Zopiclone-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOPICLONE-ZN (ZOPICLONE-ZN)

Composition:

Active substance: zopiclone;

1 tablet contains zopiclone 7.5 mg;

Excipients: lactose monohydrate; corn starch; calcium hydrogen phosphate anhydrous; sodium starch glycolate (type A); magnesium stearate; hypromellose; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round cylindrical tablets with a convex surface and a score line on one side.

Pharmacotherapeutic group. Hypnotics and sedatives. ATC code N05CF01.

Pharmacological properties.

Pharmacodynamics.

Zopiclone belongs to the cyclopyrrolone group and is 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 (referred to 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 rapid eye movement (REM) sleep, or REM stage.

Pharmacokinetics.

Absorption. Zopiclone is rapidly absorbed: peak plasma concentrations are reached within 1.5–2 hours and are 30, 60, and 115 ng/mL following 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's sex.

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

Plasma concentration decline over the dose range of 3.75 mg to 15 mg is independent of dose. 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 breastfeeding, 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. The two main metabolites are 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.

Elimination. The low renal clearance of unchanged zopiclone (average 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 by the kidneys as free metabolites (N-oxide and N-desmethylated derivative), and about 16% is excreted in feces.

Special patient populations.

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 after repeated administration in numerous studies.

Patients with renal impairment: With long-term use of the drug, no accumulation of zopiclone or its metabolites has been observed. Zopiclone penetrates dialysis membranes. Hemodialysis is not considered appropriate for treating overdose, as zopiclone has a large volume of distribution.

Patients with hepatic cirrhosis: Plasma clearance of zopiclone is significantly reduced due to slowed demethylation; therefore, dose adjustment is required for these patients.

Clinical characteristics.

Indications.

Severe sleep disorders in adults: transient and short-term insomnia.

Contraindications.

The drug must never be administered to patients with:

• hypersensitivity to zopiclone or to any of the excipients of the medicinal product;
• respiratory insufficiency;
• sleep apnea syndrome;
• severe, acute or chronic hepatic insufficiency (due to the risk of encephalopathy);
• myasthenia gravis;
• allergy to wheat products (except for wheat intolerance in celiac disease).

Interaction with other medicinal products and other forms of interaction.

Sedative agents. It should be borne in mind that many medicinal products or substances may cause additive central nervous system (CNS) depressant effects and reduce the patient's concentration ability. Impaired concentration ability may pose a danger when driving vehicles or operating machinery. Such substances include morphine derivatives (analgesics, antitussives, and opioid replacement therapy agents), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (such as meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, centrally-acting antihypertensives, baclofen, and thalidomide.

Hypnotics. Currently, hypnotics prescribed include either benzodiazepines and their derivatives (zolpidem, zopiclone), or H1-antihistamines. In addition to enhancing the sedative effect when co-administered with other CNS depressants or when alcohol is consumed, possible potentiation of respiratory depression by benzodiazepines should be considered when they are prescribed together with morphine-like substances, other benzodiazepines, or phenobarbital, especially in elderly patients.

Undesirable combinations.

Alcohol (as a beverage or excipient) potentiates the sedative effect of benzodiazepines and related substances. Due to reduced concentration ability, driving vehicles and operating machinery may be hazardous.

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

Sodium oxybate (sodium hydroxybutyrate). Enhanced central nervous system depression. Impaired concentration ability may pose a danger when driving vehicles or operating machinery.

Combinations requiring precautions.

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

Barbiturates. Increased risk of respiratory depression, which may be fatal in case of overdose.

Morphine derivatives. Increased risk of respiratory depression, which may be fatal in case of overdose.

Other hypnotics. Enhanced central nervous system depression.

Other sedative agents. Enhanced central nervous system depression.

Combinations to be taken into account.

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

Opioid analgesics enhance euphoria, which may lead to increased psychological dependence.

Zopiclone is metabolized by the cytochrome P450 CYP3A4 isoenzyme; therefore, plasma levels of zopiclone may increase when co-administered with CYP3A4 inhibitors, and may decrease when co-administered with CYP3A4 inducers.

Buprenorphine. When buprenorphine is used as replacement therapy for opioid dependence, the risk of respiratory depression increases, potentially leading to 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 the sedative effects of zopiclone.

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

Nelfinavir, ritonavir-boosted protease inhibitor. Slight enhancement of the sedative effects of zopiclone.

Special precautions for use.

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

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

Development of tolerance. When benzodiazepines or related substances are used over several weeks, their sedative and hypnotic effects may gradually diminish despite the dose remaining unchanged.

In patients whose treatment with Zopiclone-ZN did not exceed 4 weeks, no significant development of tolerance to the drug was observed.

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

Several factors contribute to the development of dependence: duration of treatment, dose, history of dependence on medicinal products or other substances (including alcohol), and anxiety.

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

In rare cases, dependence on zopiclone has been observed during use of 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 also include tremor, palpitations, tachycardia, delirium, night terrors, irritability, hyperacusis, numbness, and tingling in the extremities.

Withdrawal symptoms may develop several days after discontinuation of treatment. When short-acting benzodiazepines are used, especially at high doses, withdrawal symptoms may even occur between 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 a worsening of the insomnia for which benzodiazepines or related drugs were initially prescribed.

Psychomotor disturbances. Like any other sedative/hypnotic agents, zopiclone causes central nervous system (CNS) depression. Psychomotor disturbances may occur several hours after drug intake.

The risk of psychomotor disturbances, including impaired ability to drive a vehicle, increases in the following situations:

• use of this medicinal product less than 12 hours before performing activities requiring concentration (see section "Ability to affect reaction speed when driving or operating machinery");
• use of doses higher than recommended;
• concomitant use with other CNS depressants, alcohol, illicit substances, or other medicinal products that increase zopiclone blood concentrations (see section "Interaction with other medicinal products and other types of interactions").

Patients should be advised to avoid hazardous activities requiring full attention or motor coordination, such as operating machinery or driving vehicles, after taking zopiclone, especially within 12 hours of taking the drug.

Amnesia and psychomotor impairment. Anterograde amnesia and psychomotor impairment may occur several hours after taking the tablet. To reduce the risk of these effects, the patient should take the tablet immediately before bedtime, i.e., while already in bed (see section "Method of administration and dosage"), 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.

The following symptoms may develop:

• worsening of insomnia, night terrors, agitation, nervousness;
• delirium, hallucinations, oneirophrenic state, confusion, psychosis-like symptoms;
• mental inhibition, mild excitability;
• euphoria, irritability;
• anterograde amnesia;
• suggestibility.

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

• abnormal behavior;
• autoaggression or aggression toward others, especially if family members or friends try to prevent the patient from doing what they wish;
• automatic behavior with subsequent 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 or anxiety.

Sleepwalking and related behaviors. 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, or making phone calls—actions of which they have no memory. Although behavioral disturbances associated with sleepwalking may occur with zopiclone monotherapy at therapeutic doses, concomitant alcohol use and intake of other CNS depressants increase the risk of such behavior, as does use of zopiclone at doses exceeding the maximum recommended dose.

Patients who develop sleepwalking-related disorders should be advised to discontinue zopiclone, as this may be dangerous for both the patients and those around them (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Accumulation risk. 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 those with impaired liver function, the elimination half-life may be significantly prolonged.

After repeated dosing, 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 is achieved.

Dosage adjustment may be necessary (see section "Method of administration and dosage").

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

Elderly patients. Caution is required when treating elderly patients with benzodiazepines or related drugs due to increased risk of behavioral disorders and risk of 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 types of dependence on medicinal products or other substances (see section "Interaction with other medicinal products and other types of interactions").

Before prescribing a hypnotic, a comprehensive evaluation should always be conducted to identify and address the underlying causes of insomnia.

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 defined based on the type of insomnia present (see section "Method of administration and dosage").

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 prescribed 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 should be clearly instructed on how to gradually discontinue treatment.

In addition to the need for 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 cessation.

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 intensive care) (see section "Adverse reactions").

Elderly patients with renal insufficiency. Although no accumulation of zopiclone was observed after prolonged use, this patient group should be prescribed half the usual recommended dose as a precautionary measure (see sections "Method of administration and dosage" and "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 should not be prescribed during the initial phase of psychosis treatment.

Use during pregnancy or breastfeeding.

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

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

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

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

Lactation period. Zopiclone is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Zopiclone may have a pronounced effect on the ability to drive vehicles and operate machinery.

Patients who drive vehicles or operate machinery should be warned that, as with any other hypnotic drugs, there is a risk of drowsiness, slowed reaction time, dizziness, lethargy, blurred or double vision, and reduced attention, along with impaired ability to drive, especially within the first 12 hours after taking zopiclone (see section "Adverse reactions"). To minimize this risk, it is recommended to maintain an interval of at least 12 hours between taking zopiclone and driving, operating machinery, or working at heights.

Impaired ability to drive and behavioral changes such as falling asleep at the wheel may occur with zopiclone monotherapy at therapeutic doses.

Furthermore, these effects are potentiated by concomitant alcohol intake or use of other CNS depressants (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions"). Patients must be warned not to consume alcohol or other psychoactive substances during zopiclone treatment.

Dosage and Administration

For oral use.

Dosing. Treatment should always be initiated at the lowest effective dose; the maximum dose must not be exceeded. The medicine should be taken in bed immediately before going to sleep and must not be repeated during the night.

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

Recommended doses:

• Adults under 65 years of age: 7.5 mg once daily.
• Patients aged over 65 years: 3.75 mg once daily; the 7.5 mg dose may be used only in exceptional cases.
• Patients with hepatic impairment or chronic respiratory insufficiency: the recommended dose is 3.75 mg once daily (see section "Pharmacokinetics").
• Patients with renal insufficiency: treatment should be initiated at a dose of 3.75 mg once daily (see section "Pharmacokinetics").

In all cases, the daily dose of Zopiclone-ZN must not exceed 7.5 mg.

Duration of treatment. Treatment should be as short as possible. The treatment course should not exceed 4 weeks, including the period of gradual discontinuation (see section "Special precautions for use").

Patients should be advised to take the medicine for:

• Situational insomnia – 2 to 5 days (e.g., during travel);
• Short-term insomnia – 2 to 3 weeks (e.g., caused by a significant life event).

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

Children. Safety and efficacy of zopiclone in children and adolescents under 18 years of age have not been established. Therefore, zopiclone is not recommended for use in this patient group.

Overdose

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

Symptoms. Following ingestion of a large amount of zopiclone, overdose primarily manifests as central nervous system depression, ranging from drowsiness to coma, depending on the dose ingested. Mild overdose may present with confusion or lethargy.

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

Treatment. If overdose occurred less than one hour ago, vomiting may be induced; otherwise, gastric lavage should be performed. Activated charcoal may then be administered to reduce drug absorption.

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

Hemodialysis is not considered effective in the treatment of 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 effects opposite to those of benzodiazepines and may therefore provoke neurological disturbances (agitation, restlessness, seizures, and emotional lability), particularly in patients with epilepsy.

Adverse Reactions

Adverse reactions are classified by frequency using the following system: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Side effects depend on dose and individual patient sensitivity.

Psychiatric disorders.

Uncommon: excitement, night terrors.

Rare: impaired consciousness, changes in libido, irritability, aggression, aggressive behavior, hallucinations.

Frequency not known: behavioral disturbances, delirium, rage attacks, nervousness, somnambulism (see section "Special precautions for use"), physical and psychological dependence on the drug, even at therapeutic doses, with withdrawal syndrome or "rebound" symptoms after discontinuation (see section "Special precautions for use"), confusion, insomnia, tension.

Psychotic-like symptoms, inappropriate behavior, and other behavioral disturbances may occur during treatment with benzodiazepines and their derivatives.

In rare cases, these symptoms may be severe.

Elderly patients and children are more susceptible to developing these symptoms.

Depression. Latent depression may become manifest during treatment with benzodiazepines and their derivatives.

Nervous system disorders.

Common: reduced reaction speed or even drowsiness (especially in elderly patients), dysgeusia.

Uncommon: feeling of weakness, headache.

Rare: anterograde amnesia, which may occur with therapeutic doses (risk increases proportionally with dose).

Frequency not known: ataxia, paresthesia, cognitive disorders such as memory, attention, and speech impairment.

Respiratory, thoracic and mediastinal disorders.

Rare: dyspnea.

Frequency not known: respiratory depression.

Skin and subcutaneous tissue disorders.

Rare: skin rash, pruritus, urticaria.

Musculoskeletal and connective tissue disorders.

Frequency not known: muscle hypotonia.

General disorders.

Uncommon: asthenia.

Immune system disorders.

Very rare: angioedema, anaphylactic reactions.

Eye disorders.

Frequency not known: diplopia.

Gastrointestinal disorders.

Common: dry mouth.

Uncommon: nausea.

Frequency not known: dyspepsia, vomiting.

Hepatobiliary disorders.

Very rare: increased blood levels of transaminases and/or alkaline phosphatase, which in exceptional cases may lead to clinical signs of impaired liver function.

Injury, poisoning and procedural complications.

Rare: falls (especially in elderly patients) (see section "Special precautions for use").

Shelf life. 5 years.

Storage conditions.
Store in original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. No. 10 (10x1), No. 20 (10x2), No. 30 (10x3) in blister packs in a carton.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovye Naroda".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kuilikivska Street, building 41.

(Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovye Naroda")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, building 100.

(Limited Liability Company "FARMEKS GROUP")