This information is intended for use by health professionals

1. Name of the medicinal product

Zopiclone 3.75 mg tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 3.75 mg of the active ingredient zopiclone.

Excipients with known effect

Each film-coated tablet contains 34.55 mg lactose anhydrous. The tablet coating also contains 0.067 mg Ponceau 4R (E124).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Blue, film-coated, round tablet, 'ZE3' on one side and 'G' on the reverse.

4. Clinical particulars
4.1 Therapeutic indications

Zopiclone is indicated for the short-term treatment of insomnia in adults.

Benzodiazepines and benzodiazepine-like agents are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress. Long term continuous use is not recommended. A course of treatment should employ the lowest effective dose.

4.2 Posology and method of administration

The lowest effective dose should be used.

Zopiclone should be taken in a single dose and not re-administered during the same night.

Treatment duration

Treatment with zopiclone should be as short as possible. Generally, the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off, of four weeks.

In certain cases an extension beyond the maximum treatment period may be necessary; if so it should take place after re-evaluation of the patient's status (see section 4.4).

Posology

Adults:

The recommended dose for adults is 2 tablets (7.5 mg zopiclone). This dose should not be exceeded. The tablet should be taken just before retiring.

Impaired renal function:

Although accumulation of zopiclone and/or its metabolites has not been shown in patients with impaired renal function, a starting dose of 3.75 mg is recommended in these patients.

Impaired hepatic function:

As elimination of zopiclone may be reduced in patients with hepatic dysfunction, a lower dose of 3.75 mg zopiclone nightly is recommended.

The standard dose of 7.5 mg zopiclone may be used with caution in some cases depending on effectiveness and acceptability.

Chronic respiratory insufficiency:

In patients with chronic respiratory insufficiency, a starting dose of 3.75 mg zopiclone is recommended initially. The dosage subsequently may be increased to 7.5 mg.

Elderly:

A starting dose of 3.75 mg is recommended, this dose may consequently be increased to 7.5 mg if considered clinically necessary depending on patient effectiveness and acceptability (see section 4.4).

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.

Method of administration

Zopiclone is for oral use only.

4.3 Contraindications

Zopiclone is contraindicated in patients with any of the following:

• Hypersensitivity to zopiclone or to any of the excipients listed in section 6.1

• Myasthenia gravis

• Severe hepatic impairment

• Sleep apnoea syndrome

• Respiratory failure

Zopiclone should not be given to children or adolescents younger than 18 years of age.

4.4 Special warnings and precautions for use

Specific patient groups

Use in hepatic insufficiency

A reduced dosage is recommended, see Posology. 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 Posology.

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.

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 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).

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 off the dose before discontinuation. (see sectio 4.8.).

Suicidal ideation/suicide attempt/suicide and 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).

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 overdosage 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.

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

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 afterprolonged 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 Posology for guidance on possible treatment regimen. 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 to 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 of opioids and benzodiazepines

Concomitant use of benzodiazepines, including zopiclone, and opioids 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, 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.

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 (see section 4.5).

Excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol may enhance the sedative effect of zopiclone, this may persist to the following morning and could affect the patient's ability to drive or use machinery. Concurrent use is therefore not recommended.

Central depressive effects may be enhanced when zopiclone is used in combination with CNS depressants. Therefore, the therapeutic benefit of co-administration with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines should therefore be carefully considered.

Use of benzodiazepine-like drugs in combination with narcotic analgesics may enhance their euphoric effects, which may in turn increase the risk of dependency.

Opioids:

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as zopiclone with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).

The activity of zopiclone may be increased when used in combination with drugs which inhibit hepatic enzymes (in particular cytochrome P450)

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 CYP3A4. 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, fluconazole, tacrolimus and ritonavir. Co-administration of zopiclone with CYP3A4 inhibitors should be avoided in the elderly (see section 4.4). For all other patients, 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, nefazodone, 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 could result in a reduction of zopiclone plasma levels and reduce its hypnotic effects accordingly.

Metoclopramide increases and atropine decreases concentration of zopiclone in plasma.

Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of zopiclone is 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

Breast-feeding

Zopiclone is excreted in breast milk, although the concentration of zopiclone in the breast milk is low, use in nursing mothers must be avoided.

Fertility

Double-blind long-term studies (7.5 mg zopiclone for 84 days) in healthy volunteers revealed no changes in ejaculate volume, sperm concentration, sperm motility or morphology. In several studies infertility was seen in male animals.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. Therefore, patients should not drive or use machinery after taking a dose.

Patients should be advised not to drive or operate machinery the day after treatment until it is established that their performance is unimpaired.

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. This may also affect the patient's ability to drive and use machinery the following morning.

4.8 Undesirable effects

The following undesirable effects have been reported at the approximate frequencies shown: 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)

Immune system disorders

Rare:

Allergic reactions including skin reactions

Very rare:

Anaphylactic reactions, angioedema

Psychiatric disorders

Uncommon:

Nightmares, agitation

Rare:

confusional state, libido disorder, irritability, aggression, hallucination Not known: restlessness, delusion, anger, depressed mood, abnormal behaviour (possibly associated with amnesia) and somnambulism (see section 4.4: somnambulism and associated behaviour), dependence (see section 4.4), withdrawal syndrome (see below)

Not known:

Dependency, restlessness, delusion, anger, depressed mood, somnambulism and other abnormal behaviour (possibly associated with amnesia)

See below under 'Depression', 'Psychiatric and paradoxical reactions', 'withdrawal syndrome', 'Somnambulism and associated behaviours' and 'Dependency'.

Nervous system disorders

Common:

Somnolence (residual) during the following day, reduced alertness, dysguesia (bitter taste)

Uncommon:

Headaches, dizziness

Rare:

Anterograde amnesia

Very rare:

Seizures

See below under 'Amnesia'.

Not known:

Ataxia (predominantly at the start of therapy and usually disappears with repeated administration), paraesthesia, cognitive disorders such as memory impairment

Eye disorders

Not known:

Diplopia (predominantly at the start of therapy and usually disappears with repeated administration)

Respiratory, thoracic and mediastinal disorders

Rare:

Dyspnoea (see section 4.4)

Not known:

Respiratory depression (see section 4.4)

Gastrointestinal disorders

Common:

Dry mouth

Uncommon:

Nausea, vomiting

Rare:

Diarrhoea

Not known:

Dyspepsia

Skin and subcutaneous tissue disorders

Rare:

Urticaria or rash, pruritus, sweating

Not known:

Unusual skin sensations such as numbness, tingling, pricking, burning or creeping on the skin

Musculoskeletal and connective tissue disorders

Not known:

Muscle weakness

General disorders and administration site conditions

Uncommon:

Fatigue

Not known:

Light headedness, incoordination, unsteadiness

Investigations

Very rare:

Mild to moderate increases in serum transaminases and/or alkaline phosphatase

Injury, poisoning and procedural complications

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, hallucinations, 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.

Amnesia:

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour (see section 4.4).

Depression:

Pre-existing depression may be unmasked during use of benzodiazepines or benzodiazepine-like agents.

Psychiatric and 'paradoxical' reactions:

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like products. They are more likely to occur in the elderly.

Somnambulism and associated behaviours:

There is an increased risk of sleepwalking and other associated behaviours with amnesia for the event in patients who have taken zopiclone and were not fully awake (see section 4.4). It appears that there is an increased risk of such behaviour with the concomitant use of alcohol, other CNS depressants and the use of zopiclone at doses exceeding the maximum recommended dose (see section 4.4).

Dependence:

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4). Psychological dependence may occur. Abuse has been reported.

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 Yellow Card scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Fatal dose not known.

Symptoms

Symptoms of central nervous system depression, which can range from drowsiness to coma according to the quantity ingested. In mild cases, symptoms include drowsiness, confusion and lethargy; in more severe cases, symptoms may include ataxia, hypotonia, hypotension, methaemoglobinaemia, respiratory depression and coma. The effects of overdose may be magnified if combined with alcohol or any other CNS depressants and in severe cases may be life-threatening. Other risk factors, such as the presence of concomitant illness and the debilitated state of the patient may contribute to the severity of symptoms and very rarely can result in fatal outcome.

Management

Treatment of overdose should be symptomatic and supportive paying particular attention to respiratory and cardiac functions. Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg within an hour. Alternatively, consider gastric lavage in adults within one hour of a potentially life-threatening overdose. If CNS depression is severe consider the use of flumazenil. It has a short half-life (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A 'DIAGNOSTIC' TEST. Haemodialysis does not have any therapeutic effect in cases of zopiclone overdose.

For current practice, refer to local poison centre (or equivalent information sources) regarding management of overdose.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotic and sedatives; benzodiazepine related drugs, ATC code: N05C F01.

Zopiclone is a hypnotic agent belonging to the cyclopyrrolone class of psychotherapeutic agents. Although structurally unrelated to the benzodiazepines, zopiclone binds with high affinity and specificity to the GABAA-benzodiazepine chloride channel macromolecular receptor complex. Zopiclone binds to a site different to the benzodiazepines and induces different conformational changes to the receptor complex thus modifying the activity of the chloride ion channel.

Pharmacological properties are: anxiolysis, sedation, hypnosis, anticonvulsion and muscle relaxation

5.2 Pharmacokinetic properties

Absorption

Zopiclone is swiftly absorbed. Maximum plasma concentrations are achieved after 1½ - 2 hours and are approximately 30 and 60 ng/ml after administration of 3.75 mg and 7.5 mg respectively. Absorption is the same in men and women and is not affected by simultaneous ingestion of food or repetition of doses.

Distribution

Zopiclone is swiftly distributed from the vascular compartment. The plasma protein binding is at least 45% and is not saturable.

The decrease in plasma level does not depend on the dose between 3.75 and 15 mg.

The elimination half-life is approximately 5 hours at the recommended doses.

No accumulation occurs after repeated administration and individual differences appear slight.

Less than 1.0% of the dose ingested by the mother is eliminated in breast milk.

Biotransformation

The most important metabolites are the N-oxide derivative (pharmacologically active in animals) and the N-desmethyl metabolite (pharmacologically inactive in animals). Their apparent half-life times are approximately 4.5 hours and 7.4 hours respectively. No significant accumulation of the compound as seen following repeat dosing. (15 mg) for 14 days. In animals, no enzyme induction has been observed even at high doses.

Elimination

The low renal clearance of zopiclone (on average 8.4 ml/min compared to the plasma clearance (232 ml/min) shows that zopiclone is cleared chiefly by metabolism. Zopiclone is eliminated in the urine (approximately 80%) in the form of unconjugated metabolites (N-oxide and N-desmethyl derivatives) and in the faeces (approximately 16%).

Special patient groups:

In various trials with elderly patients, no accumulation of zopiclone was observed in the plasma after repeated doses, in spite of a slight reduction in the hepatic function and extension of the eliminated half-life to approximately 7 hours.

In renal insufficiency, no accumulation of zopiclone or its metabolites have been detected after prolonged administration. Zopiclone crosses the dialysing membrane.

In patients with cirrhosis of the liver the slow demethylating process causes the plasma clearance of zopiclone to be delayed by approximately 40%. For this reason the dosage should be adjusted for these patients.

5.3 Preclinical safety data

Hepatotoxic effects were observed in repeat dose toxicity studies conducted in rats and dogs. In dogs, anaemia was observed in some studies.

Zopiclone is not mutagenic in either in-vitro or in vivo tests.

Increased incidence of mammary carcinomas in female rats at high multiples of the maximum plasma concentration from therapeutic doses in humans has been attributed to increased 17-beta-estradiol serum levels. Increased incidence of thyroid tumours in rats has been associated with increased TSH serum levels. In humans zopiclone has no effects on thyroid hormones.

Fertility was not impaired in rabbits, in rats impairment of fertility was seen in 2 studies. In several studies infertility was seen in male animals.

Foetal developmental retardations and foetotoxic effects in rats and rabbits were observed only at doses well above the maximum human dosage. There was no evidence of a teratogenic potential.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose anhydrous

Calcium hydrogen phosphate, anhydrous

Maize starch

Povidone

Magnesium Stearate

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Indigo Carmine (E132)

Ponceau 4R (E124)

Quinoline Yellow (E104)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 25°C

Blister packs: Store in the original package.

6.5 Nature and contents of container

Blister packs comprising 60g/m2 PVdC coated PVC sealed on to 20µm hard temper aluminium foil in strips of 5, 7 or 14 tablets, available in packs of 5, 7, 10, 14, 20, 21, 28, 30, 56, 60, 84, 90 and 100 tablets.

Also available in bulk packs of 100 tablets in a polypropylene container with tamper-evident polyethylene closure.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

None.

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Herts

EN6 1TL

8. Marketing authorisation number(s)

PL 04569/0450

9. Date of first authorisation/renewal of the authorisation

05/02/2001

10. Date of revision of the text

10-07-2019