INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SОNOVAN (SONOVAN)

Composition:

Active substance: zopiclone;

1 tablet contains 7.5 mg of zopiclone;

Excipients: microcrystalline cellulose, anhydrous lactose, pregelatinized starch, calcium phosphate, sodium croscarmellose, magnesium stearate;

Film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, polysorbate 80, yellow azo dye FCF (E 110), brilliant blue FCF dye (E 133).

Dosage form. Film-coated tablets.

Main physicochemical properties: blue-colored, oval, biconvex film-coated tablets, with an imprint "7.5", a dividing line and "Z" on one side, smooth on the other side.

Pharmacotherapeutic group.

Hypnotics and sedatives. ATC code N05CF01.

Pharmacological Properties.

Pharmacodynamics.

Zopiclone belongs to the cyclopyrrolone group and is structurally related to the pharmaceutical class of benzodiazepines. The pharmacodynamic effects of zopiclone are qualitatively similar to those of other compounds in this class: it acts as a myorelaxant, anxiolytic, sedative, hypnotic agent, anticonvulsant, and amnestic (causing memory impairment).

These effects are due to its action as a specific agonist at receptors belonging to the GABA-omega macromolecular receptor complex in the central nervous system (known as BZ1 and BZ2), which modulate the opening of chloride ion channels.

In humans, zopiclone has been shown to prolong sleep duration, improve sleep quality, and reduce the frequency of nocturnal and early morning awakenings.

This effect is associated with distinct electroencephalographic characteristics that differ from those typical of benzodiazepines. Polysomnographic studies show that zopiclone reduces the duration of stage I sleep, increases the duration of stage II sleep, maintains or prolongs deep sleep stages (III and IV), and preserves paradoxical sleep, or rapid eye movement (REM) sleep.

Pharmacokinetics.

Absorption. Zopiclone is rapidly absorbed: peak plasma concentrations are reached within 1.5–2 hours and are 30, 60, and 115 ng/mL after administration of 3.75 mg, 7.5 mg, and 15 mg, respectively. Bioavailability is approximately 80%.

Absorption is not affected by the time of administration, multiple dosing, or patient gender.

Distribution. Zopiclone is very rapidly distributed from the vascular compartment. Plasma protein binding is low (approximately 45%) and non-saturable. The risk of drug interactions due to displacement at protein-binding sites is very low.

Plasma concentration decline over the dose range of 3.75 mg to 15 mg is dose-independent. The elimination half-life is approximately 5 hours.

Benzodiazepines and related compounds cross the blood-brain barrier and placenta and are excreted into breast milk. During lactation, the pharmacokinetic profiles of zopiclone in milk and maternal plasma are similar. The estimated percentage of the dose ingested by the infant does not exceed 0.2% of the dose received by the mother over 24 hours.

Metabolism. Zopiclone undergoes extensive hepatic metabolism. Two major metabolites are formed: N-oxide (pharmacologically active in animals) and N-desmethylated derivative (pharmacologically inactive in animals). Apparent elimination half-lives, determined in urinary excretion studies, are approximately 4.5 and 7.5 hours, respectively. This is consistent with the observation that no significant accumulation occurs after repeated dosing (15 mg) over 14 days. No increase in enzymatic activity was observed in animal studies, even with high-dose administration.

Excretion. The low renal clearance of unchanged zopiclone (mean 8.4 mL/min), compared to plasma clearance (232 mL/min), indicates that zopiclone is primarily eliminated in the form of metabolites. Approximately 80% of the substance is excreted renally as free metabolites (N-oxide and N-desmethylated derivative), and about 16% is excreted in feces.

Special-risk patient groups.

Elderly patients: although hepatic metabolism is somewhat reduced and the mean elimination half-life is 7 hours, no accumulation of zopiclone in plasma has been observed in extensive studies following repeated administration.

Patients with renal impairment: with long-term use, no accumulation of zopiclone or its metabolites has been observed. Zopiclone crosses dialysis membranes. However, hemodialysis is not effective in treating overdose due to the large volume of distribution of zopiclone.

Patients with liver cirrhosis: plasma clearance of zopiclone is significantly reduced due to impaired demethylation; therefore, dose adjustment is required for these patients.

Clinical characteristics.

Indications.

Severe sleep disorders: situational and temporary insomnia.

Contraindications.

The drug must never be administered to patients with:

hypersensitivity to zopiclone or to any of the excipients of the drug;
respiratory insufficiency;
sleep apnea syndrome;
severe, acute or chronic hepatic insufficiency (due to the risk of developing encephalopathy);
myasthenia gravis;
allergy to wheat products (except wheat intolerance in celiac disease);
congenital galactosemia;
glucose-galactose malabsorption syndrome or lactase deficiency (due to the presence of lactose in the drug).

Interaction with other medicinal products and other forms of interaction.

Undesirable combinations.

Alcohol potentiates the sedative effect of benzodiazepines and related substances. Due to reduced attention, driving vehicles and operating machinery may be dangerous.

Patients should avoid consuming alcoholic beverages or taking medications containing alcohol.

Combinations requiring precautions.

Rifampicin. Decreased plasma concentration and reduced efficacy of zopiclone due to enhanced hepatic metabolism; therefore, concomitant administration of zopiclone and rifampicin requires careful clinical monitoring. If necessary, another hypnotic agent may be prescribed.

Combinations to be taken into account.

Other agents that depress central nervous system activity: morphine derivatives (analgesics, antitussives, and drugs used in substitution therapy for opioid dependence, except buprenorphine), neuroleptics, barbiturates, anxiolytics, other hypnotics, sedative antidepressants, antiepileptic drugs, anesthetics, sedative H1-antihistamines, centrally-acting antihypertensive agents, baclofen, thalidomide, pizotifen. Enhanced CNS depression. Due to reduced attention, driving vehicles and operating machinery may be dangerous. Furthermore, concomitant use of zopiclone with morphine derivatives (analgesics, antitussives, and drugs used in substitution therapy for opioid dependence) and barbiturates increases the risk of respiratory depression, which may be fatal in case of overdose.

Narcotic analgesics enhance euphoria, potentially increasing psychological dependence.

Zopiclone is metabolized via the cytochrome P450 (CYP) 3A4 isoenzyme; therefore, concomitant use with CYP3A4 inhibitors may increase zopiclone plasma levels, while concomitant use with CYP3A4 inducers may decrease zopiclone plasma levels.

Buprenorphine. When used as substitution therapy for opioid dependence, the risk of respiratory depression increases, potentially resulting in a fatal outcome. The risk/benefit ratio of this combination must be carefully evaluated. Patients should be warned to strictly adhere to the doses prescribed by the physician.

Clozapine. Increased risk of collapse with respiratory arrest and/or cardiac arrest.

Clarithromycin, erythromycin, telithromycin. Slight enhancement of sedative effects of zopiclone.

Ketoconazole, itraconazole, voriconazole. Slight enhancement of sedative effects of zopiclone.

Nelfinavir, ritonavir. Slight enhancement of sedative effects of zopiclone.

Special precautions for use.

Warnings. This medicinal product contains lactose and therefore should not be used in patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product can be administered to patients with celiac disease. Wheat starch may contain gluten, but only in trace amounts, and is therefore considered safe for such patients.

Drug tolerance. When benzodiazepines or related substances are used for several weeks, their sedative and hypnotic effects may gradually decrease despite unchanged dosage.

In patients whose treatment with Sonovan did not exceed 4 weeks, no significant tolerance to the drug was observed.

Drug dependence. Treatment with benzodiazepines and related substances, especially prolonged use, may lead to physical and psychological dependence.

Several factors favor the development of dependence: duration of treatment, dosage, history of dependence on medicinal products or other substances including alcohol, and presence of anxiety.

Dependence may develop with therapeutic doses and/or in patients without specific risk factors.

In rare cases, dependence on zopiclone has been observed even with therapeutic doses.

After discontinuation of treatment, dependence may lead to withdrawal symptoms. Some of these symptoms occur frequently: insomnia, headache, excessive anxiety, myalgia, muscle tension, and irritability.

Other symptoms occur less frequently: agitation or even confusion, limb paresthesia, increased sensitivity to light, noise, and physical contact, depersonalization, derealization, hallucinations, and seizures.

Withdrawal symptoms may also include tremor, palpitations, tachycardia, delirium, night terrors, irritability, hyperacusis, numbness, and tingling in the limbs.

Withdrawal symptoms may develop several days after treatment discontinuation. With short-acting benzodiazepines, especially at high doses, withdrawal symptoms may even occur between two consecutive doses.

The risk of developing drug dependence may increase when multiple benzodiazepines are used simultaneously in treating anxiety disorders or sleep disturbances.

There have also been isolated reports of drug abuse.

Rebound insomnia. This transient rebound effect may manifest as worsening of insomnia for which benzodiazepines or related drugs were initially prescribed.

Amnesia and impaired psychomotor function. Within several hours after taking the tablet, anterograde amnesia and impaired psychomotor function may occur. To reduce the risk of these effects, patients should take the tablet immediately before bedtime, i.e., while already in bed (see section "Dosage and administration"), and ensure conditions are optimal for several hours of uninterrupted sleep (7–8 hours).

Behavioral disorders. In some patients, benzodiazepines and related substances may cause altered states of consciousness (of varying degrees) with memory and behavioral disturbances.

Symptoms that may develop include:

Worsening of insomnia, night terrors, agitation, nervousness;
Delirium, hallucinations, oneirophrenic state, confusion, psychosis-like symptoms;
Mental inhibition, mild excitability;
Euphoria, irritability;
Anterograde amnesia;
Suggestibility (susceptibility to suggestion).

These symptoms may be accompanied by disorders potentially harmful to the patient or others:

Abnormal behavior;
Self-aggression or aggression toward others, especially if family members or friends attempt to prevent the patient from doing what he or she desires;
Automatic behavior followed by amnesia.

The appearance of these symptoms requires immediate discontinuation of treatment.

Psychotic behavioral changes occur more frequently in patients with aggressive behavior and unusual reactions to sedatives, benzodiazepines, or alcohol consumption, and may also include depersonalization, restlessness, and anger.

The drug affects cognitive functions, specifically mental performance and attention concentration. The risk of these complications is higher in patients with cerebral disorders.

Some patients may experience daytime restlessness and anxiety.

Somnambulism and related behavior. In patients receiving zopiclone treatment, episodes of complex behaviors (when the patient takes a hypnotic-sedative drug and does not fully awaken) have been observed, such as: driving while asleep, preparing and eating food, making phone calls—actions of which the patient has no memory. Although behavioral disturbances associated with somnambulism may occur with zopiclone monotherapy at therapeutic doses, concomitant alcohol consumption and use of other central nervous system depressants increase the risk of such behavior, as does the use of zopiclone at doses exceeding the maximum recommended dose.

Patients who develop disorders related to somnambulism should discontinue zopiclone, as this may be dangerous for both the patients and their surroundings (see section "Interaction with other medicinal products and other forms of interaction" and section "Side effects").

Risk of drug accumulation. Benzodiazepines and related substances (like any other medicinal product) remain in the body for approximately 5 half-lives (see section "Pharmacokinetics").

In elderly patients and patients with impaired liver function, the half-life may be significantly prolonged.

After repeated doses, zopiclone or its metabolites reach steady state much later and at higher levels.

The efficacy and safety of the drug can only be evaluated once steady state has been achieved.

Dose adjustment may be necessary (see section "Dosage and administration").

During clinical studies in patients with renal impairment, no accumulation of zopiclone was observed (see section "Pharmacokinetics").

Elderly patients. Extreme caution should be exercised when treating elderly patients with benzodiazepines or related drugs due to increased risk of behavioral disorders and risk of developing sedative and/or myorelaxant effects, which may lead to falls—often with serious consequences for this patient group.

Precautions for use. Special caution is recommended when prescribing to patients with a history of alcoholism or other forms of dependence on medicinal products or other substances (see section "Interaction with other medicinal products and other forms of interaction").

Before prescribing a hypnotic, a comprehensive evaluation is required in all cases of insomnia, and underlying causes should be addressed.

Insomnia may be a symptom of a physical or mental disorder. If insomnia persists or worsens after a short treatment period, the clinical diagnosis should be re-evaluated.

Duration of treatment. The duration of treatment should be clearly determined based on the type of insomnia present (see section "Dosage and administration").

Depression – major depressive episode. Since insomnia may be a symptom of depression, depression should be treated. If insomnia persists, the clinical diagnosis should be re-evaluated.

In patients with a major depressive episode, benzodiazepines and related drugs should not be used as monotherapy, as they do not treat depression, which may continue to progress, accompanied by unchanged or increased suicide risk.

Since suicide risk may exist in such patients, the smallest possible number of zopiclone tablets should be made available to minimize the risk of intentional overdose.

Gradual dose reduction. Patients must be clearly informed about how to gradually discontinue treatment.

In addition to the necessity of gradual dose reduction, patients should also be warned about the risk of rebound insomnia to minimize the development of any insomnia that may arise due to withdrawal symptoms—even with gradual discontinuation.

Patients should be informed about possible discomfort during the period of gradual treatment discontinuation.

Respiratory insufficiency. When prescribing benzodiazepines and related drugs to patients with respiratory insufficiency, one must remember their depressant effect on the respiratory center (especially since anxiety and restlessness may be warning signs of respiratory decompensation requiring transfer to an intensive care unit).

Elderly patients with renal insufficiency. Although no accumulation of zopiclone was detected after prolonged use, this patient group should be prescribed half the usual recommended dose as a precautionary measure (see section "Dosage and administration" and section "Special precautions for use").

Caution should be exercised when prescribing to patients with depression.

The drug is not recommended for patients with severe hepatic insufficiency and encephalopathy.

The drug is not recommended at the initial stage of psychosis treatment.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have shown no teratogenic effect of zopiclone. Clinical data on the effect of this medicinal product on the mother and fetus during pregnancy are currently insufficient. By analogy with related products (benzodiazepines):

Decreased fetal motor activity and changes in fetal heart rate may occur with high-dose zopiclone administration during the second and/or third trimester of pregnancy;
When benzodiazepines are used near the end of pregnancy, even at low doses, signs of drug absorption have been observed in newborns, such as axial hypotonia and impaired sucking, and consequently, poor weight gain. These signs are reversible but may persist from 1 to 3 weeks, depending on the half-life of the administered benzodiazepine. With high-dose administration, reversible respiratory depression or apnea and hypothermia may occur in newborns. In addition, newborns may develop a withdrawal syndrome, even in the absence of signs of drug absorption. This syndrome is characterized, in particular, by excessive excitability, psychomotor agitation, and tremor in newborns, appearing some time after birth. The timing of symptom onset depends on the drug's half-life and may prolong the elimination half-life.

Given these data, the use of zopiclone during pregnancy, regardless of the trimester, is not recommended.

If treatment with zopiclone becomes necessary during pregnancy, high doses should be avoided, and the above-mentioned effects should be considered, with careful monitoring of the newborn.

Breastfeeding period. Zopiclone is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving vehicles and operating machinery.

Patients who drive vehicles or operate machinery should be warned about the risk of drowsiness.

Concomitant use of zopiclone with other sedatives is not recommended and should be taken into account when driving or operating machinery (see section "Interaction with other medicinal products and other forms of interaction").

The risk of impaired attention is further increased if sleep duration is insufficient.

Method of Administration and Dosage

For oral use.

Dosing. Treatment should always be initiated at the lowest effective dose; the maximum dose must not be exceeded. The medication should be taken in bed immediately before going to sleep!

The 3.75 mg dose is specifically intended for elderly patients aged 65 years and older, as well as individuals belonging to high-risk groups.

Recommended doses:

Adults under 65 years of age: 7.5 mg per day;
Patients aged 65 years and older: 3.75 mg per day; the 7.5 mg dose may be used only in exceptional cases;
Patients with impaired liver function or chronic respiratory insufficiency: the recommended dose is 3.75 mg per day (see section "Pharmacokinetics");
Patients with renal insufficiency: treatment should be initiated at a dose of 3.75 mg per day (see section "Pharmacokinetics").

In all cases, the daily dose of Sonovan must not exceed 7.5 mg.

Treatment duration. Treatment should be as short-term as possible. The duration of treatment should not exceed 4 weeks, including the period of gradual discontinuation (see section "Special Warnings and Precautions for Use").

Patients should be advised to take the medication:

In cases of situational insomnia – for 2–5 days (e.g., during travel);
In cases of transient insomnia – for 2–3 weeks (e.g., caused by a significant life event).

Occasionally, it may be necessary to extend the recommended treatment period. In such cases, the patient's condition should be carefully re-evaluated.

Children. The use of Sonovan in children has not been studied and therefore is not recommended for this patient group.

Overdose.

Overdose may be life-threatening, especially in cases of concomitant overdose with other central nervous system depressants (including alcohol).

Symptoms. Ingestion of large amounts of zopiclone leads primarily to central nervous system depression, ranging from drowsiness to coma, depending on the dose ingested. Mild overdose may present with symptoms of confusion or lethargy.

In more severe cases, ataxia, muscle hypotonia, arterial hypotension, methemoglobinemia, respiratory depression, and occasionally fatal outcomes have been observed. Other risk factors that may exacerbate overdose symptoms include underlying medical conditions.

Treatment. If oral overdose occurred less than 1 hour ago, emesis may be induced; otherwise, gastric lavage should be performed. Administration of activated charcoal afterward may help reduce drug absorption.

Careful monitoring of cardiac and respiratory functions in a specialized unit is recommended.

Hemodialysis is not considered appropriate for treating overdose, as zopiclone has a large volume of distribution.

Flumazenil may be useful in the diagnosis and/or treatment of accidental or intentional benzodiazepine overdose.

Flumazenil has an antagonistic effect to benzodiazepines and may therefore provoke neurological disturbances (agitation, restlessness, seizures, and emotional lability), particularly in patients with epilepsy.

Side effects

Side effects depend on the dose and individual patient sensitivity.

The most commonly observed side effect is a bitter taste in the mouth.

Neurological and psychiatric side effects (see section "Special precautions for use"):

anterograde amnesia, which may occur with therapeutic doses (risk increases proportionally with dose);
behavioral disturbances, altered consciousness, irritability, delirium, aggression, restless behavior, somnambulism (see section "Special precautions for use");
physical and psychological dependence, even when therapeutic doses are used, with withdrawal symptoms or rebound insomnia after discontinuation of treatment (see section "Special precautions for use");
feelings of intoxication, headache, euphoria, tremor, paresthesia, speech disorders, muscle spasms, dizziness, coordination disturbances, depressive mood; ataxia in rare cases;
confusion, hallucinations, reduced attention, or even drowsiness (especially in elderly patients), insomnia, night terrors, agitation, tension;
changes in libido.

Cardiovascular system: palpitations.

Skin: skin rash, itching, which may be symptoms of hypersensitivity, sweating, Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell's syndrome, erythema multiforme. The drug must be discontinued if such symptoms occur.

Systemic effects: muscle hypotonia, asthenia, chills, increased fatigue, sweating.

Immune system: urticaria, angioedema, anaphylactic reactions.

Eyes: diplopia, amblyopia.

Respiratory system: dyspnea, shortness of breath.

Gastrointestinal tract: gastrointestinal disturbances: coated tongue, unpleasant breath odor, dyspepsia, nausea, dry mouth, vomiting, diarrhea, constipation, anorexia, or increased appetite.

Laboratory test abnormalities: very rare – increased levels of transaminases and/or alkaline phosphatase, which in isolated cases may lead to clinical signs of impaired liver function.

Metabolism: weight loss.

Musculoskeletal system: heaviness in limbs, muscle weakness.

In elderly patients, palpitations, vomiting, anorexia, sialorrhea, excitement, restlessness, and tremor occur more frequently.

Post-marketing studies: anger, amnesia-related behavioral disturbances.

Withdrawal syndrome has been reported upon discontinuation of Sonovan (see section "Special precautions for use"). Withdrawal syndrome symptoms are variable and include rebound insomnia, muscle pain, anxiety, tremor, increased sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, night terrors, irritability. In severe cases, symptoms such as derealization, depersonalization, hyperacusis, numbness and tingling in the extremities, increased sensitivity to light, noise and physical contact, hallucinations may occur.

Seizures may occur very rarely.

Shelf life. 5 years.

Storage conditions.

Store in a dry, protected from light and inaccessible to children place at a temperature not exceeding 30 °C.

Packaging.

10 tablets per blister pack, 1 or 2 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Pharmascience Inc.

Manufacturer's address and place of business.

6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada /
6111 Royalmount Avenue 100, Montreal, Quebec H4P 2T4 Canada.