Zileze 7.5mg Film Coated Tablets

  • Name:

    Zileze 7.5mg 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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Medicine Name Zileze 3.75mg Film Coated Tablets Active Ingredients Zopiclone
Medicine Name Zileze 7.5mg Film Coated Tablets Active Ingredients Zopiclone
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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
  • 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 purple 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).

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.

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

Not known

1/10,000)

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

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: somnambulism

and 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 7.5

mg zopiclone resulted in mean peak plasma concentrations of 54 to 86 μ/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

relatively 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 10 mL/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 about 50% of a dose, producing inactive

metabolites 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 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 inter-individual variations appear to be very small.

 

Metabolism: Zopiclone is exensively metabolised in humans to two major metabolites, Noxide

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

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 14 April 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • 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 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
  • Change to section 11 - Dosimetry

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 6.6  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  

Section 11 Legal Category CD (Sch 4), POM added 

 

 

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