Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK
Zimovane is contraindicated in patients:
As with all hypnotics Zimovane should not be used in children.
The cause of insomnia should be identified wherever possible and the underlying factors treated before a hypnotic is prescribed.
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).
A reduced dosage is recommended (see section 4.2).
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.
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.
Elderly should be given a reduced dose (see section 4.2).
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 Zimovane 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. Zimovane 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).
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 off the dose before discontinuation (see section 4.8).
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).
Zimovane should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present therefore the least amount of Zimovane 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 Zimovane. 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.
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.
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 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).
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.
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 have been reported (see section 4.8), 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.
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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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.
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-administration with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines should therefore be carefully weighed. In the case of narcotic analgesics, enhancement of euphoria may also occur leading 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), plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir. A dose reduction for zopiclone may be required when it is co-administered 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-administered with CYP3A4 inducers.
The concomitant use of benzodiazepines and other sedative-hypnotic drugs, including zopiclone, and opioids increases the risk of sedation, respiratory depression, coma, and death because of additive CNS depressant effect. Limit dosage and duration of concomitant use of benzodiazepines and opioids (see section 4.4).
The use of zopiclone is not recommended during pregnancy.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Zopiclone crosses the placenta.
A large amount of data on pregnant women (more than 1000 pregnancy outcomes) collected from cohort studies has not demonstrated evidence of the occurrence of malformations following exposure to benzodiazepines or benzodiazepine-like substances during the first trimester of pregnancy. However, certain case-control studies reported an increased incidence of cleft lip and palate associated with benzodiazepines during pregnancy.
Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines or benzodiazepine-like substances during the second and/or third trimester of pregnancy.
Administration of benzodiazepines or benzodiazepine-like substances, including zopiclone, during the late phase of pregnancy or during labour have been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties (‘floppy infant syndrome’), and respiratory depression, due to the pharmacological action of the product. Cases of severe neonatal respiratory depression have been reported.
Moreover, infants born to mothers who took sedative/hypnotics agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at risk of developing withdrawal symptoms in the postnatal period.
Appropriate monitoring of the newborn in the postnatal period is recommended.
If zopiclone is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the product if she intends to become or suspects that she is pregnant.
Zopiclone is excreted in breast milk, although the concentration of zopiclone in the breast milk is low, use in nursing mothers must be avoided.
Because of its pharmacological properties and its effect on central nervous system, Zimovane may adversely affect the ability to drive or to use machines. The risk of psychomotor impairment, including impaired driving ability, is increased if:
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.
The following CIOMS frequency rating is used, when applicable: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Very rare: angiooedema, anaphylactic reaction
Uncommon: nightmare, agitation
Rare: confusional state, libido disorder, irritability, aggression, hallucination
Not known: restlessness, delusion, anger, abnormal behaviour (possibly associated with amnesia) and complex sleep behaviours including somnambulism (see section 4.4), dependence, withdrawal syndrome (see below)
Common: dysgeusia (bitter taste), somnolence (residual)
Uncommon: dizziness, headache
Rare: anterograde amnesia
Not known: ataxia, paraesthesia, cognitive disorders such as memory impairment, disturbance in attention, speech disorder
Not known: diplopia
Rare: dyspnoea (see section 4.4)
Not known: respiratory depression (see section 4.4)
Common: dry mouth
Uncommon: nausea, vomiting
Not known: dyspepsia
Very rare: transaminases increased and/or blood alkaline phosphatase increased (mild to moderate)
Rare: urticaria or rash, pruritus
Not known: muscular weakness
Uncommon: fatigue
Not known: light headedness, incoordination
Rare: fall (predominantly in elderly patients)
Withdrawal syndrome has been reported upon discontinuation of zopiclone (see section 4.4). Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, 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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
