Zopiclone, a cyclopyrrolone derivative, is a short-acting hypnotic agent. Zopiclone belongs to a novel chemical class which is structurally unrelated to existing hypnotics. However, the pharmacological profile of zopiclone is similar to that of the benzodiazepines. 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. With hypnotic drugs, the duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) and beta (elimination) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e., in relation to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepines or benzodiazepine-like hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased day-time anxiety (see WARNINGS). During nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepines or benzodiazepine-like hypnotics may develop. However in 2 sleep laboratory studies involving 17 patients, there was an absence of tolerance with zopiclone for treatment periods of more than 4 weeks.

Rebound insomnia:

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form, may occur on withdrawal of hypnotic treatment. Some manifestations of rebound insomnia have been reported both in sleep laboratory and clinical studies following the withdrawal of zopiclone. Zopiclone treatment was associated with dose-related residual effects (see

Pharmacokinetics:

Absorption:

Zopiclone is rapidly and well absorbed. Bioavailability is more than 75%, indicating the absence of a significant first-pass effect. After the administration of 3.75 and 7.5 mg doses, peak plasma concentrations of 30 and 60 ng/mL, respectively were reached in less than 2 hours. Absorption was similar in males and females. Repeated daily administration of a 7.5 mg oral dose for 14 days did not change the pharmacokinetic characteristics of zopiclone and did not lead to accumulation.

Distribution:

Zopiclone is rapidly distributed from the vascular compartment (distribution half-life [t1/2]: 1.2 hours) while the elimination half-life is approximately 5 hours (range: 3.8 to 6.5 hours). Plasma protein binding is low (approximately 45% in the 25 to 100 ng/mL concentration range) and non saturable. The risk of drug interaction arising from displacement of bound drug is low.

Metabolism:

Zopiclone is extensively metabolized by 3 major pathways; only about 4 to 5% of the drug is excreted unchanged in the urine. The principal metabolites are the N-oxide derivative (approximately 12%) which has weak pharmacological activity in animals, and the N-desmethyl metabolite (approximately 16%) which is pharmacologically inactive. Their apparent half-lives evaluated from the urinary data are approximately 4.5 and hours, respectively. Both metabolites are excreted renally. Other metabolites resulting from oxidative decarboxylation are partly eliminated via the lung as carbon dioxide. In animals, zopiclone did not induce hepatic microsomal enzymes.

Excretion:

Excretion studies, using C14-zopiclone have shown that more than 90% of the administered dose was excreted over a period of 5 days, 75% being eliminated in the urine and 16% in the feces. The low renal clearance of unchanged zopiclone (mean 8.4 mL/min) compared with that of plasma (232 mL/min) indicates that zopiclone clearance is mainly metabolic.

Special patient population: Elderly subjects:

The absolute bioavailability of zopiclone was increased (94% vs 77% in young subjects) and the elimination half-life prolonged (approximately 7 hours). Ac c u m u lat i on has not been observed on repeated dos ing.

Patients with hepatic insufficiency:

Elimination half-life was substantially prolonged (11.9 hours) and time to peak plasma levels delayed (3.5 hours). Consequently, lower doses are recommended (see Dosage and ADMINISTRATION).

Patients with mild to moderate renal insufficiency:

The pharmacokinetics of zopiclone were not affected. Hemodialysis did not appear to increase the plasma clearance of the drug.

Lactating women:

Zopiclone was present in the milk, its concentration paralleled plasma levels but was about 50% lower.

BIOAVAILABILITY

Zopiclone 7.5 mg tablet comparative bioavailability study

In a recently conducted study, the bioavailability of Rhoxal-zopiclone (zopiclone) mg tablets (Rhoxalpharma Inc.), was compared with respect to the Canadian Reference Product, Imovane(r), 7.5 mg tablets (Rhone Poulenc Rorer.) under single dose, fasting conditions. Of the 24 healthy adult male volunteers enrolled in this study, one did not complete the crossover. Pharmacokinetic and statistical analyses were conducted on data from 23 subjects. The relative bioavailability of Rhoxal-zopiclone (mfd by Rhoxalpharma Inc.) and Imovane(r) (mfd by Rhone Poulenc Rorer) 7.5 mg zopiclone tablets is shown in Table 1. Table 1: Summary table of the comparative bioavailability data of Rhoxalpharma Inc. (Rhoxal-zopiclone) and Rhone Poulenc Rorer (Imovane(r)) zopiclone 7.5 mg tablets under single-dose fasting conditions.

Conclusion

The 90% confidence intervals for the ln-transformed parameters AUCT and CMAX for zopiclone are within the 80-125% TPD acceptance range both before and after correction for measured content. Based on these results, the Rhoxalpharma Inc. (Rhoxal-zopiclone) and Rhone Poulenc Rorer (Imovane(r)), 7.5 mg zopiclone tablets are bioequivalent under single dose, fasting conditions.

INDICATIONS AND CLINICAL USE

Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.

Rhoxal-zopiclone

(zopiclone) is indicated for the short-term treatment and symptomatic relief of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakenings.

Treatment with Rhoxal-zopiclone should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for Rhoxal-zopiclone should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply. The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning.

CONTRAINDICATIONS

(zopiclone) is contraindicated in patients with known hypersensitivity to the drug or any component of its formulation, and in those with severe impairment of respiratory function, e.g., sleep apnea syndrome.

is contraindicated in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

WARNINGS

General:

(zopiclone) should be used with caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

The smallest possible effective dose should be prescribed for elderly patients. Inappropriate, heavy sedation in the elderly, may result in accidental events/falls. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness of the presence of sleep state misperception. Worsening of insomnia or the emergence of new abnormalities of thinking or behaviour may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of drugs that act at the benzodiazepine receptors.

(zopiclone) should be used with caution in patients who have myasthenia gravis or severe hepatic insufficiency.

Pregnancy:

Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines. Insufficient data are available on zopiclone to assess its safety during human pregnancy. Thus, the use of zopiclone during pregnancy is not recommended. If zopiclone is prescribed to a woman of child-bearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant or suspects that she is pregnant. During the last weeks of pregnancy, ingestion of therapeutic doses of a benzodiazepine hypnotic has resulted in neonatal CNS depression due to transplacental distribution. Similar effects can be expected to occur with zopiclone, due to its pharmacological effects.

Memory disturbance:

Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines or benzodiazepine-like agents. The event is rare with zopiclone. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk. Cases of transient global amnesia and "traveller's amnesia" have also been reported in association with benzodiazepines, the latter in individuals who have taken the drug, often in the middle of the night, to induce sleep while travelling. Transient global amnesia and traveller's amnesia are unpredictable and not necessarily dose-related phenomena. Patients should be warned not to take zopiclone under circumstances in which a full night's sleep and clearance of the drug from the body are not possible before they need again to resume full activity.

Abnormal thinking and psychotic behavioural changes:

Abnormal thinking and psychotic behavioural changes have been reported to occur in association with the use of benzodiazepines and benzodiazepine-like agents including zopiclone, although rarely. Some of the changes may be characterized by decreased inhibition, e.g., aggressiveness or extroversion that seems excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behaviour and a history of unusual reactions to sedatives including alcohol and the benzodiazepines or benzodiazepine-like agents. Psychotic behavioural changes that have been reported include bizarre behaviour, hallucinations, and depersonalization. Abnormal behaviours associated with the use of benzodiazepines or benzodiazepine-like agents have been reported more with chronic use and/or high doses but they may occur during the acute, maintenance or withdrawal phases of treatment. It can rarely be determined with certainty whether a particular instance of abnormal behaviours listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioural sign or symptom of concern requires careful and immediate evaluation.

Confusion:

The benzodiazepines and benzodiazepine-like agents affect mental efficiency, e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.

Anxiety, restlessness:

An increase in daytime anxiety and/or restlessness have been observed during treatment with zopiclone. This may be a manifestation of interdose withdrawal, due to the short elimination half-life of the drug.

Depression:

Caution should be exercised if zopiclone is prescribed to patients with signs and symptoms of depression that could be intensified by hypnotic drugs. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug that is feasible should be available to them at any one time.

PRECAUTIONS

Drug interactions:

Zopiclone may produce additive CNS depressant effects when co-administered with alcohol, sedative antihistamines, anticonvulsants, or psychotropic medications which themselves can produce CNS depression. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents. Examples include cimetidine or erythromycin.

Drug abuse, dependence and withdrawal:

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia) have occurred following abrupt discontinuation of benzodiazepines and benzodiazepine-like agents, including zopiclone. The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1 to 2 weeks can also have withdrawal symptoms including daytime anxiety between nightly doses. Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking the drug for more than a few weeks. The recommendation for tapering is particularly important in patients with a history of seizures. The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders. Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in zopiclone treated patients. As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.

Patients with specific conditions:

Zopiclone should be given with caution to patients with impaired hepatic or renal function, or severe pulmonary insufficiency. Respiratory depression has been reported in patients with compromised respiratory function.

Patients requiring mental alertness:

Because of zopiclone's CNS depressant effect, patients receiving the drug should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be warned against the concomitant ingestion of zopiclone and alcohol or CNS depressant drugs.

Use in pregnancy:

For teratogenic effects see WARNINGS. Non-teratogenic effects: A child born to a mother who is on benzodiazepines or benzodiazepine-like agents may be at risk for withdrawal symptoms from the drug during the postnatal period.

Use in nursing mothers:

Zopiclone is excreted in human milk, and its concentration may reach 50% of the plasma levels. Therefore, the administration of zopiclone to nursing mothers is not recommended.

Use in children:

The safety and effectiveness of zopiclone in children and young adults below the age of 18 have not been established.

Use in the elderly:

Elderly patients are especially susceptible to dose-related adverse effects, such as drowsiness, dizziness, or impaired coordination. Inappropriate, heavy sedation may result in accidental events/fall. Therefore, the lowest possible dose should be used in these subjects.

ADVERSE REACTIONS

The most common adverse reaction seen with zopiclone is taste alteration (bitter taste). Severe drowsiness and/or impaired coordination are signs of drug intolerance or excessive doses. The following adverse events were observed in patients receiving zopiclone. In the absence of an established cause-effect relationship those adverse reactions that were observed more frequently with zopiclone than with a placebo are in italics.

Central nervous system:

Somnolence, asthenia, dizziness, confusion, anterograde amnesia or memory impairment, feeling of drunkenness, euphoria, nightmares, agitation, anxiety or nervousness, hostility, depression, decreased libido, coordination abnormality, hypotonia, tremor, muscle spasms, paresthesia, speech disorder.

Cardiovascular:

Palpitations.

Digestive:

Dry mouth, coated tongue, bad breath, nausea, vomiting, dyspepsia, diarrhea,

constipation, anorexia or increased appetite.

Respiratory:

Dyspnea.

Special senses:

Amblyopia.

Dermatologic:

Rash, spots on skin, sweating. Rashes may be a sign of drug hypersensitivity; discontinue if this occurs.

Metabolic and nutritional:

Weight loss.

Others:

Bitter taste

, headache, limb heaviness, chills.

Laboratory tests:

There have been sporadic reports of abnormal laboratory test values including increase in AST, ALT or alkaline phosphatase values.

Geriatric patients:

Geriatric patients tended to have a higher incidence of palpitations, vomiting, anorexia, sialorrhea, confusion, agitation, anxiety, tremor and sweating than younger patients.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

In voluntary or accidental cases of zopiclone overdosage involving doses up to 340 mg, the principal effects reported were prolonged sleep, drowsiness, lethargy and ataxia. Full manifestation of zopiclone overdosage can be expected to be consistent with its pharmacological activity i.e., somnolence, confusion and coma with reduced or absent reflexes. Treatment should be supportive and in response to clinical signs and symptoms. Respiration, pulse and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. Intravenous fluid should be administered and an adequate airway maintained. Hemodialysis is probably of no value. It should be borne in mind that multiple agents may have been ingested. The benzodiazepine antagonist flumazenil, is a specific antidote in known or suspected overdose with benzodiazepines or benzodiazepine-like agents. (For conditions of use see flumazenil Product Monograph.)

DOSAGE AND ADMINISTRATION

Treatment with Rhoxal-zopiclone (zopiclone) should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re- evaluation of the patient. The product should be taken just before retiring for the night.

Adult dose:

The usual adult dose is 5 to 7.5 mg. The 7.5 mg dose should not be exceeded (see

Geriatric patients:

In the elderly and/or debilitated patient an initial dose of 3.75 mg at bedtime is recommended. The dose may be increased to 5 to 7.5 mg if the starting dose does not offer adequate therapeutic effect.

Patients with impaired liver function or chronic respiratory insufficiency:

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.

Rhoxal-zopiclone (zopiclone) is not indicated for patients under 18 years of age.

PHARMACEUTICAL INFORMATION

Drug substance:

Proper name: Zopiclone Chemical name: 4-methyl-1-piperazinecarboxylic acid ester with 6-(5-chloro- 2-pyridyl)-6, 7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5- one. Structural formula: Molecular formula: C17H17CIN6O3 Molecular weight: 388.82 Physical form: Fine white or slightly yellowish odourless, non hygroscopic powder. pKa: 6.70 pH: 7.94 in a 0.05% aqueous solution. Solubility: Practically insoluble in water, ethanol and ethyl ether; freely soluble in methylene chloride and chloroform; and sparingly soluble in acetone. It dissolves in dilute mineral acids. Melting point: 178degC

Composition:

5.0 mg: Each tablet contains: zopiclone 5.0 mg. Non-medicinal ingredients in alphabetical order: calcium phosphate dihydrate, corn starch, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltodextrin, polydextrose, polyethylene glycol, sodium croscarmellose, titanium dioxide and triacetin.

7.5 mg: Each tablet contains: zopiclone 7.5 mg. Non-medicinal ingredients in alphabetical order: calcium phosphate dihydrate, corn starch, D&C yellow no.10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no.2 aluminum lake, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltodextrin, polydextrose, polyethylene glycol, sodium croscarmellose, titanium dioxide and triacetin.

Stability and storage

recommendations:

AVAILABILITY OF DOSAGE FORMS

Rhoxal-zopiclone (zopiclone) 5.0 mg tablets

Each white, round, biconvex, film-coated tablet embossed "RXP" on one side and with "5" on the other, contains: zopiclone 5.0 mg.

Rhoxal-zopiclone(zopiclone) 7.5 mg tablets

Each oval, film-coated blue tablet, marked with "RXP 7.5" on one side and with a scored line on the other, contains: zopiclone 7.5 mg.

INFORMATION FOR THE PATIENT

INTRODUCTION

(zopiclone) is intended to help you sleep. It is one of several prescription sleeping pills that have generally similar properties.

If you are prescribed one of these medications, you should consider both their benefits and risks. Important risks and limitations include the following:

In order to guide you in the safe use of the product, this leaflet will inform you about this class of medication in general, and about Rhoxal-zopiclone in particular.

Safe use of Rhoxal-zopiclone

sleep. Follow your physician's advice about how to take Rhoxal-zopiclone, when to take it, and how long to take it. DO NOT TAKE Rhoxal-zopiclone if it is not prescribed for you.

EFFECTIVENESS OF Rhoxal-zopiclone

(zopiclone) is an effective medication and is relatively free of serious problems when used for the short-term management of insomnia. Symptoms of insomnia may vary: you may have difficulty in falling asleep, or awaken often during the night, or awaken early in the morning, or you may experience all three symptoms.

Insomnia may last only for a short time and may respond to brief treatment. The risks and benefits of prolonged use should be discussed with your physician.

SIDE EFFECTS

Common side effects:

Rhoxal-zopiclone

(zopiclone) may cause drowsiness, dizziness, light-headedness, and difficulty with coordination. Users must be cautious about engaging in hazardous activities requiring complete mental alertness, e.g., operating machinery or driving a motor vehicle.

Avoid alcohol while using Rhoxal-zopiclone. DO NOT USE Rhoxal-zopiclone along with other medications without first discussing this with your physician. How sleepy you are the day after you use one of these sleeping pills depends on your individual response and on how quickly your body gets rid of the medication. The larger the dose, the more likely that you will experience drowsiness, etc., the next day. It is important that you comply with the dose your physician has prescribed. Prescription sleeping pills which are eliminated rapidly, tend to cause less drowsiness the next day, but may cause withdrawal problems the day after use (see below).

SPECIAL CONCERNS

Memory problems:

Rhoxal-zopiclone

(zopiclone) may cause a special type of memory loss (amnesia); you may not recall events that occurred during some period of time, usually several hours,

after taking the drug. This lapse is usually not a problem, because the person taking the sleeping pill intends to be asleep during this critical period of time. But it can be a problem if you take the medication to induce sleep while travelling, such as during an airplane flight, because you may wake up before the effect of the drug is gone. This has been called "traveller's amnesia".

Tolerance/withdrawal symptoms:

After nightly use, sleeping pills may lose some of their effectiveness and you may also develop a degree of dependence. When taking Rhoxal-zopiclone, you may awaken during the last third of the night or feel anxious or nervous during the day. If this occurs, tell your physician. You may also experience "withdrawal effects" when you stop the medication after taking it for only one week or two. But usually, these withdrawal effects are more common and severe after prolonged periods of continuous use. For instance, on the first few nights after stopping the medication, you may find that insomnia is worse than before taking the sleeping pills. This type of withdrawal symptom is known as "rebound insomnia". Other withdrawal effects following abrupt stopping of sleeping pills may range from unpleasant feelings to a major withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremor, and rarely, convulsions. The severe symptoms are uncommon. If you have been taking sleeping pills for a long time, discuss with your physician when and how it would be best for you to stop.

Dependence/abuse:

All prescription sleeping pills can cause dependence (addiction) especially when used regularly for more than a few weeks, or at higher doses. Some people develop a need to continue taking these drugs, not only for continued therapeutic effect, but also to avoid withdrawal symptoms or to achieve non-therapeutic effects. Individuals who depend, or have depended at any time in the past, on alcohol or other drugs may be at particular risk of becoming dependent on drugs of this class. But ALL PEOPLE ARE AT SOME RISK. Consider this matter before you take these medications beyond a few weeks.

Mental and behavioural changes:

A variety of abnormal thinking and behavioural changes may occur when you use prescription sleeping pills. Some of these changes include aggressiveness and extroversion which seem out of character. Other changes, although rare, can be more unusual and extreme. These include confusion, strange behaviour, restlessness, illusions, hallucinations, feeling like you are not yourself, and feeling more depressed, which may lead to suicidal thoughts. It is rarely clear whether such symptoms are caused by the medication, or by an underlying illness, or are simply spontaneous happenings. In fact, worsened insomnia may in some cases be associated with illnesses that were present before the medication was used.

IMPORTANT NOTE

Regardless of the cause, if you take these medications, report any mental or behavioural changes promptly to your physician.

Effects on pregnancy:

Certain benzodiazepine sleeping pills have been linked to birth defects when taken during the early months of pregnancy. It is not yet known if Rhoxal-zopiclone (zopiclone) could cause similar effects. In addition, sleeping pills taken during the last weeks of pregnancy have been known to sedate the baby. Therefore, AVOID USING THIS MEDICATION DURING PREGNANCY.

PHARMACOLOGY

Zopiclone, a cyclopyrrolone derivative, is a chemically novel hypnotic agent. However, the pharmacological and behavioural evaluation of the drug has shown that its effects are similar to those of the benzodiazepines.

CNS activity

Zopiclone antagonizes chemically and electroshock-induced seizures in mice and rats. While it potently affects convulsive conditions that involve GABA, it is relatively ineffective when glycine, another inhibitory amino acid, is involved. Zopiclone exerts muscle relaxant activity; it inhibits the traction grasping reflex in mice, reduces the ability of mice and rats to remain on a rotarod and inclined screen, respectively, relaxes the hind legs of normal cats and blocks polysynaptic reflexes in chloralosed cats. Zopiclone also exerts antiaggressive activity, it inhibits footshock-induced fighting behaviour in mice and septal lesion-induced aggression in rats. In a "conflict" situation, the drug increases punishment-suppressed lever-pressing behaviour, which is indicative of anxiolytic activity. Non-punished responding, indicative of non-specific sedation, in suppressed only at higher doses. While zopiclone does not cause loss of righting reflex in normal mice, it potentiates narcosis induced by hexobarbital or ethanol. In a drug discrimination paradigm, where rats are trained to discriminate drug from saline, the zopiclone discriminative stimulus generalized to several benzodiazepines as well as to pentobarbital. The finding that the benzodiazepines and a barbiturate were able to substitute for zopiclone indicates that zopiclone belongs to the same class of drugs. Tolerance does not develop to the behavioural effects of zopiclone, since the anticonvulsant and taming ED50's are similar in naive and zopiclone-treated animals.

Receptor binding studies:

Zopiclone has a high and specific affinity for benzodiazepine binding sites in several rat brain regions. The drug can inhibit the binding of 3H-benzodiazepines, but can itself label the sites that are recognized both by benzodiazepine agonists and Ro 15-1788, a benzodiazepine antagonist. Zopiclone does not recognize the peripheral benzodiazepine receptor sites and lacks affinity for the serotonin, GABA, a1 and a2 adrenergic, and dopamine receptors. The interaction of zopiclone with the benzodiazepine receptor / GABA receptor / chloride channel complex differs somewhat from that of the benzodiazepines; while it decreases cGMP concentration in rat cerebellum, its binding is not enhanced either by GABA or by the chloride anion.

Dependence liability:

In barbital-dependant rhesus monkeys, zopiclone suppressed the abstinence symptoms which appeared upon withdrawal. Partial and complete suppression was observed at 4 and 16 mg/kg doses, respectively. Zopiclone, when administered to monkeys at a dose of 16 mg/kg/day for 28 days, precipitated withdrawal signs of moderate severity. Peak symptoms appeared three and four days after withdrawal and included hyperirritability, restlessness, tremor, and some weight loss. The administration of a higher dose for two weeks brought about similar symptoms upon withdrawal without precipitating convulsions. Zopiclone was self-administered both intravenously and intragastrically in monkeys. When the drug was changed to saline, the rate of self-administration declined rapidly.

Cardiovascular and respiratory effects:

Zopiclone was evaluated in conscious and anesthetized cats, dogs, rabbits and monkeys with regard to its effect on respiration and several cardiovascular parameters. Most of the studies involved intravenous administration. In general, respiration and blood pressure decreased in a dose-dependant fashion while heart rate and EKG showed little change. Zopiclone affected central respiratory control mechanisms to a greater extent than the cardiovascular regulatory mechanisms.

Drug interaction studies:

Zopiclone was evaluated in combination with several drugs and in general interacted either in an additive or synergistic fashion with diazepam, phenobarbital, trimethadione, chlorpromazine, hexobarbital, and ethanol. Zopiclone did not modify the effects of phenytoin, morphine, ketoprofen and gallamine. The effects of zopiclone could be reversed by Ro 15-1788 (flumazenil) a specific benzodiazepine antagonist.

TOXICOLOGY

Acute toxicity:

Studies were carried out in both sexes of several species. The results are summarized in the following table.

Symptoms of toxicity included sedation, CNS depression, ataxia, respiratory depression, and dyspnea. In dogs, the i.v. administration of zopiclone was followed by myoclonic seizures.

LONG-TERM TOXICITY STUDIES:

Ten rats/sex/dose received zopiclone by gavage six days per week at doses of 0, 6, 24 and 120 mg/kg. Dose-related sedation and paresis of hind legs were observed. Thyroid weights were increased in male rats at all dose levels. In the high dose males, heart and spleen weights were reduced.

Fifteen rats/sex/dose received zopiclone by gavage seven days per week at doses of 0, 2, 12 and 120 mg/kg. At the mid and high doses, dose-related hypotonia, adynamia and ptosis were observed, all of which subsided with time. Weight gain was slightly but significantly less in mid and high dose male rats than in controls. At the 120 mg/kg dose the following changes occurred. BSP values decreased in both sexes; the number of RBC decreased in females; liver weights increased in both males and females, accompanied by slight changes in the parenchymal liver cells, namely eosinophilia or basophilia in the portal area.

Fifty rats/sex/dose received zopiclone in the diet at doses of 0, 2, 20 and 200 mg/kg. Of these animals, 15 rats/sex/dose were sacrificed at six months. The lowest dose was well tolerated. At the high dose the following changes were seen: weight gain was reduced by about 30% in both sexes; plasma protein levels were elevated at 3 and 6 months in the males and throughout the study in the females; albumin and globulin levels were elevated; thyroid weights were increased in male rats, accompanied by thyroid hyperplasia and, in some rats, by follicular adenomas; liver weights were increased in female rats both at 6 and 18 months; hepatocellular hypertrophy occurred in both sexes.

One dog/sex/dose received zopiclone six days per week at doses of 0, 6, 24 and 120 mg/kg. Dose-related sedation and hypotonia of the hind legs were observed. High dose dogs and the intermediate dose female dog exhibited moderate weight loss. At the high dose, both dogs had Heinz bodies in circulating erythrocytes and the bone marrow showed erythroblastic hyperplasia. In addition, the male animal had marked anemia and active erythropoiesis in the spleen. BUN values were increased at all doses in a dose-related fashion; liver function tests were somewhat elevated.

Six dogs/sex/dose received zopiclone seven days per week at doses of 0, 5, 10 and 25 mg/kg. One dog/sex from each group was sacrificed after a 3-month recovery period. Zopiclone caused slight excitation, ataxia and drowsiness, and drowsiness and sleep at the 5, 10, and 25 mg/kg doses, respectively. Late in the study, four dogs had epileptoid seizures and three of them died. A reduced weight gain was observed only in high dose male dogs. Platelet counts rose substantially above normal in two high dose female dogs. Transaminase levels were elevated but not in a dose-dependant manner. Alkaline phosphatase levels were significantly elevated both in male and female dogs, receiving the 25 mg/kg dose. While liver weights increased both in male and female dogs in a dose-dependent fashion, they returned toward control values following the 3-month recovery period. In high dose male animals, relative spleen, kidney and adrenal weights were significantly increased. Examination of bone marrow smears showed that the proportion of proerythroblasts and the ratio of normoblasts to basophilic erythroblasts were significantly greater in high dose females than in controls.

Five dogs/sex/dose received zopiclone seven days per week at doses of 0, 1, 5 and 25 mg/kg. Zopiclone induced ataxia, sleepiness, lethargy, decreased activity, body tremors and excitability. The latter two effects occurred prior to dosing, while the others were seen shortly after dosing. After six months of treatment, zopiclone induced epileptoid seizures in five dogs (four high dose, one mid dose). Since the convulsions were observed early morning prior to dosing, they might have been a manifestation of withdrawal. Female dogs, treated with 5 mg/kg of zopiclone, were significantly heavier than controls. Treated animals both ate and drank more than did their respective controls. Platelet counts were elevated in both sexes at the 5 and 25 mg/kg doses. Alkaline phosphatase was elevated from the first month on in mid and high dose animals. T4 values in high dose males and BSP values in high dose females were also elevated. There was a dose-dependent increase in liver weights which became statistically significant at the 25 mg/kg dose. The elevated liver weights were associated with histopathological changes, namely vacuolation of hepatocyte cytoplasm with eosinophilic hyaline bodies.

CARCINOGENICITY

Oncogenicity studies were carried out with zopiclone in rats and mice with doses of 1, 10 and 100 mg/kg/day for two years. There was an increased incidence of mammary tumors with a shift toward more anaplastic forms in female and an increase of thyroid tumors in male rats on the high dose. In the mouse study, females on the high dose had an increased incidence of pulmonary adenocarcinomas; while males on the high dose had a high number of subcutaneous soft tissue tumors. In a wide battery of tests, it was shown that zopiclone has no mutagenic or clastogenic (chromosome-damaging) properties; urine extracts from zopiclone treated mice, rats and humans were similarly not mutagenic. The effect of zopiclone is that of a non-genotoxic oncogen; tumor redistribution phenomena are frequently observed in rodent carcinogenicity studies, particularly with drugs acting on the central nervous system and the hormonal balance. The rise of 17 beta-estradiol may be regarded as a cause for the emergence of mammary tumors and the shift from well differentiated to poorly differentiated mammary carcinomas. The altered feedback mechanism following accelerated clearance of T4 and the rise of TSH is responsible for thyroid overstimulation that leads to formation of thyroid neoplasms. The soft tissue tumors of male mice are brought about by fighting (a paradoxical reaction) and subsequent initiation by encrustation and foreign body reaction. The increased incidence of pulmonary adenocarcinomas in female mice may be regarded as fortuitous ("chance finding"), but there is not enough data available to exclude some other mechanisms. No comparable endocrine changes were observed in man given the therapeutic dose of zopiclone (7.5 mg). The tumor producing dose of zopiclone represents 800 times and the no effect level 80 times the proposed human dose (0.125 mg/kg).

MUTAGENICITY:

Zopiclone and its metabolic products were tested for mutagenic potential in the following assays:

All tests were negative. Zopiclone was neither a mutagen nor a clastogen and did not give rise to mutagenic metabolites either in experimental animals or in man.

REPRODUCTION AND TERATOLOGY

The effect of zopiclone was evaluated in three studies. First, treated male rats were mated with treated female rats, the oral doses of zopiclone being 0, 2, 12 and 120 mg/kg. The males were treated for 10 weeks prior to mating, the females for 2 weeks prior to mating, during pregnancy and throughout a 3-week lactation period. In two further experiments, treated males (120 mg/kg) were mated with untreated females and untreated males were mated with treated females (120 mg/kg). Both of the latter experimental conditions included a control group. Rate of pregnancy, number of implantations, rate of resorption and number of live fetuses were similar in control and low and medium dose-treated rats. However, mortality of pups was significantly higher in the mid dose group than in the control group. At the 120 mg/kg dose, regardless whether treated males were mated with treated or untreated females, only ~10% of the females became pregnant and even in these animals resorption was complete. When high dose-treated females were mated with untreated males, the rate of pregnancy was only slightly lower than in controls (83% vs 100%) and all pregnant females delivered live fetuses. Survival of fetuses, up to day 21 of lactation, was significantly lower than in controls. In conclusion, a 120 mg/kg dose of zopiclone induces sterility in male animals, while in females it affects pregnancy rate only slightly. Up to 12 mg/kg, the drug does not affect fertility and reproductive functions.

The study was performed in groups of 20 rats each, given zopiclone orally at doses of 0, 5, 25 and 125 mg/kg from day 5 to day 15 of gestation. In rats treated with the high dose of zopiclone, the following changes were seen when compared to the controls: food intake and final body weight (day 20) were slightly but significantly lower, the rate of resorption was somewhat higher (9% vs 6%) and the mean weight of live fetuses slightly but significantly lower (3.5 g vs 3.7 g). One pup had a sternal malformation, and five pups from the same mother had asymmetrical sternebrae. Both anomalies occur in the strain used. In conclusion, zopiclone is not teratogenic in rats in doses up to 125 mg/kg.

The study was performed in groups of 16 rabbits each given zopiclone orally at doses of 0, 5, 25 and 125 mg/kg from day 6 to day 16 of gestation. Food intake and weight gain were significantly affected and in a dose-related manner. At the 125 mg/kg dose, the rabbits actually lost some weight by the end of treatment. The mean weight of live fetuses in this group was significantly lower than in the controls (31.5 g vs 35.8 g). Three of the fetuses were malformed, 1/109 live fetuses in the mid dose and 2/129 live fetuses in the high dose, exhibiting malformations of the urinary tract, exencephaly and forelimbs with clubfeet and malformations of the large heart vessels, respectively. These malformations do occur in the strain used. In conclusion, zopiclone is not teratogenic in rabbits in doses up to 125 mg/kg.

This was a two generation study in which male and female offspring (F1 generation) of treated mothers were bred and the F2 generation also observed. Zopiclone was given orally at doses of 0, 10, 50 and 250 mg/kg from day 17 of gestation to day 28 of lactation. The following significant changes were observed: smaller litter size in the high dose group, lower body weights at birth and at weaning in the mid and high dose groups, dose-related increase of mortality at birth and between days 1 and 28. Mortality during lactation was significantly different from control even in the 10 mg/kg group. Cannibalization of pups increased in a dose-related manner; this effect might have been due to the fact that the pups were sedated, hypothermic and had problems with suckling. Gross behaviour, physical development, auditory function, spontaneous motor activity and learning behaviour were normal in the surviving F1 pups. Males and females from the F1 generation mated successfully except for three rats which were infertile (one male rat from the 50 mg/kg group and one male and one female rat from the 250 mg/kg group). The male rat from the mid dose group had bilateral hypoplastic testes and epididymis. Mortality and weights of the F2 generation were within the normal range for the strain used. One F2 pup, from the mid dose group, had oligodactyly with syndactyly of the left forelimb.

Species	Route	LD 50 (mg/kg)
Mice	i.v.	450
	i.p.	580
	p.o.	1150
Rats	p.o.	2300
Dogs	p.o.	>= 4500
Dogs	i.v.	400
Cats	p.o.	> 1500
Rabbits	p.o.	~ 2500
Monkeys	p.o.	> 4500

Assay	Indicator species or organism	Doses used
Ames' test	Salmonella typhimurium (TA98, TA100, TA1535, TA1537 & TA 1538) Escherichia coli (WP2 uvrA)	Up to 500 mcg/plate with and without rat liver microsome activating enzymes.
Ames' test	Salmonella typhimurium (5 strains as above)	Concentrated urine extracts from rats treated at 1, 10 and 100 mg/kg for 20 days.
Ames' test	Salmonella typhimurium (5 strains as above)	Up to 5000 mcg/plate with liver microsomal enzymes from B6C3F1 mice.
Ames' test	Salmonella typhimurium (5 strains as above) Escherichia coli (WP2 uvrA)	Urine samples from volunteers receiving 7.5, 10 or 15 mg with or without liver microsomal enzymes. Two major metabolites, N-oxide and N-desmethyl derivatives: up to 1000 mcg per plate.
Assay	Indicator species or organism	Doses used
In vitro and In vivo host mediated assay	Saccharomyces cerevisiae (D7)	In vitro: up to 1000 mcg/mL In vivo , in mice: 100 mg/kg p.o.
Gene forward mutation test	Chinese Hamster Ovary cells (CHO/HG PRT)	Up to 200 mcg/mL with or without metabolic activation.
In vitro mammalian cell test for clastogenicity.	Chinese Hamster Ovary cells (CHO/K 1 line).	Up to 200 mcg/mL with or without metabolic activation.
DNA repair assay (William's test)	Primary cultures of rat hepatocytes.	Up to 10 -4 M.
Dominant lethal test	Rats and mice	Up to 120 mg/kg/day p.o.
Micronucleus test	Mice	Up to 630 mg/kg/day p.o.
Sex-linked recessive lethal test	Drosophila melanogaster cells (CHO/HG PRT).	2% solution p.o. activation

PHARMACOLOGICAL CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY

Rebound insomnia:

Pharmacokinetics:

Absorption:

Distribution:

Metabolism:

Excretion:

Special patient population: Elderly subjects:

Patients with hepatic insufficiency:

Patients with mild to moderate renal insufficiency:

Lactating women:

BIOAVAILABILITY

Zopiclone 7.5 mg tablet comparative bioavailability study

Conclusion

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS

General:

Pregnancy:

Memory disturbance:

Abnormal thinking and psychotic behavioural changes:

Confusion:

Anxiety, restlessness:

Depression:

PRECAUTIONS

Drug interactions:

Drug abuse, dependence and withdrawal:

Patients with specific conditions:

Patients requiring mental alertness:

Use in pregnancy:

Use in nursing mothers:

Use in children:

Use in the elderly:

ADVERSE REACTIONS

Central nervous system:

Cardiovascular:

Digestive:

Respiratory:

Special senses:

Dermatologic:

Metabolic and nutritional:

Others:

Laboratory tests:

Geriatric patients:

SYMPTOMS AND TREATMENT OF OVERDOSAGE

DOSAGE AND ADMINISTRATION

Adult dose:

Geriatric patients:

Patients with impaired liver function or chronic respiratory insufficiency:

PHARMACEUTICAL INFORMATION

Drug substance:

Composition:

Stability and storage

recommendations:

AVAILABILITY OF DOSAGE FORMS

Rhoxal-zopiclone (zopiclone) 5.0 mg tablets

Rhoxal-zopiclone(zopiclone) 7.5 mg tablets

INFORMATION FOR THE PATIENT

INTRODUCTION

Safe use of Rhoxal-zopiclone

EFFECTIVENESS OF Rhoxal-zopiclone

SIDE EFFECTS

SPECIAL CONCERNS

Memory problems:

Tolerance/withdrawal symptoms:

Dependence/abuse:

Mental and behavioural changes:

IMPORTANT NOTE

Effects on pregnancy:

PHARMACOLOGY

CNS activity

Receptor binding studies:

Dependence liability:

Cardiovascular and respiratory effects:

Drug interaction studies:

TOXICOLOGY

Acute toxicity:

LONG-TERM TOXICITY STUDIES:

CARCINOGENICITY