1. NAME OF THE MEDICINAL PRODUCT

Zopiclone 7.5mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 7.5mg of zopiclone.

Each tablet also contains 32.0mg Lactose Monohydrate For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film coated tablet.

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

Posology

Adults:

The recommended dose is 7.5mg zopiclone by the oral route shortly before retiring.

Elderly:

A lower dose of 3.75mg zopiclone should be employed to start treatment in the elderly. Depending on effectiveness and acceptability, the dosage subsequently may be increased if clinically necessary.

Paediatric _ population

Children and young adults less than 18 years:

Zopiclone should not be used in children and adolescents less than 18 years. The safe and effective dose has not yet been established.

Patients with hepatic insufficiency:

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

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.

Chronic respiratory insufficiency

In patients with chronic respiratory insufficiency, a starting dose of 3.75 mg zopiclone is recommended initially. The dosage subsequently may be increased to 7.5 mg.

Treatment duration:

Transient Insomnia 2-5 days.

Short term insomnia 2-3 weeks.

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)

Method of administration:

Oral. Each film-coated tablet should be swallowed whole without sucking, chewing or breaking just before retiring for the night.

4.3    Contraindications

Zopiclone 7.5mg tablets 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 to any of the excipients. As with all hypnotics, Zopiclone 7.5mg tablets 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 and method of administration. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy (See section 4.3).

Use in renal insufficiency:

A reduced dosage is recommended; see Posology and method of administration.

Use in respiratory insufficiency:

As hypnotics have the capacity to depress respiratory drive, precautions should be observed if zopiclone is prescribed to patients with compromised respiratory function (see section 4.8).A lower dose is recommended for patients with chronic respiratory insufficiency due to risk of respiratory depression.

Paediatric population:

Zopiclone should not be used in children and adolescents less than 18 years of age. The safe and effective dose of Zopiclone has not been established in children and young adults less than 18 years.

Use in Elderly:

Elderly should be given a reduced dose (see section 4.2).

Risk of dependence:

Clinical experience to date with Zopiclone 7.5mg tablets 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 upon these products. The risk of dependence or abuse increases with dose and duration of treatment; use with alcohol or other psychotropics; 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 (See warnings and precautions). 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 7.5mg, tablets 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 (See section 4.8).

Depression:

As with other hypnotics, zopiclone does not constitute a treatment for depression and may even mask its symptoms (suicide may be precipitated in such patients). Any underlying cause of the insomnia should be also addressed before symptomatic treatment to avoid under treating potentially serious effects of depression. Prescribers are reminded to exclude depression as the underlying source of insomnia.

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 7.5mg tablets there is an absence of any marked tolerance during treatment periods of up to 4 weeks.

Rebound insomnia:

Rebound insomnia is a transient syndrome where the symptoms, which led to the 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. It is recommended to advise the patient accordingly.

A course of treatment should employ the lowest effective dose for the minimum length of time necessary for effective treatment. See Posology and method of administration section 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 film coated tablet. Therefore, patients should ensure that they take the film coated tablet when certain of retiring for the night and they are able to have a full night’s sleep (Uninterrupted sleep of about 7 to 8 hours).

Psychomotor impairment

Like other sedative/hypnotic drugs, zopiclone has CNS-depressant effects. The risk of psychomotor impairment, including impaired driving ability, is increased if: zopiclone is taken within 12 hours of performing activities that require mental alertness, a dose higher than the recommended dose is taken, or zopiclone is co-administered with other CNS depressants, alcohol or with other drugs that increase the blood levels of zopiclone (see section 4.5). Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle following administration of zopiclone and in particular during the 12 hours following that administration.

Other psychiatric and paradoxical reactions:

Other psychiatric and paradoxical reactions have been reported (see section 4.8, undesired effects), like restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, inappropriate behaviour and other adverse behavioural effects are known to occur when using sedative/hypnotic agents like zopiclone. Should this occur, use of zopiclone should be discontinued. These reactions are more likely to occur in the elderly.

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 coadministration of zopiclone with CYP3A4 inhibitors should be avoided (see section 4.5)

Somnambulism and associated behaviours:

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 zopilcone should be strongly considered for patients who report such behaviours (see Section 4.5 Interactions with other medicinal products and other forms of interactions)

Excipients:

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

4.5. Interaction with other medicinal products and other forms of interaction

Associations not recommended:

The sedative effect of zopiclone may be enhanced when used in combination with alcohol, concomitant use is therefore not recommended. In particular this could affect the patient’s ability to drive or use machines.

Associations to be taken into account:

In combination with CNS depressants an enhancement of the central depressive effect may occur. The therapeutic benefit of co-administration with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic 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 could 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 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 metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme (see section 5.2 Pharmacokinetic properties), plasma levels of zopiclone may be increased when co-administered with other CYP3A4 inhibitors including erythromycin clarithromycin, ketoconazole, itraconazole 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 when co-administered with CYP3A4 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin and St John’s wort. A dose increase for zopiclone may be required when it is co-administered with CYP3A4 inducers.

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 would result in a reduction of zopiclone plasma levels and reduce its hypnotic effects accordingly.

4.6 Fertility, pregnancy and lactation

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

Pregnancy:

Experience of 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, hypotonia 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 postnatal period.

Breast-feeding:

Zopiclone is excreted in breast milk and, although the concentration of Zopiclone in the breast milk is low, use in nursing mothers must be avoided.

4.7 Effects on ability to drive and use machines

Because of its pharmacological properties and its effect on central nervous system, Zopiclone may adversely affect the ability to drive or to use machines. The risk of psychomotor impairment, including impaired driving ability, is increased if:

•    zopiclone is taken within 12 hours of performing activities that require mental alertness,

•    a dose higher than the recommended dose is taken, or

•    zopiclone is co-administered with other CNS depressants, alcohol, or with other drugs that increase the blood levels of zopiclone.

Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle following administration of zopiclone and in particular during the 12 hours following that administration.

4.8 Undesirable effects

The _following CIOMS_frequency rating is used, when applicable:

Very common (>1/10); common (>1/100 to >1/10); uncommon fel/1000 to <1/100 ); rare (>1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot still be estimated from the available data).

Nervous system disorders

Common:    dysgeusia (Bitter taste), somnolence (residual)

Uncommon:    dizziness, headache and drowsiness have occurred.

Rare:    anterograde amnesia,

Not known:    ataxia, paraesthesia, cognitive disorders such as memory impairment, disturbance in

attention, speech disorder

Eye disorders

Not known:    diplopia

Respiratory, thoracic and mediastinal disorders Rare:    dyspnoea (see section 4.4)

Not known:    respiratory depression (see    section 4.4)

Withdrawal Syndrome

Withdrawal syndrome has been reported upon discontinuation of zopiclone. (See section 4.4 Special Warnings and Precautions for Use.) Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucinations, panic attacks, muscle aches/cramps, gastrointestinal disturbances 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. In very rare cases seizures may occur.

Psychiatric disorders

Uncommon:    nightmare (more likely to occur in the elderly), agitation

Rare:    confusional state, libido disorder, irritability, aggression, hallucination (more likely to

occur in the elderly),

Not known    restlessness, delusion, anger, depressed mood, abnormal behaviour (possibly

associated with amnesia) and somnambulism (see section 4.4: somnambulism and associated behaviour) dependence (see section 4.4), withdrawal syndrome (see below).

Gastrointestinal disorders Common:    Dry Mouth

Uncommon:    Mild gastrointestinal disturbances, including nausea and vomiting have occurred

Not Known:    Dyspepsia

Hepatic disorders

Very Rare:    Mild to moderate increases in serum transaminases and/or alkaline phosphatase have

been reported very rarely.

Immune System Disorders

Very Rare:    Angioedema and/or anaphylactic reactions have been reported very rarely.

Skin and subcutaneous tissue disorders

Rare:    allergic and allied manifestations such as urticaria, pruritis or rashes have been

observed.

Musculoskeletal and connective tissue disorders Not known:    muscular weakness

General disorders and administration site conditions

Common:    A mild bitter or metallic after-taste is the most frequently reported adverse effect.

Uncommon:    Fatigue

Not Known:    light headedness, incoordination

Injury, poisoning and procedural complications Rare:    fall (predominantly in elderly patients)

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the risk/benefit balance of the medicinal product. Healthcare professionals are asked to report and suspected adverse reactions via Yellow Card Scheme atwww.mhra.gov .uk/yellowcard

4.9. Overdose

Fatal dose not known

Symptoms:

Overdose is usually manifested by varying degrees of central nervous system depression ranging from drowsiness to coma according to the quantity ingested.

In the cases of overdosage reported, the main mild effects were drowsiness, confusion, and lethargy and in more severe cases ataxia, AV-block, hypotonia, hypotension, methaemoglobinaemia, respiratory depression and coma has occurred. Overdose should not be life threatening unless combined with other CNS depressants, including alcohol. Other risk factors, such as the presence of concomitant illness and debilitated state of patient, may contribute to the severity of symptoms and very rarely can result in fatal outcome.

Management:

Symptomatic and supportive treatment in adequate clinical environment is recommended, attention should be paid to respiratory and cardiovascular functions.

Consider activated charcoal if an adult has ingested more than 150mg or a child more than 1.5mg/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 short half-life (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC” TEST. Management should include general symptomatic and supportive measures including clear airway and monitoring cardiac and vital signs until stable.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: benzodiazepine related drugs

ATC code: N05CF01.

Zopiclone is an hypnotic agent, and a member of the cyclopyrrolone group of compounds. It rapidly initiates and sustains sleep with reduction of total REM sleep and with preservation of slow wave sleep. Negligible residual effects are seen the following morning. Its pharmacological properties include hypnotic, sedative, anxiolytic, anticonvulsant and muscle-relaxant actions. These are related to its high affinity and specific agonist action at central receptors belonging to the “GABA” macromolecular receptor complex modulating the opening of the chloride ion channel. However, it has been shown that zopiclone and other cyclopyrrolones act on a different site to those of benzodiazepines including different conformational changes in the receptor complex.

5.2 Pharmacokinetic properties

Absorption:

Zopiclone is absorbed rapidly. Peak concentrations are reached within 1.5-2 hours and they are approximately 30ng/ml and 60ng/ml after administration of 3.75mg and 7.5mg respectively. Absorption is not modified by gender, food or repetition of doses.

Distribution:

The product is rapidly distributed from the vascular compartment. Plasma protein binding is weak (approximately 45%) and non- saturable. There is very little risk of drug interactions due to protein binding. The volume of distribution is 91.8- 104.6 litres.

At doses between 3.75-15mg, plasma clearance does not depend on dose. The elimination half-life is approximately 5 hours. After repeated administration, there is no accumulation, and inter-individual variations appear to be very small.

Biotransformation:

The main metabolites are the n-oxide derivative (pharmacologically active in animals) and the n-desmethyl metabolite (pharmacologically inactive in animals). An in-vitro study indicates that cytochrome P450 (CYP) 3A4 is the major isoenzyme involved in the metabolism of zopiclone to both metabolites, and that CYP2C8 is also involved with N-desmethyl zopiclone formation. Their apparent half-lives (evaluated from the urinary data) are approximately 4.5 hours and 1.5 hours respectively. No significant accumulation is seen on repeated dosing (15mg) for 14 days. In animals, no enzyme induction has been observed even at high doses.

Elimination:

The low renal clearance value of unchanged zopiclone (mean 8.4ml/min) compared with the plasma clearance (232 ml/min) indicates that zopiclone clearance is mainly metabolic. The product is eliminated by the urinary route (approximately 80%) in the form of free metabolites (n-oxide and n-desmethyl derivatives) and in the faeces (approximately 16%).

Special patient groups:

In elderly patients, notwithstanding a slight decrease in hepatic metabolism and lengthening of elimination half- life to approximately 7 hours, various studies have shown no plasma accumulation of drug substances on repeated dosing. In renal insufficiency, no accumulation of zopiclone or of its metabolites has been detected after prolonged administration. Zopiclone crosses dialysis membranes. In cirrhotic patients, the plasma clearance of zopiclone is clearly reduced by the slowing of the desmethylation process: dosage will therefore have to be modified in these patients.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Calcium hydrogen phosphate dihydrate Lactose monohydrate Maize starch

Sodium starch glycollate type A

Magnesium stearate

Hydroxypropylmethylcellulose

Propylene glycol

Titanium dioxide

Talc

6.2 Incompatibilities

None stated.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25 ^oC.

Store in the original package.

6.5    Nature and contents of the container

Zopiclone 7.5mg, tablets are provided in PVC/PVdC/ aluminium foil blisters containing 28 tablets.

6.6    Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Athlone Pharmaceuticals Ltd.,

Ballymurray,

Co. Roscommon,

Ireland.

8 MARKETING AUTHORISATION NUMBER(S)

PL 30464/0127

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

15/12/2005

DATE OF REVISION OF THE TEXT

23/06/2016