Short term treatment of insomnia in adults, including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances, in situations where the insomnia is debilitating or is causing severe distress for the patient. Long term continuous use is not recommended. A course of treatment should employ the lowest effective dose.

Adults

The recommended starting dose is 1 mg. Dosing can be raised to 2 mg or 3 mg if clinically indicated.

Elderly patients

The total dose of Zonam should not exceed 2 mg in elderly or debilitated patients.

Paediatric population

Eszopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy of eszopiclone in children and adolescents aged less than 18 years have not been established.

Patients with hepatic insufficiency

As elimination of eszopiclone may be reduced in patients with hepatic dysfunction, a lower dose of 2 mg eszopiclone nightly is recommended.

Treatment duration

Transient insomnia 2 - 5 days.

Short term insomnia 2 - 3 weeks.

A single course of treatment should not continue for longer than 4 weeks including any tapering off. Extension beyond the maximum treatment period should not take place without re-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.

Zonam is contraindicated in patients with: • Myasthenia gravis • Respiratory failure • Severe sleep apnoea syndrome • Severe hepatic insufficiency • Hypersensitivity to eszopiclone or to any of the excipients. As with all hypnotics Zonam should not be used in children.

Specific 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 eszopiclone 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

Eszopiclone should not be used in children and adolescents less than 18 years. The safety and efficacy of eszopiclone 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)

Risk of dependence

Clinical experience to date with Zonam 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 Zonam 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, eszopiclone 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.

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 Zonam there is an absence of any marked tolerance during treatment periods of up to 4 weeks.

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 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).

Driving

It has been reported that the risk that eszopiclone adversely affects driving ability is increased by the concomitant intake of alcohol. Therefore, it is recommended not to drive while taking eszopiclone and alcohol concomitantly.

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 eszopiclone. Should this occur, use of eszopiclone should be discontinued. These reactions are more likely to occur in the elderly.

Somnambulism and associated behaviours

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 eszopiclone and were not fully awake. The use of alcohol and other CNS-depressants with eszopiclone appears to increase the risk of such behaviours, as does the use of eszopiclone at doses exceeding the maximum recommended dose. Discontinuation of eszopiclone should be strongly considered for patients who report such behaviours (see section 4.5).

Excipients

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Association not recommended:

The sedative effect of eszopiclone may be enhanced when used in 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. The therapeutic benefit of 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 eszopiclone has been studied in 10 healthy subjects. The AUC of eszopiclone 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 eszopiclone may be enhanced.

Since eszopiclone is metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme (see section 5.2 Pharmacokinetic properties), plasma levels of eszopiclone may be increased when co-administered with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir. A dose reduction for eszopiclone may be required when it is co-administered with CYP3A4 inhibitors. Conversely, plasma levels of eszopiclone may be decreased when co-administered with CYP3A4 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John's wort. A dose increase for eszopiclone may be required when it is co-administered with CYP3A4 inducers.

Pregnancy Category: C

Insufficient data are available on eszopiclone to assess its safety during human pregnancy and lactation.

Use during pregnancy

Experience of use of eszopiclone during pregnancy in humans is limited although there have been no adverse findings in animals. Use in pregnancy is therefore not recommended.

If the product is prescribed to a woman of child bearing potential, she should be warned to contact her physician about stopping the product if she intends to become pregnant, or suspects that she is pregnant.

If eszopiclone is used during the last three months of pregnancy or during labour, due to the pharmacological action of the product, effects on the neonate, such as hypothermia, hypotonia and respiratory depression can be expected.

Infants born to mothers who took benzodiazepines or benzodiazepine-like agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Use during lactation

Eszopiclone is excreted in breast milk, although the concentration of eszopiclone in the breast milk is low, use in nursing mothers must be avoided.

Although residual effects are rare and generally of minor significance, patients should be advised not to drive or operate machinery the day after treatment until it is established that their performance is unimpaired. The risk is increased by concomitant intake of alcohol (see section 4.4 Special Warnings and Precautions for Use).

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

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 syndrome has been reported upon discontinuation of eszopiclone (see section 4.4.). 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.

	To report any side effect(s):  The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

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.

ATC Code: N05C F01

Eszopiclone 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 to its high affinity and specific agonist action at central receptors belonging to the 'GABA' macromolecular receptor complex modulating the opening of the chloride ion channel. However, it has been shown that eszopiclone and other cyclopyrrolones act on a different site to those of benzodiazepines including different conformational changes in the receptor complex.

The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly) and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (tmax) of approximately 1 hour and a terminal-phase elimination half-life (t1/2) of approximately 6 hours. In healthy adults, ZONAM does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg.

Absorption and Distribution

Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52-59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.

Metabolism

Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of 16 eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.

Elimination

After oral administration, eszopiclone is eliminated with a mean t1/2 of approximately 6 hours. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.

Effect of Food

In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour.

The half-life remained unchanged, approximately 6 hours. The effects of ZONAM on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.

Specific Populations

Age

Compared with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of eszopiclone (t1/2 approximately 9 hours).

Cmax was unchanged. Therefore, in elderly patients the dose should not exceed 2 mg.

Gender

The pharmacokinetics of eszopiclone in men and women are similar.

Race

In an analysis of data on all subjects participating in Phase 1 studies of eszopiclone, the pharmacokinetics for all races studied appeared similar.

Hepatic Impairment

Pharmacokinetics of a 2 mg eszopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease. Exposure was increased 2-fold in severely impaired patients compared with the healthy volunteers. Cmax and tmax were unchanged.

No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Dose reduction is recommended for patients with severe hepatic impairment. ZONAM should be used with caution in patients with hepatic impairment [see Dosage and Administration (2.3)].

Renal Impairment

The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment. AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects. No dose adjustment is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

The other inactive ingredients are: Lactose Anhydrous NF D.C, Dicalcium Phosphate Anhydrous, Croscarmellose Sodium Type A, Colloidal Silicon Dioxide, and Magnesium Stearate. Coating Composition: Hydroxypropyl Methyl Cellulose, Titanium Dioxide Pharma Grade, Purified talc, Spectracol Brilliant Blue LK 815030, Polyethylene Glycol MW 6000, and Purified Water BP.

Not applicable.

24 months

Store below 30°C.

Keep the blister in the outer carton in order to protect from light and moisture.

Aluminum thin strip soft temper plain, dull side lacquer laminated to oriented polyamide film. Bright side lacquer laminated to PVC with hard tempered aluminium foil lid.

Each pack contains 28 film-coated tablets

No special requirements.