4.1. Therapeutic indications

Short term treatment of insomnia in adults, 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.

4.2. Posology and method of administration

Prior to starting treatment with Zopiclone, a discussion should be held with patients to put in place a strategy for ending treatment with Zopiclone in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).

Treatment should be given for the shortest possible duration.

Use the lowest effective dose. Zopiclone Tablets should be taken in a single intake and not be re-administered during the same night.

Adults

The recommended dose is 7.5mg Zopiclone (two tablets of 3.75 mg or one tablet of 7.5 mg) by the oral route shortly before retiring.

Elderly patients

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.

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.

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.

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.

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. Extension beyond the maximum treatment period should not take place without re-evaluation of the patient's status.

The product should be taken just before retiring for the night.

Route of administration

For oral use only.

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

4.3. Contraindications

Zopiclone is contra-indicated in patients with:

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

• Myasthenia gravis

• Respiratory failure

• Severe sleep apnoea syndrome

• Severe hepatic insufficiency

As with all hypnotics Zopiclone Tablets should not be used in children.

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 contraindications)

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)

Drug dependence, tolerance and potential for abuse

Drug addiction comprises behavioural, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use and possible tolerance or physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, which manifests as withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Addiction and dependence are related but distinct presentations and in discussing these themes, terminology that apportion blame to the individual should be avoided.

For all patients, prolonged use of this product may lead to drug dependence and addiction but can occur with short-term use at recommended therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of drug misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on- line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of symptom control as initially experienced. Patients may also supplement their treatment with additional medications to achieve the same effect. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for treatment with Zopiclone should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.

Clinical experience to date with Zopiclone Tablets 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 or abuse upon these products.

The risk of dependence or abuse increases with:

• Dose and duration of treatment

• Use with alcohol or other psychotropics

• It is also greater in patients with a history of alcohol and or drug abuse

• Those patients 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 section 4.4). 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

Prior to starting treatment with Zopiclone, a discussion should be held with patients to explain the risk of dependence, addiction, and drug withdrawal syndrome. A withdrawal strategy for ending treatment with Zopiclone should also be put in place with the patient before starting treatment (there may be exceptions to this in specific clinical situations such as symptom management in end of life palliative care,).

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take in excess of weeks or months. Patients should be informed of this when the medication is first prescribed.

The reduction schedule for a patient should be tailored to the individual and should be modified to allow intolerable withdrawal symptoms to improve before making the next reduction. If using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions.

The termination of treatment with Zopiclone Tablets 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 Undesirable Effects). Suggest a slow stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

If women take this drug during pregnancy, there is a risk that their new-born infants will experience neonatal withdrawal syndrome.

Depression

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).

Zopiclone Tablets should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present therefore the least amount of Zopiclone 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 Zopiclone Tablets. 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 Zopiclone Tablets 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 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 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 (an 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 Undesirable effects), 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

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Association not recommended:

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.

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 Pharmacokinetic properties), 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.

Opioids:

The concomitant use of benzodiazepines, 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)

4.6. Fertility, pregnancy and lactation

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 use of 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

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.

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.

4.7. Effects on ability to drive and use machines

Because of its pharmacological properties and its effect on central nervous system, Zopiclone Tablets may adversely affect the ability to drive or to use machines. 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.

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.

4.8. Undesirable effects

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).

Immune system disorders

Very rare: angioedema, anaphylactic reaction

Psychiatric disorders

Uncommon: nightmare, 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), drug dependence (see section 4.4), withdrawal syndrome (see below)

Nervous system disorders

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

Eye disorders

Not known: diplopia

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

Not known: dyspepsia

Hepatobiliary disorders

Very rare: transaminases increased and/or blood alkaline phosphatase increased (mild to moderate)

Skin and subcutaneous tissue disorders

Rare: urticaria or rash, pruritus

Musculoskeletal and connective tissue disorders

Not known: muscular weakness

General disorders and administration site conditions

Uncommon: fatigue

Not known: light headedness, incoordination

Injury, poisoning and procedural complications

Rare: fall (predominantly in elderly patients)

Withdrawal syndrome

Withdrawal syndrome has been reported upon discontinuation of Zopiclone (see section 4.4 Special Warnings and Precautions for Use). Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucination, 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 of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App

4.9. Overdose

Fatal dose not known.

Symptoms

Overdose is usually manifested by varying degrees of central nervous system depression ranging 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.

Overdose should not be life threatening unless combined with other CNS depressants, including alcohol. 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. Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Management

Symptomatic and supportive treatment in adequate clinical environment is recommended, attention should be paid to respiratory and cardiovascular functions.

Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg within one 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. Management should include general symptomatic and supportive measures including a clear airway and monitoring cardiac and vital signs until stable.