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 film-coated tablet contains 7.5 mg zopiclone
Excipient with known effect: Each film-coated tablet contains 32.0 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
White, round, biconvex film-coated tablets.
The film-coated tablets are scored on one side and are divisible.
The tablet can be divided into equal doses.
Approximately 7.2 mm diameter.
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
Treatment with Zopiclone should be for as short a period as possible.
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. 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.
Posology
Paediatric patients
Zopiclone Jubilant 7,5 mg should not be used in children and adolescents less than 18 years (see section 4.3). The safety and efficacy of zopiclone in children and adolescents less than 18 years have not been established.
Adults
The recommended dose is 7,5 mg (one tablet). This dose should not be exceeded. Elderly
In the elderly, treatment should be started at a dosage of 3.75 mg, i.e. a half tablet and the dosage subsequently may be increased to 7,5 mg if clinically necessary.
Patients with hepatic insufficiency
As elimination of zopiclone may be reduced in patients with hepatic dysfunction the treatment should be started at a dosage of 3.75 mg, i.e. a half tablet and the dosage subsequently may be increased to 7,5 mg in some cases, depending on effectiveness and acceptability.
Patients with renal insufficiency
Although no accumulation of zopiclone or its metabolites have been found in patients with renal insufficiency, it is advisable to begin treatment of patients with reduced renal function at 3.75 mg.
Patients with chronic respiratory insufficiency
The treatment should be started at a dosage of 3.75 mg, i.e. a half tablet and the dosage subsequently may be increased to 7,5 mg.
Method of administration
The product should be taken just before retiring for the night.
For oral use only.
The tablets can be broken as follows:
- lay the tablet on a desk
- take the left and right thumb or forefinger and press on both sides of the scoring line.
Each tablet should be swallowed without sucking or chewing.
4.3 Contraindications
Zopiclone is contra-indicated in the following cases:
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Myasthenia gravis
- Severe respiratory insufficiency
- Sleep apnoea syndrome
- Children and adolescents under 18 years of age
Severe hepatic insufficiency
4.4 Special warnings and precautions for use
Before starting treatment with zopiclone any underlying cause of insomnia should be addressed carefully.
Dependence
The use of benzodiazepines and benzodiazepine-like substances can lead to physical and psychological dependence on these agents. Clinical experience to date suggests that the risk of dependence is minimal when the duration of treatment is limited to not more than 4 weeks. 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 occurs, sudden discontinuation of the treatment will be accompanied by withdrawal symptoms. These may be expressed as 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 or physical contact, hallucinations or epileptic seizures.
Rebound insomnia
After discontinuation of treatment with a benzodiazepine or a benzodiazepine-like substance, a temporary syndrome may occur in which the symptoms which led to the treatment with the benzodiazepine or a benzodiazepine-like substance return in a more severe form. This syndrome may be accompanied by other reactions, including mood changes, anxiety and restlessness. Since the risk of withdrawal symptoms or rebound symptoms is greater after abrupt interruption of the treatment it is advisable to reduce the dosage gradually (see section 4.8).
Period of treatment
The period of treatment should be as short as possible (see section 4.2) but 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 to reduce the dose gradually.
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.
Anterograde amnesia
Benzodiazepines and benzodiazepine-like substances may cause anterograde amnesia, in particular a few hours after taking the product 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 will be able to have an uninterruped sleep of 7-8 hours (see section 4.8 Undesirable effects).
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 Somnambulism and associated behaviours:
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. 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 and 4.8).
It is known that reactions such as restlessness, agitation, irritability, aggression, delusions, outbursts of rage, nightmares, hallucination, psychoses, unsuitable 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.
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 Contraindications)
Use in renal insufficiency
A reduced dosage is recommended, see Posology.
Use in respiratory insufficiency
A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
Use in Elderly
Elderly should be given a reduced dose (see section 4.2). There is a risk of fall, particularly in the elderly when they get up during the night due to the muscle relaxing effect of zopiclone.
Paediatric patients : Zopiclone Jubilant 7.5 mg should not be used in children and adolescents less than 18 years. The safety and efficacy of zopiclone in children and adolescents less than 18 years have not been established.
Benzodiazepines and benzodiazepine-like substances are not recommended as the primary treatment of psychoses. 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). Benzodiazepines and benzodiazepine-like substances should be administered with extreme caution to patients with a previous history of alcohol or drug abuse.
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
Not recommended:
Simultaneous ingestion with alcohol is not recommended because the sedative effect of zopiclone may be intensified. This may affect the ability to drive or operate machines.
Take account of:
Combination with other central depressive agents, such as antipsychotic agents (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressants, narcotic analgesics, anti-epileptics, anaesthetics and sedative antihistamines may increase the suppressive effect of zopiclone on the central nervous system and should therefore be carefully weighed.
In the case of narcotic analgesics potentiation of euphoria may also occur, which can lead to increased psychological dependence.
Combination of zopiclone with muscle relaxants may increase the muscle relaxing effect.
Since zopiclone is metabolised by CYP3A4, the plasma levels of zopiclone and thus the effect of zopiclone may be increased when used in combination with drugs which inhibit CYP3A4, such as macrolide antibiotics, azole antimycotics and HIV protease inhibitors, as well as grape fruit juice. Dose reduction should be considered if zopiclone is co-administered with CYP3A4 inhibitors. Drugs which induce CYP3A4, like phenobarbital, phenytoin, carbamazepine, rifampicine and products containing St John's wort, may reduce zopiclone plasma levels and thus the effect of zopiclone.
Concomitant administration of itraconazole (that inhibits CYP 3A4-mediated metabolism) increases the biological availability of zopiclone by 70%.
Rifampicine strongly induces the metabolism of zopiclone most likely via CYP3A4. The plasma concentration of zopiclone decreases with about 80% and its effects in psychomotoric tests are reduced significantly. An increased dose of zopiclone may be needed under these conditions.
The effect of erythromycin on the pharmacokinetics of zopiclone has been studies 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.
4.6 Fertility, pregnancy and lactation
Insufficient data are available on zopiclone to assess its safety during human pregnancy and lactation.
Pregnancy
Experience of use of zopiclone during pregnancy in humans is limited although there have been no adverse findings in animals. Use in pregnancy is therefore not recommended. If zopiclone is prescribed to women of childbearing age, they should be advised that if they are planning to become pregnant or think they may be pregnant, they should contact their doctor about discontinuing the treatment.
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 and respiratory depression 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
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 warned to contact her physician about stopping the product if she intends to become pregnant, or suspects that she is pregnant.
Zopiclone caused a decrease in fertility in male rats (see section 5.3).
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. The risk is even higher when sleep duration is insufficient. Patients should be warned not to drive or operate machines until treatment has finished or it has been established that performance is unimpaired. Due to residual effects this warning should also be considered the morning after administration of zopiclone.
4.8 Undesirable effects
In this section frequencies of undesirable effects are defined as follows: 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).
Sleepiness during the day, bitter taste (dysgeusia), dry mouth and reduced alertness are the most commonly reported side effects. Ataxia and diplopia are rare, and occur mainly at the beginning of the treatment and usually disappear after repeated administration.
In addition, some serious side effects have been reported: angioedema, anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, amnesia and risk of fall (particularly in the elderly). These are rare to very rare.
The following side effects have been observed in patients treated with zopiclone:
Immune system disorders
Rare: Anaphylactic reactions and angioedema allergic reactions,
skin reactions like itching and skin rash (including urticaria). Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis/Ly ell’s
syndrome, erythema multiforme.
Psychiatric disorders Uncommon: Nightmares, agitation.
Rare: Numbed emotions, confusion, and depression2-1. Paradoxical
reactions3-1 such as restlessness, irritability, aggression, delusions, outbursts of rage, hallucinations, psychoses, decreased libido, physical and psychological dependence4-1, inappropriate behaviour and other behavioural disturbances, somnambulisme, withdrawal symptoms1 (anxiety, tremor, palpitations, tension, derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise or physical contact, hallucinations or epileptic seizures). Increased frequency of dreaming.
Nervous system disorders
Common:
Uncommon:
Rare:
Very rare:
A bitter or metallic taste (dysgeusia), sleepiness during the day, reduced alertness.
Headache, dizziness
Amnesia1-1, ataxia (occurs chiefly at the beginning of treatment and generally disappear after repeated administration), concentration problems.
Seizures
Eye disorders
Rare: Double vision (occurs chiefly at the beginning of treatment
and generally disappear after repeated administration).
Gastrointestinal disorders Common: Dry mouth.
Uncommon: Gastro-intestinal problems (including nausea and vomiting).
Rare: Dyspepsia.
Hepatobiliary disorders
Rare: Slight to moderate increases of serum transaminases and/or
alkaline phosphatase.
Skin and subcutaneous tissue disorders
Rare: Allergic reactions (including itching and skin rash).
Musculoskeletal and connective tissue disorders Uncommon: Muscle weakness.
General disorders and administration site conditions Uncommon: Tiredness.
Injury, poisoning and procedural complications
Rare: risk of fall (especially in the elderly, see section 4.4).
1) Amnesia
Anterograde amnesia may occur on therapeutic doses, and the risk is increased the higher the dose. 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.
3) Psychiatric and paradoxical reactions
Reactions such as restlessness, agitation, irritability, aggression, delusions, outbursts of rage, nightmares, hallucinations, psychoses, inappropriate behaviour, sleepwalking (see section 4.4) and other behavioral 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. 1
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in www.mhra.gov.uk/yellowcard.
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.
Management
Symptomatic and supportive treatment in adequate clinical environment is recommended, attention should be paid to respiratory and cardiovascular functions.
If CNS depression is severe consider the use of flumazenil. It has a short halflife (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.
Haemodialysis is not useful because of the high distribution volume of zopiclone.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: hypnotic-sedative ATC code: N05C F01
Zopiclone is a benzodiazepine-like hypnotic agent which belongs to the group of cyclopyrrolones. The pharmacological properties are: sedation, anxiolysis, anticonvulsion, muscle relaxation. 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 swiftly absorbed. Maximum plasma concentrations are achieved after 1/ - 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 volume of distribution is 91.8 - 104.6 liters. The kinetic profiles in plasma and breast milk are comparable during lactation.
Less than 1.0% of the dose ingested by the mother is eliminated in breast milk.
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.
Biotransformation
The most important metabolites are the N-oxide derivative (pharmacologically active in animals) and the N-desmethyl metabolite (pharmacologically inactive in animals).
An in vitro study has shown that CYP3A4 is the main isoenzym responsible for the transposition of zopiclone into these 2 metabolites. CYP2C8 is also involved in the formation of N-desmethyl zopiclone.
Their apparent half-life times 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.
Elimination
The half-life time at the recommended dose of zopiclone is approximately 5 hours.
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 liver function and extension of the elimination 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 elicited in repeated dose toxicity studies conducted in rats and dogs. In dogs anaemia was 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.
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.
Fertility was impaired in two rat studies. Zopiclone had no adverse effects on fertility in rabbits.
Double-blind long-term studies (7.5mg zopiclone for 84 days) in healthy volunteers revealed no changes in ejaculate volume, sperm concentration, sperm motility or morphology.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Calcium hydrogen phosphate dihydrate (E341)
Lactose monohydrate
Maize starch
Sodium starch glycolate
Magnesium stearate (E470b)
Film-coating:
Hypromellose (E464)
Propylene glycol (E1520)
Titanium dioxide (E171)
Talc (E553B)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Film-coated tablets in box with PVC/PVDC/Al blisters.
Pack sizes of 10, 20, 28, 30 or 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Jubilant Pharmaceuticals nv Axxes Business Park Guldensporenpark 22 - Block C 9820 Merelbeke Belgium
8 MARKETING AUTHORISATION NUMBER(S)
PL 19156/0076
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16/10/2013
10 DATE OF REVISION OF THE TEXT
18/08/2016
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.
In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise or physical contact or hallucinations. In very rare cases epileptic seizures can occur.