Zopiclone 3.75mg Tablets

1. Name Of The Medicinal Product

Zopiclone 3.75mg Tablets.

2. Qualitative And Quantitative Composition

Zopiclone 3.75mg tablets contain 3.75mg of Zopiclone per tablet.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Short term treatment of insomnia, including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances, in situations where the insomnia is debilitating or is causing severe distress for the patient.

Long term continuous use is not recommended. A course of treatment should employ the lowest effective dose.

4.2 Posology And Method Of Administration

The duration of treatment should be limited to 4 weeks, including any tapering off.

Adults: The recommended dose is one 7.5mg tablet shortly before retiring.

Elderly: A lower dose of 3.75mg should be employed to start treatment in the elderly. Depending upon effectiveness and acceptability, the dosage subsequently may be increased if clinically necessary to 7.5mg/day.

Patients with hepatic insufficiency: As elimination of zopiclone may be reduced in patients with hepatic dysfunction a lower dose of 3.75mg nightly is recommended. The standard dose of 7.5mg may be used with caution in some cases, depending upon effectiveness and acceptability.

Patients with renal insufficiency: Accumulation of zopiclone or its metabolites has not been seen during treatment of insomnia in patients with renal insufficiency. However it is recommended that patients with impaired renal function should start treatment with 3.75mg.

Zopiclone is not recommended for use in children.

4.3 Contraindications

Zopiclone is contraindicated in patients with myasthenia gravis, respiratory failure, severe sleep apnoea syndrome, severe hepatic insufficiency and those people with a hypersensitivity to zopiclone or any other ingredient in the product. As with all hypnotics, zopiclone should not be used in children.

4.4 Special Warnings And Precautions For Use

Use in hepatic insufficiency: A reduced dosage is recommended, see Posology.

Use in renal insufficiency: A reduced dosage is recommended, see Posology.

Risk of dependence: Clinical experience to date with zopiclone suggests that the risk of dependence is minimal when the duration of treatment is limited to not more than 4 weeks.

Use of benzodiazepines and benzodiazepine-like agents (even at therapeutic doses) may lead to the development of physical and psychological dependence on these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol and/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. If 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: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Rare cases of abuse have been reported.

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

Depression: As with other hypnotics, zopiclone does not constitute a treatment for depression. Any underlying cause of the insomnia should also be addressed before symptomatic treatment.

Tolerance: Some loss of efficacy to the hypnotic effect of benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks. However, with zopiclone, there is an absence of any marked tolerance during treatment periods of up to 4 weeks.

Rebound insomnia: This is a transient syndrome where the symptoms which led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form on discontinuation of therapy. It may be accompanied by other reactions including mood changes, anxiety and restlessness. Since the risk of withdrawal/rebound phenomena may be increased after prolonged treatment, or abrupt discontinuation of therapy, decreasing the dosage in a stepwise fashion may be helpful.

A course of treatment should employ the lowest effective dose for the minimum length of time necessary for effective treatment. See posology for guidance on possible treatment regimen. A course of treatment should not continue for longer than 4 weeks including any tapering off.

Amnesia: Amnesia is rare, but anterograde amnesia may occur, especially when sleep is interrupted or when retiring to bed is delayed after taking the tablet. Therefore, patients should ensure that they take the tablet when certain of retiring for the night and they are able to have a full night's sleep.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The sedative effect of zopiclone may be enhanced when used in combination with alcohol.

In combination with CNS depressants an enhancement of the central depressive effect may occur. The therapeutic effect of co-administration antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines should therefore be carefully weighed. Concomitant use of benzodiazepines or benzodiazepine-like agents with narcotic analgesics may enhance their euphoric effect and may lead to an increase in psychic dependence. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents.

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 the presence of erythromycin which indicates that erythromycin can inhibit the metabolism of drugs metabolised by CYP3A4. As a consequence, the hypnotic effect of zopiclone may be enhanced.

4.6 Pregnancy And Lactation

Experience of the use of zopiclone during pregnancy in humans is limited although there have been no adverse findings in animals. Use in pregnancy is therefore not recommended. If the product is prescribed to a woman of child bearing potential, she should be advised to contact her physician about stopping the product if she intends to become pregnant, or suspects that she is pregnant.

Moreover, if zopiclone is used during the last three months of pregnancy or during labour, due to the pharmacological action of the product, effects on the neonate, such as hypothermia and respiratory depression can be expected.

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

Zopiclone is excreted in breast milk and use in nursing mothers must be avoided.

4.7 Effects On Ability To Drive And Use Machines

Although residual effects are rare and generally of minor significance, patients should be advised not to drive or operate machinery the day after treatment until it is established that their performance is unimpaired.

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

4.8 Undesirable Effects

A mild bitter or metallic after-taste is the most frequently reported adverse effect. Less commonly, mild gastrointestinal disturbances, including nausea and vomiting, dizziness, headache, drowsiness and dry mouth have occurred.

Psychological and behavioral disturbances, such as irritability, aggressiveness, confusion, depressed mood, anterograde amnesia, hallucinations and nightmares have been reported. Rarely these reactions may be severe and may be more likely to occur in the elderly.

Rarely allergic and allied manifestations such as urticaria or rashes have been observed, and more rarely, light headness and incoordination.

Withdrawal and rebound insomnia have occasionally been observed on discontinuation of treatment, mainly in association with prolonged treatment.

4.9 Overdose

Overdose is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma according to the quantity ingested. Overdosage should not be life-threatening unless combined with other CNS depressants (including alcohol). Symptomatic and supportive treatment in an adequate clinical environment is recommended. Attention should be paid to respiratory and cardiovascular functions. Gastric lavage is only useful when performed soon after ingestion. Haemodialysis is of no value due to the large volume and distribution of zopiclone. Flumazenil may be a useful antidote.

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 GABA_A- 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: N05C F01.

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 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 3.75mg 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 is 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 (approximately16%).

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 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

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 ingredients are used in Zopiclone Tablets: lactose monohydrate, calcium hydrogenphosphate, maize starch, carmellose sodium, magnesium stearate, titanium dioxide, methylhydroxypropylcellulose, iron oxide yellow and iron oxide red.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Shelf-life

Blister

3 years.

The expiry date is printed on the outer package and on the strips. Do not use after this date. The first two digit numbers represent the month and the last two digit numbers represent the year.

Glass jar

24 months.

The expiry date is printed on the outer package and on the glass jar. Do not use after this date. The first two digit numbers represent the month and the last two digit numbers represent the year.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Store below 25°C in a dry place and protected from light

6.5 Nature And Contents Of Container

Blister: PVC/PVDC/Al (250µm/40g/m²/20µm). Enclosed within a cardboard carton containing 1, 3 or 6 strips of 10 tablets, or 1, 2 or 4 strips of 14 tablets. Each box contains a Patient Information Leaflet.

Blister: PVC/PVDC/Al (250 µm/60g/m²/20µm)

Pack Sizes: 10, 14, 28, 30, 56, 60

Glass jar: Amber coloured glass type III with a child resistant cap, containing 28, 30, 56 or 60 tablets, enclosed within a cardboard carton also containing a Patient Information Leaflet.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0449

9. Date Of First Authorisation/Renewal Of The Authorisation

4 August 1998

10. Date Of Revision Of The Text

24.04.2009