Consumer medicine information

APO-Zopiclone

Zopiclone

BRAND INFORMATION

Brand name

APO-Zopiclone Tablets

Active ingredient

Zopiclone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Zopiclone.

What is in this leaflet

This leaflet answers some common questions about zopiclone. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Zopiclone is used to help people with sleeping difficulties (insomnia). It helps you fall asleep and reduces the number of times you wake up during the night. It is used for short term treatment (7-14 days) of insomnia.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine should not be used in children. The safe and effective dose of this medicine in children and adolescents under 18 years of age has not been established.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • zopiclone
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Do not take this medicine if you have or have had any of the following medical conditions:

  • sleep apnoea
  • myasthenia gravis
  • severe liver problems
  • severe lung problems.
  • Stroke
  • have previously experienced sleep behaviours when taking zopiclone

Do not take this medicine if you recently had alcohol or believe that you may have alcohol in your bloodstream.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • thyroid problems
  • depression, psychosis or schizophrenia or are taking medication for a mental illness
  • epilepsy
  • kidney or liver problems
  • lung problems or breathing problems
  • disability
  • alcoholism or frequently consume alcohol
  • have been addicted to any drug or medicine

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

Tell your doctor if you are planning to have surgery, dental treatment or an anaesthetic.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor if you are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with zopiclone. These include:

  • medicines to treat depression, anxiety and mental illness (e.g. antipsychotics)
  • other sedatives or tranquillisers
  • strong pain relievers (e.g. codeine)
  • muscle relaxants
  • antihistamines
  • antiepileptics (e.g. phenytoin, carbamazepine, phenobarbital)
  • certain medicines used to treat infections (e.g. rifampicin, clarithromycin, erythromycin, ketoconazole, itraconazole, ritonavir)
  • St John's Wort.

If you are taking any of these, you may need a different dose, or you may need to take different medicines. Other medicines not listed above may also interact with zopiclone.

How to take this medicine

Follow carefully all directions given to you by your doctor. They may differ to the information contained in this leaflet.

Your doctor may have prescribed a different dose, depending on your condition and if you are taking any other medicines.

How much to take

The usual dose is one tablet just before you go to bed.

Elderly people and people with liver problems may need smaller doses.

How to take it

Swallow the tablet whole with a full glass of water.

When to take it

This medicine should be taken when you are able to have a full night sleep and immediately before you go to bed. It helps put you to sleep quite quickly.

If you take this medicine on an empty stomach it may work more quickly.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

This medicine should only be used for short periods (e.g. 7-14 days). Continuous long-term use is not recommended unless advised by your doctor.

If you forget to take it

If you forget to take the tablet before you go to bed, and you wake up late in the night or very early in the morning, do not take it.

You may have trouble waking at your normal time.

Take the next dose the following night when you are meant to.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking this medicine.

If you become pregnant whilst taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, surgery, anaesthetic or are going into hospital, tell your doctor.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not take more than the recommended dose unless your doctor tells you to. This can increase the risk of side effects.

Do not take for a longer time than the doctor has prescribed.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not drink alcohol before, with or after this medicine.

Things to be careful of

This medicine will cause drowsiness. You should not operate dangerous machinery or drive motors for 12 hours after you take it. You should be careful the next morning when you wake up.

Make sure you know how you react to this medicine before you drive a car or operate machinery. This is very important if you are taking other drugs that also make you drowsy.

Be careful if you are over 65 and unwell or taking other medicines. You may be more sensitive to some of the side effects of this medicine.

You should not drink alcohol while you are taking this medicine. The effects of alcohol could be made worse while taking this medicine.

If you have been addicted to alcohol or drugs in the past, it is important to tell your doctor before starting this medicine. Some medicines can cause dependence, especially when they are used regularly for longer than a few weeks. People who have been dependent on alcohol or other drugs in the past may have a higher chance of becoming addicted to sleep medicines.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking zopiclone.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following:

  • headaches
  • dry mouth, bitter taste in your mouth
  • drowsiness, fatigue

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • heartburn
  • nausea, vomiting and/or diarrhoea
  • change in appetite
  • stomach pain
  • rash
  • agitation
  • breathing difficulties
  • depression, anxiety
  • confusion
  • dizziness
  • blurred vision
  • impotence
  • sleep walking or other behaviours whilst asleep
  • delirium (a sudden and severe change in mental state that can cause a combination of confusion, disorientation and/or attention deficit)

Alcohol can increase the risk of sleep walking or other behaviours such as driving or eating food whilst asleep. This risk is also increased if you take more than the recommended dose.

Some sleep medicines may cause a short-term memory loss. When this occurs, a person may not remember what has happened for several hours after taking the medicine. This is usually not a problem since most people fall asleep after taking the medicine.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to zopiclone, do not take any more of this medicine and tell your doctor immediately or go to the Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.
  • suicidal thoughts or are experiencing changes in your behaviour

After taking it

Sometimes when medicines are stopped suddenly, after being used for a long time, withdrawal symptoms may occur. Symptoms of withdrawal may include insomnia, confusion, headache, muscle cramps and sweating.

Tell your doctor if you have any problems when you stop taking this medicine.

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C. Protect from light.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

White to off white oval film coated tablets with breakline on one side and plain on the other side.

Blister packs of 30 tablets. AUST R 213071.

Ingredients

Each tablet contains 7.5 mg of zopiclone as the active ingredient.

It also contains the following inactive ingredients:

  • calcium hydrogen phosphate dihydrate
  • lactose monohydrate
  • sodium starch glycollate type A
  • povidone
  • maize starch
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • macrogol 6000
  • titanium dioxide
  • purified talc

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes. This medicine contains lactose.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in March 2022.

Published by MIMS May 2022

BRAND INFORMATION

Brand name

APO-Zopiclone Tablets

Active ingredient

Zopiclone

Schedule

S4

 

1 Name of Medicine

Zopiclone.

2 Qualitative and Quantitative Composition

Each tablet contains 7.5 mg of the active ingredient zopiclone.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The tablets are white to off white oval film coated tablets with breakline on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Short term treatment of insomnia (7 - 14 days).

4.2 Dose and Method of Administration

For oral use only. Use the lowest effective dose for short term treatment (7-14 days). Extension beyond the maximum treatment period should not take place without re-evaluation of the patient's status, since the risk of abuse and dependence increases with the duration of treatment.
Zopiclone should be taken in a single intake and not be re-administered during the same night.

Use in adults.

7.5 mg by oral administration shortly before retiring. This dose should not be exceeded. Depending on clinical response, the dose may be lowered to 3.75 mg.
Zopiclone is for short term treatment (7-14 days). See Section 4.4 Special Warnings and Precautions for Use, Dependence for advice of gradual dose decrease after prolonged use.

Use in the elderly.

In the elderly and/or debilitated patient an initial dose of 3.75 mg is recommended. The dose may be increased to a maximum of 7.5 mg if the starting dose does not offer adequate therapeutic effect, but in clinical trials, 25% of elderly patients treated with zopiclone experienced CNS side-effects at the higher dose. Zopiclone should be used with caution in these patients. (See Section 4.4 Special Warnings and Precautions for Use.)

Use in children.

Zopiclone is contraindicated in children. Dosage has not been established.

Use in patients with renal impairment.

In patients with renal insufficiency: although no accumulation of zopiclone or of its metabolites has been detected in cases of renal insufficiency, it is recommended that patients with impaired renal function should start treatment with 3.75 mg.

Use in patients with hepatic impairment.

The recommended dose is 3.75 mg depending on acceptability and efficacy. Up to 7.5 mg may be used with caution in appropriate cases.

Alternative therapy.

For long term treatment of insomnia, alternative non-pharmacological methods should be considered. Effective practical management of insomnia must respond to the presenting characteristics of the complaint. Giving accurate information is a form of treatment; there is benefit in discussing some simple facts with the patient and relating them to the problem, thereby assisting the patient to place the sleep problem in its context. Sleep hygiene such as reduction of caffeine intake, should be exercised. Programs designed to establish an optimal sleeping pattern for the patient may also be useful as are relaxation techniques designed to assist the patient deal with tension and intrusive thoughts in bed.

4.3 Contraindications

Patients with known hypersensitivity to zopiclone or any of the excipients.
Prior or concomitant use of alcohol.
Myasthenia gravis.
Severe impairments of respiratory function.
Acute cerebrovascular accident.
Sleep apnoea syndrome.
Severe hepatic insufficiency.
Patients who have previously experienced complex sleep behaviours after taking zopiclone.
Zopiclone is contraindicated in children.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Prolonged use of hypnotics is not recommended especially in the elderly.
The cause of insomnia should be identified wherever possible and the underlying factors treated before a hypnotic is prescribed.

Dependence.

Zopiclone should be prescribed for short periods only (7-14 days). Continuous long term use is not recommended. Use of zopiclone may lead to the development of abuse and/or physical and psychological dependence. It is therefore recommended that after prolonged use the dose should be decreased gradually and the patient advised about such a possibility (see Section 4.8 Adverse Effects (Undesirable Effects)).
The risk of dependence or abuse increases with dose and duration of treatment. Cases of dependence have been reported more frequently in patients treated with zopiclone for longer than 4 weeks. The risk of abuse or dependence is also increased in patients with a history of psychiatric disorders and/or alcohol or drug abuse. The risk of dependence or abuse increases with the use of alcohol or other psychotropics. Zopiclone should be used with extreme caution in patients with current or a history of alcohol or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms.

Rebound insomnia.

A transient syndrome whereby the symptoms that led to treatment with sedative-hypnotic agents recur in an enhanced form, may occur on withdrawal of hypnotic treatment. Since the risk of such phenomena is greater after abrupt discontinuation of zopiclone, especially after prolonged treatment, it is, therefore, recommended to decrease the dosage gradually and to advise the patient accordingly (see Section 4.8 Adverse Effects (Undesirable Effects)).

Amnesia.

Anterograde amnesia may occur, especially when sleep is interrupted or when retiring to bed is delayed after the intake of the tablet. To reduce the possibility of anterograde amnesia, patients should ensure that: they take the tablet strictly when retiring for the night; and they are able to have a full night sleep.

Other psychiatric and paradoxical reactions.

Other psychiatric and paradoxical reactions have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)), like restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, abnormal behaviour, delirium 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 behaviours.

Complex sleep behaviours, including sleep walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of zopiclone. Patients can be seriously injured or injure others during complex sleep behaviours. Such injuries may be fatal. Other complex sleep behaviours (e.g. preparing and eating food, or making phone calls, or having sex, with amnesia for the event) have also been reported. Patients usually do not remember these events. Postmarketing reports have shown that complex sleep behaviours may occur with zopiclone alone at recommended doses, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Discontinue zopiclone immediately if a patient experiences a complex sleep behaviour. (See Section 4.3 Contraindications.)

Depression, suicidality, psychosis and schizophrenia.

As with other hypnotics, zopiclone does not constitute a treatment of depression and may even mask its symptoms.
As with other sedative/hypnotic drugs, zopiclone should be administered with caution in patients exhibiting symptoms of depression, including those with latent depression. Suicidal tendencies may be present and protective measures may be required. Therefore the lowest possible quantity of zopiclone should be supplied to these patients to reduce the risk of intentional overdosage by the patient.
Pre-existing depression may be unmasked during use of zopiclone.
Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.
Several epidemiological studies show an increased incidence of suicide and suicide attempt in patients with or without depression, treated with benzodiazepines and other hypnotics, including zopiclone.

Epilepsy.

Patients with a history of seizures should not be abruptly withdrawn from any CNS depressant drug, including zopiclone.

Severe anaphylactic and anaphylactoid reactions.

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zopiclone. Some patients have had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zopiclone should not be rechallenged with the drug.

Use in hepatic impairment.

In patients with severe hepatic insufficiency (serum albumin less than 30 g/L or presence of gross oedema), the elimination of zopiclone may be significantly reduced. Treatment should be initiated on a dose of 3.75 mg and if necessary, may be increased to 7.5 mg.

Use in renal impairment.

Zopiclone is removed by dialysis.

Respiratory insufficiency.

Caution should be exercised in treating patients with chronic respiratory insufficiency. Treatment should be initiated on a dose of 3.75 mg and if necessary, should be carried out at 7.5 mg.
As hypnotics have the capacity to depress respiratory drive, precautions should be observed if zopiclone is prescribed to patients with compromised respiratory function.

Hormonal systems.

Treatment of rats with zopiclone increases hepatic thyroid hormone metabolism of T4, resulting in increases in thyroid stimulating hormone (TSH) and T3 levels, and decreases in T4 levels. It is suggested that zopiclone not be administered to individuals with impaired thyroid hormone homeostatic mechanisms or with conditions linked to hormonal imbalances.

Risks from concomitant use with opioids.

Concomitant use of opioids with benzodiazepines or other sedative-hypnotic drugs, including zopiclone, may result in sedation, respiratory depression, coma and death. Because of these risks, reserve concomitant prescribing of opioids and zopiclone 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 Interactions with Other Medicines and Other Forms of Interactions).

Abuse.

Caution must be exercised in administering zopiclone to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative.

Use in elderly.

Such patients may be particularly susceptible to the sedative effects of zopiclone and associated giddiness, ataxia and confusion, which may increase the possibility of a fall. (See Section 4.2 Dose and Method of Administration.)

Paediatric use.

The safe and effective dose of zopiclone in children and adolescents under 18 years of age has not been established (see Section 4.3 Contraindications).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alcohol.

Concomitant intake with alcohol is not recommended. The sedative effect of zopiclone may be enhanced when the product is used in combination with alcohol.

CNS depressants.

Additive CNS depressant effects should be expected if zopiclone is administered concomitantly with other medications which themselves produce CNS depression, for example, barbiturates, benzodiazepines, alcohol, sedatives, tricyclic antidepressants, non-selective MAO inhibitors and other antidepressants, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, narcotic analgesics, anaesthetics, neuroleptics, hypnotics, anxiolytics, antiepileptics (see Section 4.4 Special Warnings and Precautions for Use). In the case of narcotic analgesics, enhancement of euphoria may also occur leading to an increase in psychic dependence.

CYP450 inhibitors and inducers.

Erythromycin has been reported to increase significantly zopiclone concentrations at 0.5 and 1 hour after ingestion of zopiclone. The total AUC of zopiclone increased by 80% in 10 healthy volunteers which indicates that erythromycin can inhibit the metabolism of drugs metabolised by CYP3A4. Accelerated absorption of zopiclone in the presence of erythromycin may lead to enhanced hypnotic effects.
Plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors, such as erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir.
Plasma levels of zopiclone may be decreased when co-administered with CYP3A4 inducers, such as rifampicin, carbamazepine, phenobarbital (phenobarbitone), phenytoin, and St. John's wort.

Opioids.

The concomitant use of benzodiazepines and other sedative-hypnotic drugs, 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 zopiclone and opioids (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Zopiclone has been shown to severely reduce fertility in male rats treated with 50 mg/kg/day or greater. The significance of this finding for humans is not known.
(Category C)
The use of zopiclone during pregnancy is not recommended. Studies in animals have not shown evidence of an increased occurrence of foetal damage. However, zopiclone has been shown to cross the placenta, and increase postnatal mortality in rats given 10 mg/kg/day and above. Although the significance of this for humans is not known, it is likely that zopiclone may be harmful to the neonate.
Cases of reduced foetal movement and foetal heart rate variability have been described after administration of benzodiazepines and other sedative-hypnotic drugs, such as zopiclone, during pregnancy.
Administration of zopiclone during the last three months of pregnancy or during labour, has been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties and respiratory depression, due to the pharmacological action of the product.
Zopiclone is for short term treatment of insomnia (7-14 days). 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 some risk for 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 regarding discontinuation of the product if she intends to become or suspects she is pregnant.
Zopiclone and/or its metabolites are excreted in breast milk so therefore should not be used in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Zopiclone can impair daytime function in some patients even when taken as instructed. Some patients may still have zopiclone blood levels in the morning on the day following use that are high enough to produce impairment. Patients should be warned that impairment can occur despite feeling fully awake, in the absence of symptoms, or even with subjective improvement.
Zopiclone is not to be taken with alcohol or other sedative hypnotics (including other zopiclone products). If concomitant use of another CNS depressant or a drug that increases zopiclone blood levels is clinically warranted, dosage adjustments of zopiclone may be necessary.
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;
zopiclone is taken with less than a full night sleep remaining;
a higher dose than recommended 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 Adverse Effects (Undesirable Effects)

The side-effects most commonly seen in clinical trials is taste alteration (bitter taste).

More common reactions.

Nervous system disorders.

Drowsiness, headaches, fatigue.

Gastrointestinal disorders.

Bitter taste, dry mouth.

Less common reactions.

Immune system disorders.

Angioedema and/or anaphylactic reactions have been reported very rarely.

Nervous system disorders.

Agitation, anxiety, loss of memory including retrograde amnesia, anterograde amnesia, confusion, dizziness, weakness, somnolence, asthenia, feeling of drunkenness, euphoria, depression, co-ordination abnormality, hypotonia, speech disorder, hallucinations (auditory and visual), behavioural disorders, aggression, tremor, rebound insomnia, nightmares, irritability, abnormal and/or inappropriate behaviour possibly associated with amnesia, complex sleep behaviours, including sleep walking (see Section 4.4 Special Warnings and Precautions for Use, Somnambulism and associated behaviours), restlessness, delirium, delusion, anger, dependence, ataxia, paresthesia, cognitive disorders such as memory impairment, disturbance in attention, speech disorder.
Withdrawal syndrome has been reported upon discontinuation (see Section 4.4 Special Warnings and Precautions for Use). Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucinations, 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.

Eye disorders.

Blurred vision and diplopia.

Cardiac disorders.

Palpitations in elderly patients.

Respiratory, thoracic and mediastinal disorders.

Dyspnea and respiratory depression have been reported.

Gastrointestinal disorders.

Heartburn, constipation, diarrhoea, nausea, coated tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pains, dyspepsia.

Hepatobiliary disorders.

Mild to moderate increases in serum transaminases and/or alkaline phosphatase have been reported very rarely.

Skin and subcutaneous tissue disorders.

Pruritus, rash, urticaria, and tingling have been rarely reported.

Musculoskeletal and connective tissue disorders.

Muscular weakness.

Renal and urinary disorders.

Micturition.

Reproductive system and breast disorders.

Impotence, ejaculation failure, libido disorder.

Injury, poisoning and procedural complications.

Falls, predominantly in elderly patients.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Overdose of zopiclone can be manifested by varying degrees of CNS 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. Overdosage could be life threatening when 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.

Treatment.

Symptomatic and supportive treatment in an adequate clinical environment is recommended, attention should be paid to respiratory and cardiovascular functions. Activated charcoal is only useful when performed soon after ingestion. Haemodialysis is of no value due to the large volume of distribution of zopiclone. Flumazenil may be useful as an antidote. As in the management of overdosage with any medication, it should be borne in mind that multiple agents may have been taken.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Benzodiazepine related drugs, ATC code: N05C F01.

Mechanism of action.

Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Zopiclone belongs to a novel chemical class which is structurally unrelated to existing hypnotics. The pharmacological profile of zopiclone is similar to that of the benzodiazepines.

Pharmacological actions.

In sleep laboratory studies of 1 to 21-day duration in man, zopiclone reduced sleep latency, increased the duration of sleep and decreased the number of nocturnal awakenings. Zopiclone delayed the onset of REM sleep but did not reduce consistently the total duration of REM periods. The duration of stage 1 sleep was shortened, and the time spent in stage 2 sleep increased. In most studies, stage 3 and 4 sleep tended to be increased, but no change and actual decreases have also been observed. The effect of zopiclone on stage 3 and 4 sleep differs from that of the benzodiazepines which suppress slow wave sleep. The clinical significance of this finding is not known.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Zopiclone is rapidly absorbed and distributed after oral administration, the time of maximum observed plasma concentration being about 1.75 hours.

Distribution.

A study of 16 healthy volunteers receiving a single dose of 7.5 mg of zopiclone intravenously demonstrated the apparent volume of distribution of zopiclone to be 104 ± 15.5 L. Autoradiographic studies in the rat showed rapid distribution into the blood and peak tissue levels at 0.5 hours in the liver, small intestines, stomach, kidneys and the adrenals. After twenty four hours the total residual radioactivity in the body of the rat was 8%.
The bioavailability of the 7.5 mg tablets in man is 76.3 ± 9.6%, a hepatic first pass effect has been demonstrated. In fresh human plasma, zopiclone is approximately 45% protein bound in the 25 - 100 nanogram/mL concentration range.

Metabolism.

Zopiclone is extensively and rapidly metabolised by the liver. A large number of metabolites have been isolated and characterised, with the two major ones being the N-oxide, produced by oxidation of the piperazine nitrogen and the N-desmethyl produced by oxidative demethylation of the N-methyl piperazine. Only the N-oxide analogue has weak pharmacological activity.

Excretion.

Zopiclone is rapidly eliminated, mainly by means of hepatic metabolism. The elimination half-life after a single oral dose is 5.26 ± 0.76 hours. The elimination half-life for the N-oxide metabolite is 4.44 ± 0.66 hours and that for the N-desmethyl metabolite is 7.28 ± 0.49 hours.
Renal clearance is 13.9 ± 7.0 mL/min which further shows that the major elimination pathway is by hepatic metabolism.
The amount of renal excretion is also low; unchanged zopiclone 3.6%, the N-oxide metabolites 11.4% and the N-desmethyl metabolite 13.4%.

Pharmacokinetics in special patient groups.

Elderly.

In elderly patients, the absolute bioavailability is increased (94% vs 77% in young subjects), and the elimination half-life prolonged (approximately 7 hours).

Renal impairment.

In patients with mild to moderate renal insufficiency, the pharmacokinetics of zopiclone are not altered. Haemodialysis does not appear to increase the plasma clearance of the drug.

Hepatic impairment.

In patients with hepatic insufficiency, elimination half-life is prolonged (11.9) and time to peak plasma levels delayed (3.5 hours).

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies, using a standard battery of tests, showed no evidence of gene mutations or chromosomal damage.

Carcinogenicity.

Treatment with zopiclone by dietary administration for 2 years increased the incidence of thyroid carcinomas in male rats dosed with 100 mg/kg/day, and increased the incidence of mammary carcinoma in female rats dosed with 100 mg/kg/day, probably due to interference with thyroid hormone and 17β-estradiol metabolism. Studies with mice treated with zopiclone at dietary doses up to 100 mg/kg/day showed no evidence of drug-related carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Calcium hydrogen phosphate dihydrate, lactose monohydrate, sodium starch glycollate type A, povidone, maize starch, colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide, purified talc.

6.2 Incompatibilities

No data available.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C and protect from light.

6.5 Nature and Contents of Container

Blister packs (Opaque PVDC coated PVC/Aluminium) of 30 tablets (AUST R 213071).
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zopiclone is a fine white or slightly cream crystalline powder with a melting point of 176-178°C. Practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in acetone, practically insoluble in ethanol (96 per cent). It dissolves in dilute mineral acids.

Chemical structure.

Structural Formula:
Chemical name: (5RS)-6- (5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazin-5-yl 4- methylpiperazine-1-carboxylate.
Molecular Formula: C17H17ClN6O3.
Molecular Weight: 388.8.

CAS number.

43200-80-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes