Zileze 3.75mg Film Coated Tablets

  • Name:

    Zileze 3.75mg Film Coated Tablets

  • Company:
    info
  • Active Ingredients:

    Zopiclone

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 21/04/17

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Summary of Product Characteristics last updated on medicines.ie: 25/4/2017
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Chiesi Limited

Chiesi Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 25 April 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 25 April 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



A Type IB variation was submitted to update sections 4.2, 4.3, 4.4, 4.8, 5.2 & 5.3 of the SPC

The following sections text indicated in blue has been added/updated in all 4 SPCs. The text with red has been deleted.

4.2. Posology and method of administration

Posology

 

Adults:

The usual dose of zopiclone in healthy adults is 7.5 mg, taken orally 30 to 60 minutes before retiring.

Posology

 

Use in Older people The Elderly:

In older people aAn initial dose of 3.75 mg is recommended. This can be increased, if necessary, to

7.5 mg per day.

Use in patients with a diminished renal and/or hepatic function renal & hepatic impairment:

In general, in patients who have a decrease in renal and/or hepatic function, the dose should be kept

to a minimum. In patients with mild hepatic and mild to moderate renal insufficiency, a daily dose of

3.75 mg should be used with caution. In patients with severe hepatic and renal insufficiency a daily

dose of 3.75 mg should not be exceeded.

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.

4.3. Contraindications

- Hypersensitivity to zopiclone or any other excipient in the tablet (listed in section 6.1)

- Myasthenia gravis

- Severe sleep apnoea

- Severe respiratory insufficiency

- Severe hepatic insufficiency

4.4. Special warnings and precautions for use

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 ages less than 18 years have not been established.

Risk of Dependence:

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

development of physical and psychic 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 or drug abuse and 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.

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

withdrawal symptoms. 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.

Rebound insomnia:

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine and

benzodiazepine – like agents recur in an enhanced form, may occur on withdrawal of treatment. It

may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and

restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after prolonged

treatment, or abrupt discontinuation of treatment, it is therefore, recommended that the dosage is

decreased gradually.

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

section 4.8).

Duration of treatment:

The duration of treatment should be as short as possible (see Posology) depending on the indication,

but should not exceed 4 weeks for insomnia and 8 to 12 weeks in case of anxiety, including tapering

off process. 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

section 4.8). Extension beyond these periods should not take place without re-evaluation of the

situation.

Amnesia:

Benzodiazepines and benzodiazepine - like agents may induce anterograde amnesia. The condition

occurs most often several hours after ingesting the product and therefore to reduce the risk patients

should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also Undesirable

Effects).

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.

Psychiatric and ‘paradoxical’ reactions:

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

restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations

psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when

using benzodiazepines and benzodiazepine - like agents. Should this occur, use of the drug should be

discontinued.

Specific patient groups:

Elderly should be given a reduced dose (see Posology). A lower dose is also recommended for

patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Benzodiazepines and benzodiazepine – like agents are not indicated to treat patients with severe

hepatic insufficiency as they may precipitate encephalopathy.

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

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

Excipients

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

 

Withdrawal

The termination of treatment with Zileze 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.).

 

Depression

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). Any underlying cause of the

insomnia should also be addressed before symptomatic treatment to avoid under treating potentially

serious effects of depression.

4.8. Undesirable effects

For this product no modern clinical documentation is available to determine frequency of adverse

effects.

 

Bitter taste is the most common side effect observed with zopiclone.

 

Frequency

MedDRA SOC Very rare

(<1/10,000)

Not known

Investigations Transaminases increased,

alkaline phosphatise increased

Nervous system disorders

Taste bitter, drowsiness,

alertness decreased, confusion,

headache, dizziness, muscle

weakness, ataxia, double

vision, anterograde amnesia.

Gastrointestinal disorders

Gastrointestinal disorder

General disorders and

administration site conditions

Fatigue

Immune system disorders Angioedema, anaphylactic

reaction

Allergic reaction (such as

pruritus or rash)

Psychiatric disorders

Affective blunting, libido

disorder, restlessness, agitation,

irritability, aggressiveness,

delusion, rage, nightmare,

hallucination, psychosis,

abnormal behaviour,

somnambulism (see section 4.4

Somnambulism and associated

behaviours) drug

dependence physical, drug

dependence

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).

System organ class Frequency Adverse reaction

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: somnambulismand associated behaviour),

dependence (see section 4.4),

withdrawal syndrome (see below),

affective blunting, psychosis

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, double

vision

Eye disorders Not known diplopia

Respiratory, thoracic and

mediastinal disorders

Rare dyspnoea (see section 4.4)

Not known respiratory depression (see section

4.4)

Gastrointestinal disorders Common dry mouth

Uncommon nausea, vomiting

Not known dyspepsia

Hepatobiliary disorders Very rare transaminases increased and/or

blood alkaline phosphatase

increased (mild to moderate)

Skin and subcutaneous tissue

disorders

Rare urticaria or rash, pruritus

Musculoskeletal and connective

tissue disorders

Not known muscular weakness

General disorders and

administration site conditions

Uncommon fatigue

Not known light headedness, incoordination

Injury, poisoning and

procedural complications

Rare fall (predominantly in elderly

patients)

Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor,

sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares,

hallucinations, panic attacks, muscle aches/cramps, gastrointestinal disturbances and irritability. In

severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis,

numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact,

hallucinations. In very rare cases seizures may occur.

5.2. Pharmacokinetic properties

Zopiclone is rapidly absorbed following oral administration. The oral administration of 7.5mg

zopiclone resulted in mean peak plasma concentrations of 54 to 86 μg/L at 0.5 to 2.5 hours after

administration, yet the hypnotic effect enters already after 15 to 30 minutes. Zopiclone demonstrates

linear pharmacokinetics between dosages of 3.5 to 15 mg.

After absorption zopiclone is widely distributed into body tissues including the brain, with relative

high concentrations in the liver and the left hypochondrium. The volume of distribution is about 100

L.

 

Zopiclone is reported to be bound to plasma proteins at a percentage of 45 to 80%.

The renal clearance of unchanged zopiclone is about 10mL/min, the plasma clearance reaches values

up to 230 mL/min.

 

Zopiclone has an elimination half-life of 3.5 to 6.5 hours. Because of this short elimination half-life

there is no accumulation of zopiclone in the body after repeated administration. In patients with renal

and/or hepatic insufficiency and in elderly the elimination half-life of zopiclone can be prolonged.

 

Zopiclone is extensively metabolised in the liver by three major pathways: Oxidation of the side

chain resulting in the formation of the less active metabolite zopiclone N-oxide (11%),

demethylation leading to the inactive metabolite N-desmethyl zopiclone (15%) and ester hydrolysis

involving oxidative decarboxylation of 50% of a dose, producing inactive metabolises partly

eliminated via the lung as carbon dioxide. Only 4 to 5% of the dose is excreted unchanged in the

urine. About 16% of the dose is excreted in the faeces.                                                                   

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 interindividual

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 (noxideand 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

Mutagenicity: Both in vitro and in vivo studies failed to show mutagenicity produced by zopiclone.

 

Carcinogenicity: From studies performed in rats and mice it can be concluded that for patients

receiving long-term medication with zopiclone no carcinogenic potential exists.

 

Fertility: In animal studies zopiclone caused a decrease in fertility in rats.

 

Teratogenicity: Zopiclone did not show any teratogenic or embryotoxic effect in animal studies.

 

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

included in other sections of the SPC.

 

10. DATE OF REVISION OF THE TEXT

July 2015

01/2017

Updated on 21 April 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 21 April 2017 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 2 - driving and using machines
  • Change to section 3 - how to take/use
  • Change to section 3 - overdose, missed or forgotten doses
  • Change to section 4 - possible side effects

Updated on 14 August 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 14 August 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 7 – Marketing Authorisation Holder - Chiesi Limited Cheadle Royal Business Park Highfield Cheadle SK8 3GY United Kingdom changed to Chiesi Limited 333 Styal Road Manchester M22 5LG United Kingdom

Section 10 – Date of revision of text February 2015 changed to July 2015

Updated on 26 March 2015 SmPC

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.1 Therapeutic indications – added- in adults  

Section 4.2 Dosage recommendations changed to Posology  

Use in elderly patients changed to Use in Older people   

In elderly patients changed to older people    

 

Use in children changed to Paediatric population    

Posology and method of administration – changed from - Use in children: No studies have been carried out in children, and consequently the administration of zopiclone in children is not recommended.

To - 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 children changed to Paediatric population  

Section 4.4 Special warnings and precautions for use added - 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 ages less than 18 years have not been established

Section 4.8 added 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

Section 6.1 List of excipients –Macrogol added 

Section 6.6  changed from - Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product -  Special precautions for disposal and other handling 

Section 9 Date of first authorisation/ Renewal of Authorisation changed to The Authorisation 

Section 10 Date of revision of text – changed to February 2015  

Updated on 25 March 2015 PIL

Reasons for updating

  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 3 September 2013 PIL

Reasons for updating

  • Change to side-effects

Updated on 18 February 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about missed dose
  • Change to instructions about overdose
  • Change to side-effects
  • Change to drug interactions
  • Change to information about drinking alcohol
  • Change to information about pregnancy or lactation
  • Change to further information section
  • Change to date of revision
  • Change to dosage and administration
  • Change to improve clarity and readability
  • Change due to user-testing of patient information

Updated on 13 December 2010 PIL

Reasons for updating

  • New PIL for medicines.ie