Drug Class Description

Generic Name

Drug Description

Presentation

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.

Adult Dosage

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

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.

Treatment duration

Transient insomnia 2 - 5 days. Short term insomnia 2 - 3 weeks. A single course of treatment should not continue for longer than 4 weeks including any tapering off.

Route of administration

Oral. Each tablet should be swallowed whole without sucking, chewing or breaking.

Child Dosage

The safe and effective dose has not been established.

Elderly Dosage

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.

Contra Indications

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

Special Precautions

Use in hepatic insufficiency: A reduced dosage is recommended.

Use in renal insufficiency: A reduced dosage is recommended.

Risk of dependence: Clinical experience to date with Zimovane 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 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 (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 Zimovane 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: Zopiclone does not constitute a treatment for depression. Any underlying cause of the insomnia should also be addressed before symptomatic treatment to avoid under treating potentially serious effects of depression.

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

Rebound insomnia 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.

Driving: It has been reported that the risk that zopiclone adversely affects driving ability is increased by the concomitant intake of alcohol. Therefore, it is recommended not to drive while taking zopiclone and alcohol concomitantly.

Other psychiatric and paradoxical reactions:

Other psychiatric and paradoxical reactions have been reported.

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 zopiclone should be strongly considered for patients who report such behaviours.

Excipients:

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

Interactions

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.

In combination with CNS depressants an enhancement of the central depressive effect may occur. The therapeutic benefit of co-adminstration 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, plasma levels of zopiclone may be increased when co-adminstered with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir. A dose reduction for zopiclone may be required when it is co-adminstered with CYP3A4 inhibitors.

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-adminstered with CYP3A4 inducers.

Adverse Reactions

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 behavioural disturbances, such as irritability, aggressiveness, confusion, depressed mood, anterograde amnesia, sleep walking, 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 headedness and incoordination. Angiodema and/or anaphylactic reactions have been reported very rarely.

Withdrawal syndrome has been reported upon discontinuation of zopiclone. Withdrawal symptoms vary and may include rebound insomnia, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucinations, panic attacks, muscle aches/cramps, gastrointestinal disturbances and irritability. In very rare cases, seizures may occur.

Mild to moderate increases in serum transaminases and/or alkaline phosphatase have been reported very rarely.

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