Summary of Product Characteristics (SmPC) - Zopiclone 7.5 mg tablets
1 NAME OF THE MEDICINAL PRODUCT
Zopiclone 7.5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 7.5 mg of zopiclone.
Excipient(s) with known effect
Each tablet contains 31.37 mg lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
White, odourless, round, convex film-coated tablets with embossing “ZOC 7.5” with score line on one side and snap tab on the other side. Diameter approximately 7.0 mm.
The tablet can be divided into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Zopiclone is indicated for the treatment of insomnia in adults
4.2 Posology and method of administration
Posology
Treatment with Zopiclone should be for as short a period as possible. Long-term continuous use is not recommended (see section 4.4).
Use the lowest effective dose. Zopiclone should be taken in a single intake and not be re-administered during the same night.
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.
The period of treatment should generally vary between a few days to 2 weeks, with a maximum of 4 weeks including the tapering off phase. It is recommended that the patient should be informed of this prior to commencing treatment. In certain cases it may be necessary to prolong treatment to beyond the maximum period. If this is the case, however, it should only take place after re-evaluation of the patient’s condition, since the risk of abuse and dependence increases with the duration of treatment (see section 4.4).
Adults
The usual dose of Zopiclone in healthy adults is 7.5 mg, taken by oral administration in an upright position 30 to 60 minutes before retiring.
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.
Special populations
In the elderly, patients with hepatic insufficiency or chronic respiratory insufficiency, treatment should be started at a dosage of 3.75 mg (see section 4.4).
Method of administration
Oral. Each film coated tablet should be swallowed whole without sucking, chewing or breaking.
Treatment should be started with the lowest recommended dose. A total daily dose of 7.5 mg should not be exceeded.
4.3 Contraindications
Zopiclone tablets are contraindicated in the following cases
- hypersensitivity to zopiclone, benzodiazepines or other benzodiazepine-like substances or to any of the excipients listed in section 6.1
- myasthenia gravis
- respiratory failure
- severe sleep apnoea syndrome
- severe hepatic insufficiency
- patients who have previously experienced complex sleep behaviours (see section 4.)
- children and adolescents under the age of 18 years (see section 4.2).
4.4 Special warnings and precautions for use
Before starting treatment with zopiclone any underlying cause of insomnia should be addressed carefully.
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.
Drug withdrawal syndrome
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.
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 newborn infants will experience neonatal withdrawal syndrome.
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).
Zopiclone 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. 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.
Benzodiazepines and benzodiazepine-like substances should not be used as the sole treatment for depression or anxiety linked with depression (suicide may be triggered in such patients).
Rebound insomnia
After discontinuation of treatment with a benzodiazepine or benzodiazepine-like agent, a temporary syndrome may occur in where the treated symptoms return in an enhanced form. It may be accompanied by other reactions including mood changes, sleep disturbances, anxiety and restlessness. Since the risk of withdrawal symptoms or rebound symptoms is greater after prolonged treatment, or abrupt interruption of the treatment it is advisable to reduce the dosage gradually.
Period of treatment
The period of treatment should employ the lowest effective dose and should be as short as possible (see section 4.2) and not longer than 4 weeks including the tapering off process. This period should only be exceeded after re-evaluation of the patient’s condition. It may be of benefit to inform the patient at the beginning of treatment that the treatment will be of short duration, and to explain precisely how the dose will be gradually reduced. It is also important to point out to the patient the possibility of the occurrence of rebound phenomena in order to keep to a minimum any worries about the occurrence of such symptoms during the tapering off period of the treatment. In the case of benzodiazepines and benzodiazepine-like substances with a short period of action, there are indications that withdrawal symptoms may occur within the dosage interval, especially if the dose is high.
Tolerance
The hypnotic effect of short-acting benzodiazepines and benzodiazepine-like substances may diminish after repeated use for a few weeks. For zopiclone however, no pronounced tolerance has occurred during a treatment period of up to 4 weeks.
Amnesia
Benzodiazepines and benzodiazepine-like substances may cause anterograde amnesia, especially when sleep is interrupted or when retiring to bed is delayed after taking the tablet. In order to reduce the risk, patients should ensure that they take the tablet when certain of retiring for the night and should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see section 4.8).
Psychiatric and paradoxical reactions
It is known that reactions such as restlessness, agitation, irritability, aggression, delusions, outbursts of rage, nightmares, hallucination, psychoses, inappropriate behaviour and other behavioural disturbances may occur during the use of benzodiazepines and benzodiazepine-like substances. If this is the case administration of the medicinal product should be discontinued. The risk of these reactions is greater in children and the elderly. Other psychiatric and paradoxical reactions have been reported (see Section 4.8).
Benzodiazepines and benzodiazepine-like substances are not recommended as the primary treatment of psychoses.
Somnambulism and associated behaviours
Complex sleep behaviour, including sleepwalking 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. These events may occur following the first or any subsequent use of zopiclone. 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 4.3 and 4.5).
Specific patient groups
Elderly
Because of the myorelaxant effect of zopiclone there is a danger of falling over, particularly for elderly patients when they get up at night. A reduced dosage is recommended (see section 4.2).
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.
Chronic respiratory insufficiency
Precautions should be observed if zopiclone is prescribed to patients with compromised respiratory function (See section 4.8). A lower dose is advised for patients with chronic respiratory insufficiency due to the risk of masking the symptoms (anxiety, agitation) of respiratory depression, especially at night. Administration of Zopiclone in these patients should be considered carefully and a daily dose of 7.5 mg should not be exceeded (see section 4.2).
Hepatic insufficiency
A reduced dosage is recommended (see section 4.2). Benzodiazepines and benzodiazepine-like substances are not suitable for the treatment of these patients since they may precipitate encephalopathy.
Renal insufficiency
A reduced dosage is recommended (see section 4.2).
Patients with a history of alcohol or drug abuse
Benzodiazepines and benzodiazepine-like substances should be administered with extreme caution to these patients.
Risk from concomitant use of opioids
Concomitant use of zopiclone and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as zopiclone with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe zopiclone concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2). The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
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.
Haemolysis
Haemolysis/haemolytic anaemia have been reported in cases of Zopiclone overdose (see Section 4.9).
Excipient(s)
Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol
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.
Other medicinal products
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 considered. Concomitant use of benzodiazepines or benzodiazepine-like agents with narcotic analgesics may enhance their euphoric effect and could lead to increased psychological dependence.
Compounds which inhibit or induce certain hepatic enzymes (particularly cytochrome P450) may enhance or reduce the activity of benzodiazepines and benzodiazepine-like agents.
Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.
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 mainly metabolised by CYP 3A4, plasma levels of zopiclone and thus the effects of zopiclone may be increased when used in combination with drugs which inhibit CYP 3A4, such as macrolide antibiotics, azole antimycotics and HIV protease inhibitors, as well as grapefruit juice, erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir. A dose reduction for zopiclone may be required when it is co-administered with CYP3A4 inhibitors.
Drugs which induce CYP 3A4, like phenobarbital, phenytoin, carbamazepine, rifampicin and products containing St John’s wort, may reduce zopiclone plasma levels and thus the effect of zopiclone.
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.
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).
4.6 Fertility, pregnancy and lactation
Pregnancy
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 foetal movement and foetal heart rate variability have been described after administration of benzodiazepines or benzodiazepine-like substances during the second and/or third trimester of pregnancy.
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, moderate respiratory depression, decreased muscle tone and suckling reflex (“floppy infant syndrome”) can be expected. Cases of severe neonatal respiratory depression have been reported.
Infants born to mothers who took benzodiazepines or benzodiazepine-like agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some 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.
Breastfeeding
The safety of use during lactation has not been established. Zopiclone is excreted in breast milk in very low concentrations and use in nursing mothers must be avoided.
4.7 Effects on ability to drive and use machines
Because of its pharmacological properties and its effect on central nervous system, zopiclone 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, delirium, delusion, anger, abnormal behaviour (possibly associated with amnesia) and complex sleep behaviours including somnambulism (see section 4.4), 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). 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.
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 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.
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.
Symptoms
In the cases of overdosage reported, the reports were not accompanied by life-threatening effects unless the agent was ingested in combination with other drugs which have a suppressive effect on the central nervous system, including alcohol. In mild cases, symptoms include drowsiness, mental confusion, and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, methaemoglobinaemia, respiratory depression, rarely coma and very rarely death. Overdose of benzodiazepines or benzodiazepine-like agents is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma, depending on the amount ingested. Rarely, A-V block has occurred. 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.
Treatment
Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg within 1 hour. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose. If CNS depression is severe consider the use of Flumazenil. It has a short shelf-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.
Treatment should be aimed at supporting vital functions and is chiefly symptomatic
(e.g. monitor the heart function and respiration). Gastric lavage or activated charcoal is only useful shortly after ingestion.
Haemodialysis is not useful because of the high distribution volume of zopiclone. Flumazenil may be beneficial as an antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and sedatives; benzodiazepine related drugs, ATC code: N05CF01
Zopiclone is a hypnotic agent, and a member of the cyclopyrrolone which possesses similar sedative, anxiolytic, muscle relaxant and anticonvulsant properties as the benzodiazepines. Zopiclone recognizes specifically and with high affinity the central receptors of the GABAA-benzodiazepine chloride ion channel macromolecular receptor complex in the central nervous system. After binding of Zopiclone to this receptor complex (at a site distinct from, but closely related to the benzodiazepine binding site), the affinity of the receptor complex for GABA increases. Binding of GABA to the complex induces opening of the chloride channels, through which hyperpolarisation of the cell membrane and inhibition of the neurons takes place.
Zopiclone has no affinity for peripheral benzodiazepine receptors.
Significant improvements in sleep onset time, sleep quality, number of awakenings and total sleep time were observed after administration of a single zopiclone dose. The influence of zopiclone on sleep architecture is minimal.
5.2 Pharmacokinetic properties
Absorption: Zopiclone is absorbed rapidly. Peak concentrations are reached within 1.5 - 2 hours and they are approximately 30 ng/ml and 60 ng/ml after administration of 3.75mg and 7.5mg respectively. Absorption is not modified by gender, food or repetition of doses.
Distribution: The product is rapidly distributed from the vascular compartment. Plasma protein binding is weak (approximately 45%) and non saturable. There is very little risk of drug interactions due to protein binding. The volume of distribution is 91.8 - 104.6 litres. At doses between 3.75 - 15mg, plasma clearance does not depend on dose. The elimination half life is approximately 5 hours. After repeated administration, there is no accumulation, and inter-individual variations appear to be very small.
Metabolism: Zopiclone is extensively metabolised in humans to two major metabolites, N-oxide zopiclone (pharmacologically active in animals) and N desmethyl zopiclone (pharmacologically inactive in animals). An in-vitro study indicates that cytochrome P450 (CYP) 3A4 is the major isoenzyme involved in the metabolism of zopiclone to both metabolites, and that CYP2C8 is also involved with N-desmethyl zopiclone formation. Their apparent half-lives (evaluated from the urinary data) are approximately 4.5 hours and 1.5 hours respectively. No significant accumulation is seen on repeated dosing (15mg) for 14 days. In animals, no enzyme induction has been observed even at high doses.
Excretion: The low renal clearance value of unchanged zopiclone (mean 8.4ml/min) compared with the plasma clearance (232ml/min) indicates that zopiclone clearance is mainly metabolic. The product is eliminated by the urinary route (approximately 80%) in the form of free metabolites (N-oxide and N-desmethyl derivatives) and in the faeces (approximately 16%).
Special patient groups: In elderly patients, notwithstanding a slight decrease in hepatic metabolism and lengthening of elimination half-life to approximately 7 hours, various studies have shown no plasma accumulation of drug substance on repeated dosing. In renal insufficiency, no accumulation of zopiclone or of its metabolites has been detected after prolonged administration. Zopiclone crosses dialysis membranes. In cirrhotic patients, the plasma clearance of zopiclone is clearly reduced by the slowing of the desmethylation process: dosage will therefore have to be modified in these patients.
5.3 Preclinical safety data
Carcinogenicity: From studies performed in rats and mice it can be concluded that for patients receiving long-term medication with Zopiclone no carcinogenic potential exists.
Mutagenicity: Both in vitro and in vivo studies failed to show mutagenicity produced by Zopiclone.
Fertility: In animal studies Zopiclone caused a decrease in fertility in rats. Zopiclone did not affect fertility in rabbits.
Teratogenicity: Zopiclone did not show any teratogenic or embryotoxic effect in animal studies.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet Core:
Calcium hydrogen phosphate dihydrate,
lactose monohydrate,
maize starch,
starch, pregelatinised,
croscarmellose sodium,
silica, colloidal anhydrous,
magnesium stearate.
Film Coating:
Hypromellose,
titanium dioxide (E171).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25 ˚C. Store in the original container.
6.5 Nature and contents of container
Lithographed carton boxes containing 1, 3 or 6 PVC/PVDC/aluminium strips of 10 tablets, and lithographed carton boxes containing 1, 2 or 4 PVC/PVDC/aluminium strips of 14 tablets. Each box contains a patient insert.
Lithographed carton boxes containing 1 jar (glass type III) with 28, 30, 56 or 60 tablets. Each box contains a patient insert.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited
Ridings Point,
Whistler Drive,
Castleford,
WF10 5HX,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/2549
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/11/2000 / 03/05/2006
10 DATE OF REVISION OF THE TEXT
21/09/2026