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 stag