Document: Zopiclone Actavis tablet ENG SmPC change

• Zopiclone Actavis tablet SmPC
• Zopiclone Actavis tablet ENG SmPC

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Zopiclone Actavis 5 mg film-coated tablet

Zopiclone Actavis 7.5 mg film-coated tablet

Excipient(s)with known effect:

Lactose monohydrate

Each film-coated tablet contains 5 or 7.5 mg of zopiclone.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Adults

Transient and short-term insomnia. Supportive therapy for a limited time in treatment of chronic insomnia.

Posology

Paediatric population

Zopiclone Actaivs 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.

Adults

The usual initial dose is 5 mg at bedtime. Patients who do not respond to this dose should take 7.5 mg. Treatment should not exceed four weeks.

Method of administration

To be taken immediately before bedtime. The tablets should be taken in an upright position as absorption may otherwise be prolonged.

Hypersensitivity to the active substance or to any of the excepients listed in 6.1.

Severe hepatic impairment, sleep apnoea, respiratory impairment and myasthenia gravis.

Caution should be exercised in patients with hepatic impairment, respiratory impairment, addicts, in treatment of elderly, and patients with impaired general condition. The risk of dependence should be taken into consideration when prescribing this medicine. The risk of dependence increases with dose and duration of treatment.

Caution should also be exercised in concomitant treatment with other psychotropic drugs. Concomitant use of alcohol should be avoided. Insomnia may be caused by psychiatric or somatic disorder. Patients with long-term insomnia should therefore be examined for determination of a diagnosis. Treatment with hypnotic drugs should be transient or intermittent to reduce the risk of withdrawal symptoms. If physical dependence has developed, abrupt termination of treatment may lead to withdrawal symptoms. These may consist of headaches, myalgia, extreme anxiety, muscle tension and irritability. In serious withdrawal cases the following symptoms may occur: derealisation, depersonalisation, hypersensitivity to light, noises and physical contact and paresthesias in the extremities, hallucinations or epileptic seizures.

Zopiclone Actavis should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

Some loss of efficacy to the hypnotic effect of Zopiclone Actavis may develop after repeated use for a few weeks.

Transient rebound insomnia may be experienced, where the symptoms that led to treatment with Zopiclone Actavis may recur in an enhanced form on withdrawal of treatment.

The duration of treatment should be as short as possible. Including the gradual tapering phase, it should not exceed 4 weeks (see section 4.2).

Zopiclone Actavis may induce anterograde amnesia.

Somnambulism and associated behaviour

Sleep walking and other associated behaviours such as “sleep driving”, sleep eating, 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.

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

Paediatric population

Zopiclone Actavis 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.

Concomitant use of alcohol should be avoided. The sedative effect of Zopiclone Actavis may be enhanced when used in combination with alcohol.

Combined use of CNS depressants should be avoided.

The combination with CNS depressants (neuroleptics, sedative antidepressants, hypnotics, anxiolytics/sedative H1 antihistamines) may result in intensification of the CNS depressing action.

The combination with narcotic analgesics may enhance the euphoric effect and could lead to an increase in psychic dependence.

Combinations which may require dose adjustment:

The effect of erythromycin on the pharmacokinetics of zopiclone has been studied in healthy volunteers. AUC of zopiclone is increased by 80% in the presence of erythromycin most likely because erythromycin inhibits the metabolism of drugs metabolised by CYP 3A4.

If co-administered with itraconazole (which inhibits CYP 3A4-mediated metabolism), the bioavailability of zopiclone is increased by about 70%.

Rifampicin potently induces zopiclone metabolism, most likely via CYP 3A4. Its plasma concentration is reduced by about 80%, and its effects in psychomotor tests are reduced significantly.

Pregnancy

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

Clinical experience from pregnant women is limited. Data from animal experiments do not indicate any increased risk of fetotoxicity. If zopiclone is taken chronically during the latter stages of pregnancy, withdrawal symptoms may occur postnatally in the newborn. During the last trimester, there is a risk of adverse pharmacological effects on the foetus and/or the neonate, such as hypotonia, respiratory depression and hypothermia. Zopiclone Actavis should therefore not be used during pregnancy.

Breast-feeding

Zopiclone Actavis passes into breast milk. Zopiclone Actavis to breast feeding women is not recommended although the concentration in breast milk is low.

Zopiclone Actavis may impair the ability to react. This should be taken into consideration when alertness is required, e.g. when driving or performing precision work.

The undesirable effects are listed below according to MedDRA Organ Class and frequency. The following frequency classification has been used: 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).

	Common (>1/100)	Uncommon (≥1/1,000 to <1/100)	Rare (<1/1000)	Not known (cannot be estimated from the available data)
Nervous system disorders	Drowsiness. Taste alteration (bitter taste).	Headache. Dizziness..	Memory loss (anterograde amnesia).
Psychiatric disorders		Agitation. Abnormal dreams	Anxiety. Irritability. Aggressiveness. Hallucinations. Confusion. Difficulty in concentrating.	Abnormal behaviour (possibly associated with amnesia) and somnambulism
Gastrointestinal disorders	Dry mouth General discomfort
Skin and subcutaneous tissue disorders			Angiooedema and/or anaphylactic reactions. Exanthema.
Hepatobiliary disorders			Mild to moderate elevations in serum transaminases and/or alkaline phosphatases.

About 10% of treated patients experience some kind of undesirable effect. The most common

undesirable effect is a bitter taste, generally transient, which is seen in about 4% of the patients. Another undesirable effect is drowsiness which is dose-dependent.

Dependence withdrawal or rebound insomnia have been observed on discontinuation of treatment.

Reporting of suspected adverse reactions

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 national reporting system listed in Appendix V*.

[*For the printed material, please refer to the guidance of the annotated QRD template.]

Toxicity

Great individual variation.

5 mg to an 11 year old caused mild intoxication.

About 30 mg to a 6 year-old caused moderate intoxication.

22.5 mg to an adult and 40 mg to an elderly caused mild intoxication.

<50->100 mg to adults caused mild to moderate intoxication.

100 mg to adults caused deep unconsciousness.

187 mg and alcohol to adults caused severe intoxication.

Symptoms

Fatigue, somnolence, unconsciousness (in the elderly sometimes very long term), sometimes preceded or followed by agitation and hallucinations. Respiratory depression (mainly in combination with alcohol or CNS depressants). Hypotension, sinus tachycardia or bradycardia. Intraventricular block, AV block. Hypokalaemia, hyperglycaemia. Transient prolongation of APTT, slightly increased bilirubin. Gastrointestinal symptoms. Methemoglobinemia has been reported in more severe cases.

Treatment

If relevant, gastric lavage, charcoal. Flumazenil acts as an antidote and may be tried against severe intoxication. Note that the duration of action of flumazil is shorter than that of zopiclone. Symptomatic treatment.

Pharmacotherapeutic group: Hypnotics & Sedatives, ATC code: N05CF01.

The active substance of Zopiclone Actavis is zopiclone which belongs to the group of cyclopyrrolones, which structurally differ from other hypnotic agents.

Mechanism of action

Like benzodiazepines, zopiclone binds with high affinity to the macromolecular GABA receptor complex and induces specific conformational changes, thus increasing the normal transmission of the signal substance GABA in the central nervous system.

Clinical efficacy and safety

Zopiclone has a rapid onset of action (within about 30 minutes), shortens sleep onset latency, prolongs sleep duration and reduces the number of awakenings during the night. The amount of REM sleep and deep sleep (stages III and IV) remains constant at the recommended dose.

Development of tolerance to the hypnotic effect has not been established.

Absorption

The bioavailability of zopiclone is about 80%. Peak plasma concentration is reached within 1-2 hours and is about 60 ng/ml after a dose of 7.5 mg. Absorption may be prolonged if zopiclone is not taken in an upright position.

Distribution

Distribution volume is 1.3 l/kg and protein binding is about 45%.

Biotransformation

Zopiclone is extensively metabolised by the liver through decarboxylation. The metabolism is not fully described, about 15% is converted into inactive N-desmethyl zopiclone and about 11% is converted into N-oxide zopiclone which is less active than the mother substance and without clinical significance.

Elimination

The half-life is 4‑6 hours, increased to 7 hours in the elderly. The half-life is significantly longer in patients with hepatic impairment. Total plasma clearance is about 19 l/hour. About 5% of the administered dose of zopiclone is excreted unchanged in the urine.

No special data.

Lactose monohydrate

Calcium hydrogen phosphate dihydrate

Maize starch

Carmellose sodium

Magnesium stearate

Titanium dioxide (E171)

Hypromellose

5 mg tablets also contain yellow iron oxide (E172) and macrogol

Not applicable.

Tablets 5 mg: 4 years

Tablets 7.5 mg: 3 years

Store below 25 C.

PVC/PVDC/aluminium blister: 10, 30, 100 and 50x1 tablets (single dose)

HDPE plastic container: 500 tablets (only for dose dispensing and hospital use).

Not all pack sizes may be marketed

No special requirements.

<To be completed nationally>

<To be completed nationally>

<[To be completed nationally]>

29 September 2016