at 0.5 to 2.5 hours after administration, yet the hypnotic effect enters already after 15 to 30 minutes. Zopiclone demonstrates linear pharmacokinetics between dosages of 3.5 to 15 mg.

After absorption Zopiclone is widely distributed into body tissues including the brain, with relative high concentrations in the liver and the left hypochondrium. The volume of distribution is about 100 L.

Zopiclone is reported to be bound to plasma proteins at a percentage of 45 to 80 %.

The renal clearance of unchanged Zopiclone is about 10 mL/min, the plasma clearance reaches values up to 230 mL/min.

Zopiclone has an elimination half-life of 3.5 to 6.5 hours. Because of this short elimination half-life there is no accumulation of Zopiclone in the body after repeated administration. In patients with renal and/or hepatic insufficiency and in elderly the elimination half-life of Zopiclone can be prolonged.

Zopiclone is extensively metabolised in the liver by three major pathways: Oxidation of the side chain resulting in the formation of the less active metabolite Zopiclone N-oxide (11 %), demethylation leading to the inactive metabolite N-desmethyl Zopiclone (15 %) and ester hydrolysis involving oxidative decarboxylation of 50 % of a dose, producing inactive metabolites partly eliminated via the lung as carbon dioxide. Only 4 to 5 % of the dose is excreted unchanged in the urine. About 16 % of the dose is excreted in faeces.

5.3. Preclinical Safety Data

Carcinogenicity: From studies performed in rats and mice it can be concluded that for patients receiving long-term medication with Zopiclone no carcinogenic potential exists.

Mutagenicity: Both in vitro and in vivo studies failed to show mutagenicity produced by Zopiclone.

Fertility: In animal studies Zopiclone caused a decrease in fertility in rats. Zopiclone did not affect fertility in rabbits.

Teratogenicity: Zopiclone did not show any teratogenic or embryotoxic effect in animal studies.

6 PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

The following inactive ingredients are used in Zopiclone Tablets 3.75mg:

Lactose monohydrate Calcium hydrogen phosphate Maize starch Carmellose sodium Magnesium stearate Titanium dioxide (E171)

Methylhydroxypropylcellulose Iron oxide yellow (E172)

Iron oxide Red (E172)

6.2. Incompatibilities

Not applicable.

6.3. Shelf Life

2 years.

6.4. Special Precautions for Storage

Store in dry place below 25°C. Protect from light.

Nature and Contents of Container

Lithographed carton boxes containing 1, 3 or 6 PVC/PVdC/aluminium strips of 10 tablets, and lithographed carton boxes containing 1, 2 or 4 PVC/PVdC/aluminium strips of 14 tablets. Each box contains a patient insert.

Lithographed carton boxes containing 1 jar (glass type III) with 28, 30, 56 or 60 tablets. Each box contains a patient insert.

6.6. Instruction for Use, Handling and Disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Synthon BV Microweg 22 6545 CM Nijmegen The Netherlands

8. MARKETING AUTHORIZATION NUMBER

PL 14048/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/08/2010

10    DATE OF REVISION OF THE TEXT

04/08/2010