Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
The cause of insomnia should be identified wherever possible and the underlying factors treated before a hypnotic is prescribed.

Specific patient groups

Use in hepatic insufficiency
A reduced dosage is recommended (see section 4.2). 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 section 4.2).

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 the risk of respiratory depression.

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Use in 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.

Use in elderly patients
Elderly should be given a reduced dose (see section 4.2).

Risk of dependence
Use of zopiclone may lead to the development of abuse and/or physical and psychological dependence.

The risk of dependence increases with dose and duration of treatment. Cases of dependence have been reported more frequently in patients treated with Imovane for longer than 4 weeks.
The risk of abuse and dependence is also greater in patients with a history of psychiatric disorders and/or alcohol, substance or drug abuse.

Imovane should be used with extreme caution in patients with current or a history of alcohol, substance or drug abuse or dependence.

If physical dependence is developed, a sudden discontinuation of treatment will be accompanied by withdrawal symptoms (see section 4.8).

Withdrawal
The termination of treatment with Imovane is unlikely to be associated with withdrawal effects when duration of treatment is limited to 4 weeks. Patients may benefit from tapering off the dose before discontinuation (see section 4.8).

Suicidal ideation/suicide attempt/suicide depression
Some epidemiological studies show an increased incidence of suicidal ideation, suicide attempt and suicide in patients with or without depression, and treated with benzodiazepines and other hypnotics, including zopiclone. However, a causal relationship has not been established.

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).

Imovane should be administered with caution in patients exhibiting symptoms of depression.
Suicidal tendencies may be present therefore the least amount of Imovane that is feasible should be supplied to these patients to avoid the possibility of intentional overdose by the patient. Pre-existing depression may be unmasked during use of Imovane. Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.

Any underlying cause of the insomnia should also be addressed before symptomatic treatment to avoid under treating potentially serious effects of depression.


In patients with a major depressive episode:
Benzodiazepines and related drugs should not be prescribed alone as they do not treat 

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depression, which will therefore follow its own course, with a persistent or higher risk of suicide.

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

Rebound insomnia
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, it is, therefore, recommended to decrease the dosage gradually and 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 section 4.2). A course of treatment should not continue for longer than 4 weeks including any tapering off (see section 4.8).

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, to reduce the possibility of anterograde amnesia, 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 (uninterrupted sleep of about 7 – 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.

Risks from concomitant use with opioids
Concomitant use of opioids with benzodiazepines or other sedative-hypnotic drugs, including zopiclone may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe zopiclone concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation (see section 4.5).

Other psychiatric and paradoxical reactions
Other psychiatric and paradoxical reactions have been reported (see section 4.8), like restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, 

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abnormal behaviour, delirium 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.

Somnambulism and associated behaviours
Complex sleep behaviour, including sleep walking and other associated behaviours such as “sleep driving”, preparing and eating food, making phone calls or having sex, with amnesia for the event have been reported in patients who had taken zopiclone and were not fully awake. These events may occur following the first or any subsequent use of zopiclone.
Discontinue treatment immediately if a patient experiences a complex sleep behaviour, due to the risk to the patient and others (see section 4.3). 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.
Risk of drug accumulation

Benzodiazepines and related drugs, (like any medicinal product), remain in the body for a period of approximately 5 elimination half-lives (see section 5.2).
In elderly patients and those with hepatic insufficiency, the elimination half-life may be considerably longer. Following repeated doses, zopiclone or its metabolites reach steady state much later and at a much higher level. The efficacy and safety of the drug can only be evaluated once steady state has been reached.
Dosage may need to be adjusted (see section 4.2).
Clinical studies of zopiclone have not revealed any plasma accumulation in patients with renal insufficiency (see section 5.2).

Duration of treatment
The duration of treatment must be clearly indicated to the patient depending on the type of insomnia (see section 4.2).

Tapering-off process
Patients should be clearly instructed on how to gradually discontinue treatment.
In addition to the need to gradually decrease dosage, patients should be warned of the risk of rebound insomnia in order to minimize any insomnia that might result from the withdrawal symptoms caused by treatment discontinuation, even when this is gradual.
Patients must be informed of possible discomfort during the tapering-off period.

Special Precautions for use
Insomnia may be a sign of an underlying physical or psychiatric disorder. The clinical diagnosis should be re-evaluated if the insomnia persists or worsens after a short treatment period.

Excipients with known effect

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

Sodium:
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.


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Wheat starch (containing gluten):
This medicine contains only very low levels of gluten (from wheat starch) and is very unlikely to cause problems in case of coeliac disease.
One 7.5 mg tablet contains no more than 6 micrograms of gluten.
Patients with wheat allergy (different from coeliac disease) should not take this medicine.

Effects on Driving

4.7   Effects on ability to drive and use machines

Because of its pharmacological properties and its effect on central nervous system, Imovane 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.