Zopiclone 3.75 Mg Film-Coated Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zopiclone 3.75 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 3.75 mg zopiclone

Excipient: 30,8 mg lactose monohydrate/film-coated tablet For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

film-coated tablet

Visual description of the appearance

Orange round biconvex tablets. The tablets are embossed with “ZOC 3.75” on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Short-term treatment of insomnia in adults.

Benzodiazepines and benzodiazepine-like substances are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

4.2 Posology and method of administration

Posology

Treatment with Zopiclone should be for as short a period as possible. Long-term continuous use is not recommended.

The period of treatment should generally vary between a few days to 2 weeks, with a maximum of 4 weeks including the tapering off phase. It is recommended that the patient should be informed of this prior to commencing treatment. In certain cases it may be necessary to prolong treatment to beyond the maximum period. If this is the case, however, it should only take place after re-evaluation of the patient’s condition.

Paediatric population

Zopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy of zopiclone in children and adolescents aged less than 18 years have not been established.

The recommended dose for adults is 7.5 mg (two tablets). This dose should not be exceeded.

In the older people, patients with hepatic insufficiency or chronic respiratory insufficiency, treatment should be started at a dosage of 3.75 mg, i.e. one tablet. Although no accumulation of zopiclone or its metabolites has been found in patients with renal insufficiency, it is advisable to begin treatment of patients with reduced renal function at 3.75 mg.

Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.

Method of administration

The medicinal product should be taken orally immediately before going to bed.

4.3 Contraindications

Zopiclone is contra-indicated in the following cases:

- Hypersensitivity to zopiclone or to any of the excipients, benzodiazepines, or other benzodiazepine-like substances

- Myasthenia gravis

- Severe respiratory insufficiency

- Sleep apnoea syndrome

- Children and adolescents under the age of 18 years

- Severe hepatic insufficiency

4.4 Special warnings and precautions for use

Before starting treatment with zopiclone any underlying cause of insomnia should be addressed carefully.

Dependence

The use of benzodiazepines and benzodiazepine-like substances can lead to physical and psychological dependence on these agents. This may not only occur with misuse of high doses but also with therapeutical doses. The risk of dependence increases the higher the dose and the longer the period of treatment; the risk of dependence is also greater in patients with a history of alcohol or drug abuse or those who have marked personality disorders. The decision to use a hypnotic in such patients should be taken only with this clearly in mind. These patients should be under careful surveillance when receiving zopiclone. If physical dependence occurs, sudden discontinuation of the treatment will be accompanied by withdrawal symptoms. These may be expressed as headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, insomnia and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise or physical contact, hallucinations or epileptic seizures. Rare cases of abuse have been reported.

Rebound insomnia

After discontinuation of treatment with a benzodiazepine or a benzodiazepine-like substance, a temporary syndrome may occur in which the symptoms which led to the treatment with the benzodiazepine or a benzodiazepine-like substance return in a more severe form. This syndrome may be accompanied by other reactions, including mood changes, sleep disturbances, anxiety and restlessness. Since the risk of withdrawal symptoms or rebound symptoms is greater after prolonged treatment, or abrupt interruption of the treatment it is advisable to reduce the dosage gradually.

Period of treatment

The period of treatment should employ the lowest effective dose and should be as short as possible (see section 4.2) and 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 the dose will be gradually reduced. 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.

Tolerance

The hypnotic effect of short-acting benzodiazepines and benzodiazepine-like substances may diminish after repeated use for a few weeks. For zopiclone however, no pronounced tolerance has occurred during a treatment period of up to 4 weeks.

Anterograde amnesia

Benzodiazepines and benzodiazepine-like substances may cause anterograde amnesia, especially when sleep is interrupted or when retiring to bed is delayed after taking the tablet. In order to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see section 4.8).

Psychiatric and “paradoxical” reactions

It is known that reactions such as restlessness, agitation, irritability, aggression, delusions, outbursts of rage, nightmares, hallucination, psychoses, inappropriate 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. The risk of these reactions is greater in children and the elderly.

Somnambulism and associated behaviour

Sleep walking 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. The use of alcohol and other CNS-depressants with zopiclone appears to increase the risk of such behaviours, as does the use of zopiclone at doses exceeding the maximum recommended dose. Discontinuation of zopiclone should be strongly considered for patients who report such behaviours (see Section 4.5 Interactions with other medicinal products and other forms of interactions).

Specific patient groups

For the elderly: see section 4.2. A lower dose is advised for patients with chronic respiratory insufficiency due to the risk of masking the symptoms (anxiety, agitation) of respiratory depression. Benzodiazepines and benzodiazepine-like substances are not suitable for the treatment of patients with severe hepatic insufficiency, since they may precipitate encephalopathy. For patients with hepatic insufficiency or reduced renal function see section 4.2. 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 history of alcohol or drug abuse. Because of the myorelaxant effect of zopiclone there is a danger of falling over, particularly for elderly patients when they get up at night.

Paediatric population

Zopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy of zopiclone in children and adolescents aged less than 18 years have not been established.

Lactose monohydrate

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Zopiclone should not be taken simultaneously with alcohol because the effects may be intensified. This may affect the ability to drive or operate machines.

Combination with other central depressive agents, such as antipsychotic agents (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressants, narcotic analgesics, anti-epileptics, anaesthetics and sedative antihistamines may increase the suppressive effect of zopiclone on the central nervous system and should therefore be carefully considered.

In the case of narcotic analgesics potentiation of euphoria may also occur, which can lead to increased psychological dependence.

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

Compounds which inhibit or induce certain hepatic enzymes (in particular cytochrome P450) may enhance or reduce the activity of benzodiazepines and benzodiazepine-like substances.

The effect of erythromycin on the pharmacokinetics of zopiclone has been studied in 10 healthy subjects. The AUC of zopiclone is increased by 80% in presence of erythromycin which indicates that erythromycin can inhibit the metabolism of drugs metabolised by CYP 3A4. As a consequence, the hypnotic effect of zopiclone may be enhanced.

Since zopiclone is mainly metabolised by CYP 3A4, the plasma levels of zopiclone and thus the effect of zopiclone may be increased when used in combination with drugs which inhibitCYP 3A4, such as macrolide antibiotics, azole antimycotics and HIV protease inhibitors, as well as grape fruit juice. Dose reduction should be considered if zopiclone is co-administered with CYP 3A4 inhibitors. Drugs which induce CYP 3A4, like Phenobarbital, phenytoin, rifampicin and products containing St. John's wort, may reduce zopiclone plasma levels and thus the effect of zopiclone.

A single dose study has indicated that when zopiclone and carbamazepine are taken in combination, their sedative effects are additive. However, as carabamazepine 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.

4.6 Pregnancy and lactation

The safety of use in pregnant women and during lactation has not been established.

To date zopiclone has not produced injurious effects in animal studies except at very high maternally toxic doses. However, use in pregnancy is not recommended.

If zopiclone is prescribed during the last three months 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”) may be expected due to the pharmacological properties of the product. Because of the development of physical dependence, withdrawal symptoms may occur in neonates of mothers who have used zopiclone for long periods during the last months of pregnancy.

If zopiclone is prescribed to women of child-bearing age, they should be advised that if they are planning to become pregnant or think they may be pregnant, they should contact their doctor about discontinuing the treatment. Although the concentration of zopiclone in breast milk is very low, zopiclone should not be prescribed to women during the lactation period.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may reduce the capability to drive or operate machines. The risk is increased with concomitant alcohol intake. The risk is even higher when sleep duration is insufficient. Patients should be warned not to drive or operate machines until treatment has finished or it has been established that performance is unimpaired. As the above mentioned effects can remain, patients should be careful until the following morning.

4.8 Undesirable effects

Frequencies mentioned in this section are based on the following percentages: Very common (>10%)

Common (1-10%)

Uncommon (0,1-,1%)

Rare (0,01-0,1%),

Very rare (<0,01%)

Not known (can not be estimated form the available data)

Undesirable effects seem to be related to individual sensitivity and to appear more often during the first hour following intake. The following adverse reactions have been observed in patients treated with zopiclone:

Immune system disorders

Very rare

Anaphylactic reactions Psychiatric disorders

Rare

Numbed emotions, confusion and depression . Paradoxical reactions such as restlessness, agitation, irritability, aggression, delusions, outburst of rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural disturbances.

Very rare Decreased libido Unknown

Physical and psychological dependence

See also below under “Depression”, “Psychiatric and paradoxical reactions” and “Dependence”.

Nervous system disorders

A bitter taste or metallic after-taste is the most common adverse reaction of zopiclone.

Common

Sleepiness during the following day, reduced alertness, headache, dizziness Rare

Amnesia, , incoordination, ataxia (predominantly at the beginning of treatment; generally disappears after repeated administration), light headedness.

4.9 Overdose

In the few cases where overdosage with zopiclone has been reported, these reports were not accompanied by life-threatening effects unless the agent was ingested in combination with other medicaments which have a suppressive effect on the central nervous system, including alcohol. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death. Overdose of benzodiazepines or benzodiazipines-like agents is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma.

Treatment should be aimed at supporting vital functions and is chiefly symptomatic (e.g. monitor the heart function and respiration).

Haemodialysis is not useful because of the high distribution volume of zopiclone. Flumazenil may be beneficial as an antidote.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine related drugs, ATC code N05C F01

Zopiclone is a benzodiazepine-like hypnotic agent which belongs to the group of cyclopyrrolones. The pharmacological properties are: sedation, anxiolysis, anticonvulsion, muscle relaxation. These effects are related to a specific agonistic effect on central receptors belonging to the GABAA ,macromolecular complex which regulates the opening of chloride channels. These effects are similar to those of benzodiazepines.

5.2 Pharmacokinetic properties

Absorption

Zopiclone is swiftly absorbed. In general maximum plasma concentrations are achieved after 0.75 - 2 hours and are approximately 30 and 60 ng/ml after administration of 3.75 mg and 7.5 mg 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 15 mg.

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 is seen following repeat dosing, (15mg) for 14 days.

Elimination

The low renal clearance of zopiclone (on average 8.4 ml/min) compared to the plasma clearance (232 ml/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 elicited in repeated dose toxicity studies conducted in rats and dogs. In dogs anaemia were evident in some studies.

Both in vitro and in vivo studies failed to show mutagenicity produced by zopiclone.

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 in thyroid tumours in rats were associated with increased TSH serum levels. In humans zopiclone has no effects on thyroid hormones.

Fertility was impaired in two rat studies, whereas zopiclone had no adverse effects on fertility in rabbits. Double-blind long-term studies (7.5 mg zopiclone for 84 days) in healthy volunteers revealed no changes in ejaculate volume, sperm concentration, sperm motility as well as morphology.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core

- Lactose monohydrate

- calcium hydrogen phosphate

- maize starch

- carmellose sodium

- magnesium stearate.

Film coat

- titanium dioxide (E171)

- hypromellose

- iron oxide yellow (E172)

- iron oxide red (E172)

6.2 Incompatibilities

Not applicable

Shelf life

6.3

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Lithographed carton boxes containing 10, 14, 20, 28, 30, 56 or 60 film-coated tablets in blister (PVC/PVDC/Aluminium)

Lithographed carton boxes containing 50 film-coated tablets in blister (PVC/PVDC/Aluminium) “HUD” (Hospital Unit Dosage).

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

TEVA UK Limited

Brampton Road, Hampden Park

Eastbourne, East Sussex, BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00258/0413

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/11/2006

10 DATE OF REVISION OF THE TEXT

02/10/2015