Download SUMMARY OF PRODUCT CHARACTERISTICS

SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
®
SOMNOLS 7,5 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 7,5 mg zopiclone.
Exicipient(s): each tablet contains 0,57 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet.
White round, film-coated biconvex tablets with single breakline on one side. The tablet can be
divided into equal halves.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Treatment of transient, short-term insomnia for adults (including difficulties in falling asleep,
nocturnal awakening and early awakening).
A support therapy for a limited period of time in the treatment of chronic insomnia.
Zopiclone is only indicated when the disorder is severe, which limits patient activity
or is subjecting the individual to extreme distress.
4.2
Posology and method of administration
For oral use.
Always should be taken right before bedtime.
Doses
The dose should be adjusted according to the age, weight and general condition of the patient
in addition to the type of insomnia.
Adults till age of 65: one tablet (7,5 mg) once per day.
Patients older than 65: recommended dose is 3,75 mg (½ of tablet) per day, which may be
increased to 1 tablet per day (only in exceptional case).
Patients with liver disorders or respiratory failure: recommended dose is ½ of tablet (3,75
mg) per day (see section 5.2).
Patients with renal dysfunction: although accumulation of zopiclone or its metabolites has
not been seen in patients with renal insufficiency, it is recommended to start treatment with ½
of tablet (3,75 mg) per day (see section 5.2).
In any case the dose may not exceed 7,5 mg per day.
Children: zopiclone should not be used in children (< 18 years) because of safety and
efficacy concerns (see section 4.3).
Treatment duration
Treatment should be as short as possible, ranging from a few days to a maximum
of 2-4 weeks, including tapering off period (see section 4.4):
- transient insomnia (for example, during travel): 2-5 days,
- short term insomnia: 2-3 weeks (for example, after serious accident),
The treatment should begin with the lower dose recommended.
How to discontinue therapy
Before starting to take medicines, the patients should be explained that the therapy is not
long-term and how to discontinue it in a stepwise fashion.
Gradual discontinuation of treatment reduces the risk of rebound insomnia (see section 4.4).
Patients should be warned about the possibility of rebound insomnia after the therapy
discontinuation in order to reduce the anxiety that may be caused by the possible
discontinuation symptoms.
4.3
Contraindications
SOMNOLS is contraindicated in the following cases:
- hypersensitivity to zopiclone and/or to any of the excipients,
- severe respiratory failure,
- severe hepatic insufficiency,
- sleep apnoea syndrome,
- myasthenia gravis,
- children under the age of 18.
4.4
Special warnings and precautions for use
Warnings
The film-coating of SOMNOLS tablets contains lactose and therefore the patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
This medicine is not recommended to use in combination with alcohol and during the breastfeeding (see section 4.6).
Tolerance
Some loss of efficacy to the activity of benzodiazepines and benzodiazepine-like agents may
develop after repeated use for a few weeks. However, with zopiclone there is an absence
of any marked tolerance cases. The dose may not be increased.
Dependence
Use of sedative/sleeping drugs similar to zopiclone may lead to the development of physical
(somatic) and psychological dependence or tolerance.
If the used dose is larger than the therapeutic dose, the risk of dependence increases with the
dose, duration of treatment and combination with other benzodiazepines. It is also greater
in patients with a history of alcohol or drug abuse. These patients should be carefully observed.
In case of physical dependence, the abrupt discontinuation of treatment will be accompanied by
abstinence symptoms: insomnia, headaches, muscle pain, anxiety, tension, agitation, cognition
disorder and irritability.
In severe cases the following symptoms may occur: derealisation, depersonalisation,
hyperacusis, numbness and tingling of the extremities, hypersensitivity to light or any physical
irritation, hallucinations and seizures.
Abstinence symptoms may occur within few days after discontinuation of therapy.
Separate abstinence symptoms can occur during regular benzodiazepines and their short-acting
analogue therapy between two doses, particularly in case of large dose usage (see section 4.8).
Rebound insomnia and anxiety
On discontinuation of therapy with sleeping drug a transient syndrome, where the symptoms,
which led to treatment with sedative/sleeping drugs, can recur in an enhanced form. It may be
accompanied by other symptoms: mood changes, anxiety and agitation.
This syndrome mainly occurs due to abrupt discontinuation of prolonged therapy or usage
of dose exceeding the recommended dose. Therefore the abrupt discontinuation of therapy
must be avoided, the dosage should be decreased in a stepwise fashion and the patient should
be informed about it (see section 4.2).
Amnesia
Usually anterograde amnesia may occur several hours after taking the tablet, especially when
sleep is interrupted or when retiring to bed is delayed after taking the tablet. Therefore, it is
recommended to take the tablet when certain of retiring for the night (see section 4.2) and to
provide the circumstances for unbroken sleep for several hours.
Automatic actions under influence of amnesia also have been reported.
Other psychiatric and paradoxical reactions
For some patients benzodiazepine or benzodiazepine-like agent can cause paradoxical
reactions:
- intensifying of insomnia, nightmares,
- nervousness, irritability, agitation, aggressiveness, floods of anger,
- delirium, hallucinations, oneiric delirium, psychotic symptoms, inadequate behaviour and
other behavioural disorders (see section 4.8).
These symptoms most often may occur for elder people and children. If it happens,
the therapy must be stopped.
Somnambulism and associated behaviour: sleep walking and other associated behaviour 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
behaviour, 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).
Instructions
Always, when it is possible, the reason of insomnia should be established and the possible
reasons should be eliminated before ordination of hypnotic.
Benzodiazepine or benzodiazepine-like agent must not be used for monotherapy of depression
and treatment of anxiety caused by it, because this medicine may stimulate to suicide.
Benzodiazepine or benzodiazepine-like agents are not indicated as main remedies in therapy
of psychoses.
Treatment with zopiclone should be of short duration or intermittent in order to reduce
the risk of discontinuation symptoms.
Groups of high risk:
- higher precaution must be observed in cases, where a history of alcoholism
or tolerance/dependence of other substances,
- patients with respiratory failure, because benzodiazepine or benzodiazepine-like agents may
have possible dispiriting influence on respiratory centre, particularly because anxiety and
agitation may be the symptoms of decompensated respiration (see section 4.2),
- patients with severe liver disorder, because benzodiazepine or benzodiazepine-like agents
may stimulate occurrence of encephalopathy and in such cases they are contraindicated,
- patients who are older than 65 (see section 4.2).
4.5
Interaction with other medicinal products and other forms of interaction
Concomitant use is not recommended
Alcohol
The sedative effect of benzodiazepine or benzodiazepine-like agents may be enhanced when
used in combination with alcohol. Delayed attention could affect the patient's ability to drive
or use machines. Concomitant use of alcoholic drinks and medicine containing ethanol must
be avoided.
Interaction has to be taken into account
Morphine derivatives (analgesics, cough-drugs and replacement therapy), barbiturates:
Increased risk of respiratory depression; overdose can lead to lethal result.
Concomitant use with CNS depressants
• Morphine derivatives (analgesics, cough-drugs and replacement therapy), barbiturates,
antidepressants and sedative H1 antihistamines, anxiolytics, neuroleptics, clonidine and its
analogues, thalidomide
Enhanced depressing effect on CNS.
Delayed attention could affect the patient's ability to drive or use machines.
• Clozapine
Increased risk of shock with respiration and/or cardiac arrest.
• Erythromycin
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 via cytochrome P450 (CYP) 3A4 isoenzyme (see section 5.2),
plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors
such as erythromycin, chlarithromycin, ketoconazole, itraconazole and ritonavir. The dose
of zopiclone might need to be decreased if co-administered with CYP3A4 inhibitors.
Vice versa, plasma levels of zopiclone in plasma may be decreased when co-administered with
CYP3A4 inducers such as rifampicin, carbamazepin, phenobarbital, phenytoin and St John’s wort.
The dose of zopiclone might need to be increased if co-administered with CYP3A4 inducers.
4.6
Pregnancy and lactation
Pregnancy
There are no adequate data from use during pregnancy. Studies in animals have shown
reproductive toxicity (see section 5.3), indicating a potential risk for the human fetus.
If zopiclone is used in the third trimester of pregnancy, adverse pharmacological effects on
the fetus/newborn child like hypotonia, respiratory effects and hypothermia cannot be
excluded. Moreover infants born to mother who took zopiclone chronically during the latter
stages of pregnancy may have developed physical dependence and may be at some risk for
developing withdrawal symptoms in the postnatal period. Zopiclone should therefore not be
used during pregnancy.
Lactation
Zopiclone is excreted in human milk, and a milk : plasma ratio of 0,5 has been reported. It is
estimated that a breastfed infant may receive 1,4 % of the mother’s weight adjusted dose, and
pharmacological effects on the suckling infant cannot be excluded. Zopiclone should
therefore not be used during breast-feeding.
Fertility
There are no adequate data from potential effects on human fertility. Studies in animals have
shown reversible effects on male fertility at high doses (see section 5.3). The clinical
relevance of these findings is not known.
4.7
Effects on ability to drive and use machines
SOMNOLS essentially influences the ability to drive or operate machines due to the observed
sedation, difficulties to concentrate, blurred vision and disorder of muscle function. This risk is
increased by concomitant intake of alcohol (see section 4.4). Therefore it is recommended not
to drive or operate machinery while taking SOMNOLS and alcohol concomitantly. The risk of
impaired vigilance is greater if the person has not slept sufficiently.
4.8
Undesirable effects
A bitter taste in the mouth is the most frequently reported adverse effect. Other possible
adverse effects are given further. The occurrence is connected to individual sensitivity and
most often the effects are observed within one hour after medicine taking, if the patient is not
immediately going to bed and falling asleep (see section 4.2).
Adverse effects are presented according to the MedDRA system organ classes and MedDRA
frequency convention: 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).
Nervous system disorders
Common: drowsiness during daytime, impaired vigilance, cognition disorder.
Uncommon: vertigo, headache, dizziness.
Gastrointestinal disorders
Very common: a bitter taste in the mouth is the most frequently reported adverse effect.
Common: dry mouth.
Uncommon: nausea, dyspepsia.
Skin and subcutaneous tissue disorders
Rare: itch and rashes.
Eye disorders
Double vision has been reported.
Immune system disorders
Very rare: anaphylactic reactions and/or angioedema.
Musculoskeletal and connective tissue disorders
Uncommon: muscle weakness.
Not known: muscular hypotonia.
Ataxia has been reported.
Reproductive system and breast disorders
Rare: libido changes.
Psychiatric disorders and paradoxical reactions (see section 4.4)
Rare: restlessness, agitation, rages, psychosis, nightmarish dreams, hallucinations, delirium,
irritability, confusion, aggressiveness, inadequate behaviour which possibly is connected with
amnesia, sleep walking (see section 4.4).
Amnesia: Anterograde amnesia may occur if therapeutic doses are used. The risk is increased
if large doses are used. In some cases additionally behaviour disorders can be observed
(see section 4.4).
Dependence, rebound insomnia when stopping use medicine
Insomnia, anxiety, tremor, sweating, agitation, confusion, headache, palpitation, tachycardia,
delirium, nightmarish dreams, hallucinations and irritability. In very rare cases seizures also
may occur (see section 4.4).
General disorders and administration site conditions
Common: fatigue.
Hepatobiliary disorders
Very rare: mild to moderate increases in serum transaminases and/or alkaline phosphatase.
4.9
Overdose
As in all cases of overdose, the poisoning with several medicines at the same time must be
always considered, as they can worsen the prognosis. Overdose is generally manifested by
depression of central nervous system ranging from drowsiness to coma. In mild cases,
symptoms include drowsiness, confusion, and lethargy; in more serious cases, symptoms
may include ataxia, hypotonia, hypotension, respiratory depression and coma. Overdose
usually is not dangerous to life, in case if the medicine is not used in combination with other
CNS depressants, including alcohol. Other risk factors, such as the presence of concomitant
disease and the debilitated state of the patient, may contribute to the severity of the
symptoms and very rarely can result in fatal outcome.
In case of overdose the usual precautions should be performed: committal in the specialized
department, observance of respiratory and cardiovascular parameters and in case of necessity –
infusion of suitable solutions. If the overdose has occurred less than one hour ago, vomiting
should be caused (if the patient is conscious); otherwise the stomach wash is performed,
providing the penetrability of respiratory pipes. If the overdose has occurred earlier, the
resolution of medicine can be reduced by activated carbon.
Flumazenil may be useful for diagnosing and/or treatment of intentional or accidental
overdose. Antagonism of Flumazenil can case neurological disorders (cramps) for activity
of zopiclone. Haemodialysis is of no value in case of overdose due to the large volume
of distribution of zopiclone.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and sedatives, benzodiazepine related drugs,
ATC code: N05CF01
Zopiclone (SOMNOLS) is a benzodiazepine-like hypnotic agent. It belongs to the
cyclopyrrolone group of compounds. Although zopiclone has no structural similarity with
benzodiazepines, its pharmacological properties are the same as for benzodiazepines: anxiolytic,
sedative, hypnotic, anticonvulsant and muscle-relaxant actions.
These are related to the selective agonist action at central receptors belonging to the GABA
(BZ1 and BZ2) macromolecular receptor complex modulating the opening of the chloride
ion channel. Zopiclone has been found to increase the duration of sleep and improve the
quality of sleep, reduce the nightly and early morning awakenings in humans. This activity
is supplemented by characteristic results of electroencephalography. Sleep registration has
proven that zopiclone decreases the phase-one sleep and increases the phase-two sleep,
while maintaining and lengthening the deep sleep phases (III and IV) and does not affect the
paradoxical (REM) sleep in patients suffering from insomnia.
In an objective study concerning clarification of withdrawal syndrome
by polysomnography, no significant rebound insomnia was seen while the duration
of 28 days after treatment. Other studies also have shown that tolerance to the hypnotic
activity of zopiclone has not been developed in treatment period of 17 weeks.
5.2
Pharmacokinetic properties
Absorption
Zopiclone is absorbed rapidly if used orally per 7,5 mg. Peak concentrations in plasma 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. The bioavailability of zopiclone is about
80 %. Absorption is not modified by usage time, repeated dose or user’s gender.
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 of zopiclone.
The volume of distribution is 91,8-104,6 litres.
At recommended doses the elimination half life of zopiclone is approximately 5 hours.
After repeated administration, there is no accumulation, and inter-individual variations
appear to be very small.
Benzodiazepines and benzodiazepine-like agents cross blood-brain and placental barrier and
are extracted in breast milk. During lactation the kinetic profile of zopiclone is similar
in the breast milk and in the plasma. The estimated amount of zopiclone received by the
breast-fed child is at the highest 1,0 % of the amount given to mother daily.
Metabolism
Zopiclone extensively is metabolized in liver.
The main metabolites of zopiclone in humans are the N-oxide zopiclone (pharmacologically
active in animals) and the N-desmethyl zopiclone (pharmacologically inactive in animals).
In-vitro study revealed that cytochrome P450 (CYP) 3A4 is the main isoenzyme participating
in the metabolism of zopiclone to both metabolites and CYP2C8 participates in formation
of N-desmethyl zopiclone.
Their apparent half-lives (evaluated from the urinary data) are approximately 4,5 hours and
7,4 hours respectively. In animals, no enzyme induction has been observed even at high doses.
Elimination
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 %).
High risk groups
In elderly patients, 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. Hemodialysis is useless in the treatment of overdose because of the
significant volume of distribution (see section 4.9).
In cirrhotic patients, the plasma clearance of zopiclone is clearly reduced (approximately
40 %) by the decreasing of the desmethylation process: dosage will therefore have to be
modified in these patients.
5.3
Preclinical safety data
High doses in dogs and rats caused hepatotoxic effects, as well as anaemia in dogs. Increase
of risk of affection with malignant breast tumour was stated in studies in rats, which can be
explained by increase of 17-beta-estradiol level. Amount of thyroid gland tumour cases
increased due to increase of TSH level.
In reproductive toxicity studies in rats and rabbits, drug related fetal weights were observed.
In a peri- and postnatal study in rats there was a dose related reduction in live pups at birth,
reduced pup weight and reduced postnatal survival. Reduced male fertility was observed
at high doses in rats due to reduced sperm motility and abnormal sperm morphology.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Tablets core
Calcium hydrogen phosphate, anhydrous
Potato starch
Magnesium stearate
Sodium starch glycolate (type A)
Silicon dioxide (Syloid 244 FP)
Tablets film-coating
Opadry 33G28707 White, which contains:
- Hydroxypropylmethylcellulose (Hypromellose)
- Titanium dioxide (E 171)
- Lactose monohydrate
- Polyethylene glycol 3000 (Macrogol)
- Triacetin
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
2 years
6.4
Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from light and moisture.
6.5
Nature and contents of container
10 tablets are packed in blisters, formed from aluminium foil and polyvinylchloride film
coated with polyvinylidenechloride; 1, 2 or 3 blisters are packed per cardboard box.
6.6
Special precautions for disposal and other handling
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist
how to dispose of medicines no longer required. These measures will help to protect the
environment.
7.
MARKETING AUTHORISATION HOLDER
AS GRINDEKS.
Krustpils iela 53, Rīga, LV-1057, Latvia
Phone: +371 67083205
Fax: +371 67083505
E-mail: [email protected]
8.
MARKETING AUTHORISATION NUMBER(S)
99-0260
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06.11.2009.
10.
DATE OF REVISION OF THE TEXT
02/2011