IMOVANE

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

Imovane

Film-coated Tablets 7.5 mg

Composition:

Each tablet contains: Zopiclone 7.5 mg

For information about inactive and allergenic ingredients in the

preparation: see section 2 “Important information about some of the

ingredients of the medicine” and section 6 “Further information”.

Read this leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine. If you have

further questions, refer to the doctor or pharmacist.

This medicine has been prescribed to treat you. Do not pass it on to

others. It may harm them even if it seems to you that their medical

condition is similar.

This medicine is not intended for children and adolescents under 18

years of age.

1. WHAT IS THE MEDICINE INTENDED FOR?

Imovane is intended for treatment of the following conditions of severe

sleep disorders: a. transient insomnia. b. short-term insomnia.

Therapeutic group: Hypnotic and sedative from the cyclopyrrolone

group.

2. BEFORE USING THE MEDICINE

X

Do not use the medicine if:

you are sensitive (allergic) to the active ingredient or to any of the

additional ingredients contained in the medicine (see section 6).

Signs of an allergic reaction include: a rash, swallowing or breathing

problems, swelling of the lips, face, throat or tongue.

you suffer from a problem that causes severe muscle weakness

(myasthenia gravis).

you suffer from a problem in lung function (respiratory failure).

you suffer from a problem in which you stop breathing for short

periods at night (sleep apnoea).

you suffer from severe liver problems.

you are under the age of 18. The safety and efficacy of Imovane

in children and adolescents aged less than 18 years have not been

established.

Do not take this medicine if any of the above conditions applies to

you. If you are not sure, talk to your doctor or pharmacist before taking

Imovane.

Special warnings regarding use of the medicine:

- Before treatment with Imovane, tell your doctor if:

you suffer from depression or have had another mental illness in

the past.

you suffer from any liver problems (see also in section above “Do

not use the medicine if”). The doctor may need to give you a lower

dose of Imovane.

you suffer from any kidney problems. The doctor may need to give

you a lower dose of Imovane.

you suffer from mild breathing problems. The doctor will decide

if you should receive Imovane (also see in section above “Do not

use the medicine if”).

you have a history of addiction to alcohol or drugs.

you have been told by a doctor that you suffer from a personality

disorder.

you have recently used Imovane or other similar medicines for

more than 4 weeks.

you do not feel you will ever be able to stop taking Imovane or

other medicines used to treat sleep problems.

drowsiness, breathing difficulties, coma and death may occur if

Imovane is taken together with opioids. Imovane and opioids

should only be used concomitantly when other treatment options

are inadequate. Please tell your doctor about all the opioid

medicines you are taking and closely follow your doctor’s dosage

recommendations.

- Prolonged use may lead to physical and psychological dependence!

- The medicine is not intended for treatment of depression.

Some studies have shown an increased risk of suicidal ideation, suicide

attempt and suicide in patients taking certain sedatives and hypnotics,

including this medicine. However, it has not been established whether

this is caused by the medicine or if there may be other reasons. If you

have suicidal thoughts, contact your doctor as soon as possible for

further medical advice.

Before taking Imovane, it is important to make sure that you can have

at least 7 to 8 hours of uninterrupted sleep, to help reduce the risk of

some side effects (see section 4 - “Side effects”).

If you are not sure if one of the above conditions applies to you, talk

to your doctor or pharmacist before taking Imovane.

!

Children and adolescents:

This medicine is not intended for children and adolescents under 18

years of age.

!

Tests and follow up:

Imovane may change the liver enzyme levels that appear in blood tests.

This may indicate liver dysfunction.

If you are going to have a blood test, it is important to tell your doctor

that you are taking Imovane.

!

Drug interactions:

If you are taking, or have recently taken, other medicines, including

non-prescription medicines and nutritional supplements, tell the

doctor or pharmacist. This is because Imovane may affect the way

some other medicines work. Also some medicines may affect the way

Imovane works. Especially if you are taking:

Imovane may increase the effect of the following medicines:

Medicines for treatment of mental diseases (antipsychotics)

Medicines for treatment of depression

Medicines for treatment of epilepsy (anticonvulsants)

Medicines used in surgeries (anesthetics)

Medicines to calm or reduce anxiety or medicines for sleep problems

(hypnotics)

Medicines for treatment of hay fever, rashes or other allergies, that can

make you sleepy (sedative antihistamines) such as chlorphenamine

or promethazine

Some medicines to relieve moderate to severe pain (narcotic

analgesics) such as codeine, methadone, morphine, oxycodone,

pethidine or tramadol

The following medicines may increase the chance of side effects when

taken with Imovane. To make this less likely, your doctor may decide

to lower the dosage of Imovane that you are taking:

Some antibiotics, such as clarithromycin or erythromycin

Some medicines for the treatment of fungal infections, such as

ketoconazole and itraconazole

Ritonavir (from the protease inhibitor group), for treatment of HIV

infection

Concomitant use of Imovane and opioids increases the risk of

drowsiness, breathing difficulties, coma and death. Closely follow

your doctor’s dosage instructions.

The following medicines may reduce the effect of Imovane:

Some medicines for treatment of epilepsy such as carbamazepine,

phenobarbital or phenytoin

Rifampicin (an antibiotic), for treatment of infections

St. John’s wort (a herbal medicine), for treatment of mood swings

and depression

!

Use of the medicine and alcohol consumption

Do not drink alcohol while using Imovane. Alcohol may increase the

effect of Imovane and make you sleep very deeply, so that you will not

breathe properly or will have difficulty waking up.

!

Pregnancy and breast-feeding:

Pregnancy

Use of Imovane is not recommended during pregnancy. Consult your

doctor if you are pregnant, think you might be pregnant, or are planning

to become pregnant.

If used during pregnancy, there is a risk that the baby is affected. Some

studies have shown that there may be an increased risk of cleft lip and

palate (sometimes called “harelip”) in the newborn baby.

Reduced fetal movement and fetal heart rate variability may occur after

taking Imovane during the second and/or third trimester of pregnancy.

If Imovane is taken at the end of pregnancy or during labor, your baby

may show muscle weakness, a drop in body temperature, difficulty

feeding and breathing problems (respiratory depression).

If this medicine is taken regularly in the late stages of pregnancy, your

baby may develop physical dependence and may be at risk of developing

withdrawal symptoms such as agitation or shaking. In this case the

newborn should be closely monitored during the postnatal period.

Breast-feeding

Do not take Imovane if you are breast-feeding or are planning to breast-

feed. This is because small amounts may pass into mother’s milk. If you

are breast-feeding or planning to breast-feed, consult the doctor or

pharmacist before using any medicine. Consult a doctor or pharmacist

before taking any medicine if you are pregnant or breast-feeding.

!

Driving and operating machinery

Like other medicines used for sleep problems, Imovane can cause

slowing of normal brain functioning (central nervous system depression).

The risk of psychomotor impairment, including impairment of the

ability to drive, is increased if:

you perform activities that require alertness within 12 hours of taking

Imovane

You take a higher dose than the recommended dose of Imovane

you take Imovane while taking another central nervous system

depressant, or another medicine which increases levels of Imovane

in your blood, or while drinking alcohol

Do not engage in hazardous activities requiring complete alertness,

such as driving or operating machinery, after taking Imovane, and in

particular during the 12 hours after taking the medicine.

For more information about possible side effects which could affect

your driving, see section 4 in this leaflet.

!

Important information about some of the ingredients of the

medicine:

Imovane contains:

Lactose. This is a type of sugar. If you have been told by your doctor

that you cannot tolerate certain types of sugar (intolerance to some

sugars), consult the doctor before starting to use this medicine.

Wheat starch. People with a wheat allergy should not use this

medicine. Wheat allergy is not the same as celiac disease. People

with Celiac disease can take Imovane.

3. HOW SHOULD YOU USE THE MEDICINE?

The treatment should be as short as possible and should not exceed

4 weeks (including the period of tapering off).

Always use the preparation according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain about the

dosage and treatment regimen of the preparation.

The dosage and treatment regimen will be determined by the doctor

only.

Adults:

The usual dosage is one Imovane tablet (7.5 mg) just before bedtime.

Elderly:

The usual starting dosage is half a tablet (3.75 mg) just before

bedtime. Later, the dosage may be increased, as necessary.

Be careful and lean on something when getting out of bed!

Children and adolescents:

Imovane is not intended for use in children and adolescents under

18 years of age. The efficacy and safety of Imovane in children and

adolescents aged less than 18 years have not yet been established.

Patients with liver, respiratory or kidney problems:

The usual starting dosage is half a tablet (3.75 mg) just before

bedtime.

Do not exceed the recommended dosage.

Duration of treatment:

The usual duration of treatment is two days to 3 weeks.

Method of administration:

Swallow the medicine with water.

Do not crush or chew the tablets.

The tablet can be halved if a lower dose of 3.75 mg is required.

Take the required dose of Imovane in a single intake, and do not

take another dose during the same night.

Take the preparation when you are in bed, just before bedtime,

and make sure that you will be able to sleep 7-8 hours without

interruption.

If you took a higher dosage or if a child has accidentally swallowed

the medicine, refer immediately to a doctor or proceed to a hospital

emergency room and bring the package of the medicine with you.

Taking an overdose of Imovane is very dangerous. You may suffer

from the following effects:

Feeling drowsy, confused, sleeping deeply and even the possibility

of coma

Floppy muscles (hypotonia)

Feeling lightheaded or faint. These effects are due to low blood

pressure.

Falling over or losing balance (ataxia)

Shallow breathing or difficulty breathing (respiratory depression)

If you forget to take the medicine:

Imovane must only be taken at bedtime.

If you forgot to take the medicine at bedtime, do not take the

medicine at any other time. Otherwise, you may feel drowsy, dizzy

and confused during the day.

Never take two doses together instead of the forgotten dose!

If you stop taking the medicine:

Keep taking Imovane until your doctor tells you to stop. Do not stop

taking Imovane suddenly, but tell your doctor if you want to stop the

treatment. Your doctor will instruct you on how to stop the treatment.

If you stop the treatment with Imovane suddenly, your sleep

problems may come back and you may suffer from a “withdrawal

effect”.

If this happens, you may suffer from some of the effects listed below.

Refer to a doctor immediately if you suffer from any of the following

effects:

Feeling anxious, shaky, irritable, agitated, confused or you have

panic attacks

Sweating

Headache

Faster or uneven heartbeat (palpitations)

A lower level of awareness and problems with focusing or

concentrating

Nightmares, seeing or hearing things that are not real

(hallucinations)

Hypersensitivity to light, noise and touch

Poor reality perception

Numbness and tingling in the hands and feet

Aching muscles

Stomach problems

In rare cases, fits (seizures) may also occur.

Do not take medicines in the dark! Check the label and the dose

each time you take medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Imovane may cause side effects in

some users. Do not be alarmed by the list of side effects. You may

not suffer from any of them.

Discontinue use and refer to a doctor or hospital immediately if:

- you suffer from an allergic reaction to Imovane. The signs may

include: a rash, swallowing or breathing problems, swelling of

the lips, face, throat or tongue.

Refer to the doctor as soon as possible if you have any of the

following side effects:

Rare side effects, effects that occur in 1-10 in 10,000 users:

- Memory impairment since taking Imovane (amnesia). You can

reduce the chance of this effect by making sure that you have 7-8

hours of continuous and uninterrupted sleep after taking Imovane.

- Seeing or hearing things that are not real (hallucinations)

- Falling, especially in the elderly

Side effects of unknown frequency (effects whose frequency has not

yet been determined):

- Thinking things that are not true (delusions)

- Feeling low or sad (depressed mood)

Refer to the doctor or pharmacist if any of the following side

effects get serious or lasts longer than a few days:

Common side effects, effects that occur in 1-10 in 100 users:

- A mild bitter or metallic taste in the mouth or a dry mouth

- Feeling drowsy or sleepy

- Dry mouth

Uncommon side effects, effects that occur in 1-10 in 1,000 users:

- Feeling sick (nausea) or being sick (vomiting)

- Feeling dizzy or sleepy

- Headache

- Nightmares

- Feeling physically or mentally tired

- Agitation

Rare side effects, effects that occur in 1-10 in 10,000 users:

- Feeling confused

- Itchy, lumpy rash (urticaria)

- Feeling irritable or aggressive

- Reduced sex drive

- Difficulty in breathing or shortness of breath

Side effects of unknown frequency (effects whose frequency has not

yet been determined):

- Feeling restless or angry

- Feeling light-headed or having problems with your coordination

- Double vision

- Moving unsteadily or staggering

- Muscular weakness

- Indigestion

- Becoming dependent on Imovane

- Slower breathing (respiratory depression)

- Unusual skin sensations such as numbness, tingling, pricking,

burning or creeping on the skin (paresthesia)

- Mental problems such as poor memory

- Difficulty paying attention

- Disrupted normal speech

Sleep-driving and other strange behaviors:

There have been some reports of people who, after taking sleep

medicines, performed different activities while asleep, and after

waking up did not remember doing them. These included sleep-

driving and sleep-walking, preparing food, eating, making phone

calls. Alcohol and certain medicines for treatment of depression or

anxiety can increase the chance that this severe effect will happen.

If a side effect occurs, if one of the side effects worsens, or

if you suffer from a side effect not mentioned in the leaflet,

consult with the doctor.

Side effects can be reported to the Ministry of Health by clicking

on the link “Report Side Effects of Drug Treatment” found on the

Ministry of Health homepage (www.health.gov.il) that directs you to

the online form for reporting side effects, or by entering the link:

https://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine, should be

kept in a safe place out of the reach and sight of children and/or

infants in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) that appears

on the package. The expiry date refers to the last day of that month.

Storage conditions: Store at a temperature that does not exceed 25°C.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Lactose (each tablet contains 31.575 mg lactose monohydrate) and

traces of gluten (each tablet contains 60 mg wheat starch).

Wheat starch; Calcium hydrogen phosphate, dihydrate; Lactose

monohydrate; Hypromellose; Sodium starch glycolate type A;

Titanium dioxide; Macrogol 6000; Magnesium stearate.

What the medicine looks like and the contents of the package:

Imovane tablets are white, elliptical-shaped, film-coated tablets,

with a score line on one side.

Package size: 20 tablets per package.

This leaflet does not contain all the information about the

preparation. If you have any questions or are uncertain about

anything, please refer to the doctor.

License holder and address: sanofi-aventis Israel Ltd., 10 Beni Gaon

Street, Netanya 4250499.

Manufacturer and address: Sanofi Winthrop Industrie, Compiègne,

France.

Revised in September 2020.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health: 1011924581.

Page 1

IMOV-PO-7.5MG-SPC-20.0

SUMMARY OF PRODUCT CHARACTERISTICS

IMOVANE

1.

NAME OF THE MEDICINAL PRODUCT

Imovane

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Zopiclone 7.5 mg.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film coated tablet.

White, elliptical film-coated tablets with a score-line on one side. The tablet can be divided into equal

halves.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypnotic when the disorder of insomnia is severe and disabling.

4.2

Posology and method of administration

Dose

Use the lowest effective dose. Imovane should be taken in a single intake and not be re-administered

during the same night.

Adults:

The recommended dose is one Imovane tablet (7.5mg zopiclone) by the oral route shortly before

retiring.

Elderly patients:

A lower dose of 3.75mg zopiclone should be employed to start treatment in the elderly. Depending on

effectiveness and acceptability, the dosage subsequently may be increased if clinically necessary.

Paediatric population:

Zopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy

of zopiclone in children and adolescents aged less than 18 years have not been established.

Patients with hepatic insufficiency:

As elimination of zopiclone may be reduced in patients with hepatic dysfunction, a lower dose of

3.75mg zopiclone nightly is recommended.

The standard dose of 7.5mg zopiclone may be used with caution in some cases, depending on

effectiveness and acceptability.

Renal insufficiency:

Accumulation of zopiclone or its metabolites has not been seen during treatment of insomnia in

patients with renal insufficiency. However, it is recommended that patients with impaired renal

function should start treatment with 3.75mg.

Page 2

Chronic respiratory insufficiency:

In patients with chronic respiratory insufficiency, a starting dose of 3.75 mg zopiclone is

recommended initially. The dosage subsequently may be increased to 7.5 mg.

Treatment duration

Treatment should be as short as possible, from a few days to 4 weeks, including the tapering-off

period (see 4.4 Special warnings and special precautions for use).

The patient must be informed of the duration of treatment:

2 to 5 days for transient insomnia (caused by travel, for example)

2 to 3 weeks for short-term insomnia (i.e. caused by the occurrence of a serious event)

In some cases, it may be necessary to extend treatment beyond the recommended period. This

requires detailed and repeated evaluation of the patient’s status.

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

Route of administration

For oral use only.

Each tablet should be swallowed without sucking or chewing.

4.3

Contraindications

Imovane is contraindicated in patients with:

Myasthenia gravis

Respiratory failure

Severe sleep apnoea syndrome

Severe hepatic insufficiency

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

As with all hypnotics Imovane should not be used in children.

4.4

Special warnings and precautions for useSpecific patient groups

Use in hepatic insufficiency

A reduced dosage is recommended, see Posology. Benzodiazepines are not indicated to treat

patients with severe hepatic insufficiency as they may precipitate encephalopathy (see section 4.3).

Use in renal insufficiency

A reduced dosage is recommended, see Posology.

Use in respiratory insufficiency

As hypnotics have the capacity to depress respiratory drive, precautions should be observed if

zopiclone is prescribed to patients with compromised respiratory function (see section 4.8).

A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of

respiratory depression.

Use in paediatric population

Zopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy

of zopiclone in children and adolescents aged less than 18 years have not been established.

Use in Elderly patients

Page 3

Elderly should be given a reduced dose (see section 4.2).

Risk of dependence

Clinical experience to date with Imovane suggests that the risk of dependence is minimal when the

duration of treatment is limited to not more than 4 weeks.

Use of benzodiazepines and benzodiazepine-like agents (even at therapeutic doses) may lead to the

development of physical and psychological dependence or abuse upon these products.

The risk of dependence or abuse increases with:

Dose and duration of treatment

Use with alcohol or other psychotropics

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

Those patients who have marked personality disorders.

The decision to use a hypnotic in such patients should be taken only with this clearly in mind.

If physical dependence has developed, abrupt termination of treatment will be accompanied by

withdrawal symptoms (see section 4.4). These may consist of headaches, muscle pain, extreme

anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may

occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities,

hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rare cases of abuse have been reported.

Withdrawal

The termination of treatment with Imovane 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).

Suicidal ideation/suicide attempt/suicide 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).

Imovane should be administered with caution in patients exhibiting symptoms of depression.

Suicidal tendencies may be present therefore the least amount of Imovane 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 Imovane. 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.

In patients with a major depressive episode:

Benzodiazepines and related drugs should not be prescribed alone as they do not treat depression,

which will therefore follow its own course, with a persistent or higher risk of suicide.

Tolerance

Some loss of efficacy to the hypnotic effect of benzodiazepines and benzodiazepine-like agents may

develop after repeated use for a few weeks.

However, with Imovane there is an absence of any marked tolerance during treatment periods of up to

4 weeks.

Page 4

Rebound insomnia

A transient syndrome where the symptoms which led to treatment with a benzodiazepine or

benzodiazepine-like agent recur in an enhanced form on discontinuation of therapy. It may be

accompanied by other reactions including mood changes, anxiety and restlessness. Since the risk of

withdrawal/rebound phenomena may be increased after prolonged treatment, or abrupt

discontinuation of therapy, it is, therefore, recommended to decrease the dosage gradually and to

advise the patient accordingly.

A course of treatment should employ the lowest effective dose for the minimum length of time

necessary for effective treatment. See Posology for guidance on possible treatment regimen. A

course of treatment should not continue for longer than 4 weeks including any tapering off. (see also

section 4.8).

Amnesia

Amnesia is rare, but

anterograde amnesia may occur, especially when sleep is interrupted or when

retiring to bed is delayed after taking the tablet.

Therefore, to reduce the possibility of anterograde amnesia, patients should ensure that they take the

tablet when certain of retiring for the night and they are able to have a full night's sleep (uninterrupted

sleep of about 7 to 8 hours).

Psychomotor impairment

Like other sedative/hypnotic drugs, zopiclone has CNS-depressant effects.

The risk of psychomotor impairment, including impaired driving ability, is increased if: zopiclone is

taken within 12 hours of performing activities that require mental alertness, a dose higher than the

recommended dose is taken, or zopiclone is co-administered with other CNS depressants, alcohol, or

with other drugs that increase the blood levels of zopiclone (see section 4.5).

Patients should be cautioned against engaging in hazardous occupations requiring complete mental

alertness or motor coordination such as operating machinery or driving a motor vehicle following

administration of zopiclone and in particular during the 12 hours following that administration.

Risks from concomitant use of opioids and benzodiazepines

Concomitant use of benzodiazepines, including zopiclone, and opioids may result in sedation,

respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of

opioids and benzodiazepines for use in patients for whom alternative treatment options are

inadequate.

If a decision is made to prescribe zopiclone concomitantly with opioids, prescribe the lowest effective

dosages and minimum durations of concomitant use, and follow patients closely for signs and

symptoms of respiratory depression and sedation (see section 4.5).

Other psychiatric and paradoxical reactions

Other psychiatric and paradoxical reactions have been reported (see section 4.8), like restlessness,

agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, inappropriate behaviour

and other adverse behavioural effects are known to occur when using sedative/hypnotic agents like

zopiclone. Should this occur, use of zopiclone should be discontinued. These reactions are more

likely to occur in the elderly.

Somnambulism and associated bahaviours

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.

Page 5

Discontinuation of zopiclone should be strongly considered for patients who report such behaviours

(see section 4.5).

Risk of drug accumulation

Benzodiazepines and related drugs, (like any medicinal product), remain in the body for a period of

approximately 5 elimination half-lives (see section 5.2).

In elderly patients and those with hepatic insufficiency, the elimination half-life may be considerably

longer. Following repeated doses, zopiclone or its metabolites reach steady state much later and at a

much higher level. The efficacy and safety of the drug can only be evaluated once steady state has

been reached.

Dosage may need to be adjusted (see section 4.2).

Clinical studies of zopiclone have not revealed any plasma accumulation in patients with renal

insufficiency (see section 5.2).

Duration of treatment

The duration of treatment must be clearly indicated to the patient depending on the type of insomnia

(see section 4.2).

Tapering-off process

Patients should be clearly instructed on how to gradually discontinue treatment.

In addition to the need to gradually decrease dosage, patients should be warned of the risk of

rebound insomnia in order to minimize any insomnia that might result from the withdrawal symptoms

caused by treatment discontinuation, even when this is gradual.

Patients must be informed of possible discomfort during the tapering-off period.

Special Precautions for use

Insomnia may be a sign of an underlying physical or psychiatric disorder. The clinical diagnosis

should be re-evaluated if the insomnia persists or worsens after a short treatment period.

Excipients

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:

sedative

effect

zopiclone

enhanced

when

used

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.

therapeutic

benefit

co-administration

with

antipsychotics

(neuroleptics),

hypnotics,

anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics

and sedative antihistamines should therefore be carefully weighed. In the case of narcotic analgesics,

enhancement of euphoria may also occur leading to an increase in psychic dependence. Compounds

which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of

benzodiazepines and benzodiazepine-like agents.

The effect of erythromycin on the pharmacokinetics of zopiclone has been studied in 10 healthy

subjects. The AUC of zopiclone is increased by 80% in presence of erythromycin which indicates that

erythromycin can inhibit the metabolism of drugs metabolised by CYP 3A4. As a consequence, the

hypnotic effect of zopiclone may be enhanced.

Since zopiclone is metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme (see section 5.2

Pharmacokinetic properties), plasma levels of zopiclone may be increased when co- administered

Page 6

with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir.

A dose reduction for zopiclone may be required when it is co-administered with CYP3A4 inhibitors.

Conversely, plasma levels of zopiclone may be decreased when co-administered with CYP3A4

inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John's wort. A dose

increase for zopiclone may be required when it is co-administered with CYP3A4 inducers.

Opioids

The concomitant use of benzodiazepines, including zopiclone, and opioids increases the risk of

sedation, respiratory depression, coma, and death because of additive CNS depressant effect.

Limit dosage and duration of concomitant use of benzodiazepines and opioids (see section 4.4)

4.6

Fertility, pregnancy and lactation

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 fetal movement and fetal heart rate variability have been described after

administration of benzodiazepines or benzodiazepine-like substances during the second and/or

third trimester of pregnancy.

Administration of benzodiazepines or benzodiazepine-like substances, including zopiclone, during

the late phase

of pregnancy or during labour have been associated with effects on the neonate,

such as hypothermia, hypotonia, feeding difficulties (‘floppy infant syndrome’),and respiratory

depression, due to the pharmacological action of the product. Cases of severe neonatal

respiratory depression have been reported.

Moreover, infants born to mothers who took sedative/hypnotics agents chronically during the latter

stages of pregnancy may have developed physical dependence and may be at risk of developing

withdrawal symptoms in the postnatal period.

Appropriate monitoring of the newborn in the postnatal period is recommended.

If zopiclone is prescribed to a woman of childbearing potential, she should be warned to contact

her physician about stopping the product if she intends to become or suspects that she is

pregnant.

Breast-feeding

Zopiclone is excreted in breast milk, although the concentration of zopiclone in the breast milk is low,

use in nursing mothers must be avoided.

4.7

Effects on ability to drive and use machines

Page 7

Because of its pharmacological properties and its effect on central nervous system, Imovane 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: angiooedema, anaphylactic reaction

Psychiatric disorders

Uncommon: nightmare, agitation

Rare: confusional state, libido disorder, irritability, aggression, hallucination

Not known: restlessness, delusion, anger, depressed mood, abnormal behaviour (possibly associated

with amnesia) and somnambulism (see section 4.4: somnambulism and associated behaviour),

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

Page 8

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

been

reported

upon

discontinuation

zopiclone

(see

section

4.4).

Withdrawal

symptoms

vary

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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form:

/https://sideeffects.health.gov.il

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.

Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg

within one hour. Alternatively, consider gastric lavage in adults within one hour of a potentially life-

threatening overdose. If CNS depression is severe consider the use of flumazenil. It has a short half-

life (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC” TEST.

Management should include general symptomatic and supportive measures including a clear airway

and monitoring cardiac and vital signs until stable.

5.

PHARMACOLOGICAL PROPERTIES

Page 9

5.1

Pharmacodynamic properties

ATC Code: N05C F01

Zopiclone is an hypnotic agent, and a member of the cyclopyrrolone group of compounds. It rapidly

initiates and sustains sleep without 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

high

affinity

specific

agonist

action

central

receptors

belonging

'GABA'

macromolecular receptor complex modulating the opening of the chloride ion channel. However, it has

been

shown

that

zopiclone

other

cyclopyrrolones

different

site

those

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 3.75mg 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 exensively 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

There are no preclinical data of relevance to the prescriber which are additional to that already

included in other sections of the SPC.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Page 10

Wheat starch; Calcium hydrogen phosphate, dihydrate; Lactose Monohydrate; Hypromellose; Sodium

starch glycollate type A; Titanium dioxide; Macrogol 6000; Magnesium stearate.

6.2

Storage: Store at a temperature no higher than 25

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4

Nature and contents of container

PVC/aluminium foil blisters containing 20 film-coated tablets.

7.

MANUFACTURER

Sanofi-Winthrop Industrie, France.

8.

LICENSE HOLDER

Sanofi-aventis Israel ltd., 10 Beni Gaon, POB 8090, Netanya.

Revised in May 2020.