Zopiclone 7.5 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zopiclone 7.5 mg, film coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 7.5 mg of zopiclone.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film coated tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Short term treatment of insomnia in adults.
Benzodiazepines and benzodiazepine-like substances are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.
4.2 Posology and method of administration
Posology
Adults:
The recommended dose is 7.5 mg (one tablet) by the oral route. This dose should not be exceeded.
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 has not been established.
Severe hepatic insufficiency:
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 7.5mg 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 3.75 mg.
Chronic respiratory insufficiency
Treatment should be started at a dosage of 3.75 mg 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).
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.
Treatment with Zopiclone should be for as short a period as possible. Long-term continuous use is not recommended (see section 4.4).
It is recommended that the patient should be informed of this prior to commencing treatment.
Route of administration:
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.
The medicinal product should be taken orally immediately before going to bed.
4.3 Contraindications
Zopiclone is contraindicated in the following cases:
• Myasthenia gravis
• Severe respiratory insufficiency
• Sleep apnoea syndrome
• Severe hepatic insufficiency
• Hypersensitivity to zopiclone or to any of the excipients, benzodiazepines or other benzodiazepine-like substances
• 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.
Specific patient groups For the 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 dose should be given (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 has not been established.
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 advised for patients with chronic respiratory insufficiency due to the risk of respiratory depression (see section 4.2) and masking the symptoms (anxiety, agitation) of respiratory depression.
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 (see section 4.3).
Renal insufficiency function.
A reduced dosage is recommended (see section 4.2).
Dependence:
Clinical experience to date with zopiclone suggests that the risk of dependence is minimal when the duration of treatment is limited to not more than 4 weeks.
The use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychological dependence or abuse upon these products. This may occur not only with misuse of high doses but also with therapeutical doses.
The risk of dependence increases the higher the dose and the longer the period of treatment; the risk of dependence is also greater in patients with a history of alcohol or drug abuse or those who have marked personality disorder. The decision to use a hypnotic in such patients should be taken only with this clearly in mind. These patients should be under careful surveillance when receiving Zopiclone. Benzodiazepines and benzodiazepine-like substances should be administered with extreme caution to patients with a history of alcohol or drug abuse.
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, insomnia and irritability. In severe cases, the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise or physical contact, hallucinations or epileptic seizures. Rare cases of abuse have been reported (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 section 4.8.).
A course of treatment should employ the lowest effective dose for the minimum length of time necessary for effective treatment. For guidance on treatment regimen, see section 4.2.
Depression:
As with other hypnotics, zopiclone does not constitute a treatment for depression and may even mask its symptoms. Any underlying cause of the insomnia should also be addressed before symptomatic treatment to avoid under treating potentially serious effects of depression. Pre-existing depression may be unmasked during use of zopiclone. Since insomnia may be a symptom of depression, the patient should be reevaluated if insomnia persists.
Benzodiazepines and benzodiazepine-like substances should not be used as the sole treatment of depression or anxiety linked with depression (suicide may be triggered in such patients).
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 tolerance has occurred during a treatment period 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, 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.
Anterograde 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 will be able to have an uninterruped sleep of 7-8 hours (see section 4.8).
Driving
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.
Other psychiatric and “paradoxical” reactions
Other psychiatric and paradoxical reactions have been reported (see Section 4.8 Undesirable effects), like restlessness, agitation, irritability, aggression, delusions, outbursts of rage (anger), nightmares, hallucination, psychoses, inappropriate behaviour and other behavioural disturbances may occur during the use of benzodiazepines and benzodiazepine-like substances (sedative/hypnotic agents like zopiclone). 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:
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 Interactions with other medicinal products and other forms of interactions).
Excipients:
This medicinal product contains lactose. 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
Association not recommended:
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.
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 considered.
Concomitant use of benzodiazepines or benzodiazepine-like agents with narcotic analgesics may enhance their euphoric effect and could lead to increased psychological dependence.
Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.
Compounds which inhibit or induce certain hepatic enzymes (particularly cytochrome P450) may enhance or reduce 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 mainly metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme (see section 5.2), plasma levels and thus the effect of zopiclone may be increased when co-administered with CYP3A4 inhibitors such as macrolide antibiotics (erythromycin, clarithromycin), azole antimycotics (ketoconazole, itraconazole) HIV protease inhibitors e.g. ritonavir as well as grapefruit juice. 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.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Experience of use of zopiclone during pregnancy in humans is limited although there have been no adverse findings in animals and the safety of use in pregnant women has not been established. To date, zopiclone has not produced injurious effects in animal studies except at very high maternally toxic doses. Use in pregnancy is therefore not recommended. 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.
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.
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.
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
Sedation, amnesia, impaired concentration and impaired muscular function may reduce the capability to drive or operate machines. The risk is increased with concomitant alcohol intake or after insufficient sleep duration. 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.
Use of zopiclone with alcohol may enhance the sedative effect and affect the patient’s ability to drive and use machinery the following morning.
4.8 Undesirable effects
List of adverse reactions
The frequencies of adverse events are ranked according to the following: 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).
Undesirable effects seem to be related to individual sensitivity and to appear more often during the first hour following intake. The following adverse reactions have been observed in patients treated with zopiclone:
|
MedDRA system organ class |
Very commo n |
Common |
Rare |
Very rare |
Not known |
|
Immune system disorders |
Anaphylacti c reactions | ||||
|
Psychiatric disorders |
Numbed emotions, confusion and depression2. Paradoxical reactions2, such as restlessness, agitation, irritability, aggression, |
Decreased libido |
Physical and psychologica l dependence2 |
|
MedDRA system organ class |
Very commo n |
Common |
Rare |
Very rare |
Not known |
|
delusions, outburst of rage, nightmares, hallucinations , psychoses, inappropriate behaviour and other behavioural disturbances. | |||||
|
Nervous system disorders |
Bitter taste or metallic aftertaste |
Sleepines s during the following day, reduced alertness, headache, dizziness |
Amnesia1, incordination, 3 ataxia , lightheadness |
Sleep walking (see Section 4.4 Special warnings and precautions for use) | |
|
Eye disorders |
Double vision3 | ||||
|
Gastrointestinal disorders |
Gastro intestinal problems including nausea and vomiting |
Dry mouth | |||
|
Skin and subcutaneous disorders |
Skin reactions including allergic and allied manifestation s such as urticaria and rashes |
Angioedem a | |||
|
Musculoskeleta l, connective tissue and bone disorders |
Muscle weakness |
|
MedDRA system organ class |
Very commo n |
Common |
Rare |
Very rare |
Not known |
|
General disorders and administration site conditions |
Tiredness | ||||
|
Investigations |
Slight to moderate increases of serum transminases and/or alkaline phosphotase |
1 Amnesia
Anterograde amnesia may occur on therapeutic doses, and the risk is increased the higher the dose. This undesirable effect has been observed rarely. Amnesia may be accompanied by inappropriate behaviour (see section 4.4).
2 Depression
Pre-existent depression may become manifest during the use of benzodiazepines and benzodiazepine-like substances (see section 4.4). Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, delusions, outbursts of rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural disturbances may occur during the use of benzodiazepines and benzodiazepine-like substances. In rare cases they may become quite severe with this agent. The risk of these reactions is greater in children and the elderly (see section 4.4).
Dependence
Use may lead to physical dependence even at therapeutic dosages: discontinuation of the treatment may lead to withdrawal or rebound phenomena (see section 4.4). Psychological dependence may also occur. Misuse has been reported.
3 Predominantly at the beginning of treatment; generally disappears after repeated administration
Withdrawal syndrome
Withdrawal syndrome has been reported upon discontinuation of zopiclone. (See section 4.4). Withdrawal symptoms vary and may include rebound insomnia, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucinations, panic attacks, muscle aches/cramps, gastrointestinal disturbances and irritability. In very rare cases, seizures may occur.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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 By reporting side effects you can help provide more information on the safety of this medicine.
4.9 Overdose
Fatal dose not known.
Symptoms
In the few cases where overdosage with zopiclone has been reported, these 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: benzodiazepine related drugs. ATC code: N05CF01
Zopiclone is a benzodiazepine-like hypnotic agent, and a member of the cyclopyrrolone group of compounds. It rapidly initiates and sustains sleep with reduction of total REM sleep and with preservation of slow wave sleep. Negligible residual effects are seen the following morning. Its pharmacological properties include hypnotic, sedative, anxiolytic, anticonvulsant and muscle-relaxant actions. These are related to its high affinity and specific agonist action at central receptors belonging to the “GABA” macromolecular receptor complex modulating the opening of the chloride ion channel. However, it has been shown that zopiclone and other cyclopyrrolones act on a different site to those of benzodiazepines including different conformational changes in the receptor complex.
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 3.75 mg and 7.5 mg 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 3.75-15 mg, plasma clearance does not depend on dose. The elimination half life is approximately 5 hours at the recommended doses. After repeated administration, there is no accumulation, and inter-individual variations appear to be very small.
Less than 1.0% of the dose ingested by the mother is eliminated in breast milk.
Metabolism:
Zopiclone is exensively metabolised in humans to two major metabolites, The main metabolites are 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 the 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 (15 mg) 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 8.4 ml/min) compared with the plasma clearance (232 ml/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 substances 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, which causes plasma clearance of zopiclone to be delayed by approximately 40%: dosage will therefore have to be modified in these patients.
5.3 Preclinical safety data
Hepatotoxic effects were elicited in repeated dose toxicity studies conducted in rats and dogs. In dogs anaemia were evident in some studies.
Both in vitro and in vivo studies failed to show mutagenicity produced by zopiclone.
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 in thyroid tumours in rats were associated with increased TSH serum levels. In humans zopiclone has no effects on thyroid hormones.
Fertility was impaired in two rat studies, whereas zopiclone had no adverse effects on fertility in rabbits. 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 as well as morphology.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate
lactose monohydrate maize starch
sodium starch glycollate type A
magnesium stearate
hydroxypropylmethylcellulose
propylene glycol
titanium dioxide
talc
6.2 Incompatibilities
None stated.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
Zopiclone 7.5 mg, film coated tablets are provided in PVC/PVdC/aluminium foil blisters containing 28 tablets.
6.6 Special precautions for disposal
No special instructions.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG
MARKETING AUTHORISATION NUMBER(S)
PL 00289/1478
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/12/2005
10
DATE OF REVISION OF THE TEXT
28/06/2016