Normason

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMASON® (NORMASON)

Composition:

Active substance: zopiclone;

One tablet contains 7.5 mg of zopiclone calculated as 100 % substance;

Excipients: lactose monohydrate; potato starch; povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, flat cylindrical tablets with beveled edges and a score line.

Pharmacotherapeutic group.
Hypnotics and sedatives. ATC code N05CF01.

Pharmacological properties.

Pharmacodynamics.

Zopiclone belongs to the cyclopyrrolone group and is pharmacologically related to benzodiazepines. The pharmacodynamic effects of zopiclone are qualitatively similar to those of other compounds in this class: muscle relaxant, anxiolytic, sedative, hypnotic agent, anticonvulsant, and amnestic (causes memory impairment).

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

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 have shown that zopiclone reduces stage I sleep, increases stage II sleep, maintains or prolongs deep sleep stages (III and IV), and preserves paradoxical (REM) sleep.

Pharmacokinetics.

Absorption. Zopiclone is rapidly absorbed: peak plasma concentrations are reached within 1.5–2 hours and are 30, 60, and 1,15 ng/mL after administration of 3.75 mg, 7.5 mg, and 15 mg, respectively. Bioavailability is approximately 80%.

Absorption is not influenced by the timing of administration, repeated dosing, or patient gender.

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

Plasma concentration decline: between 3.75 mg and 15 mg, and this process 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 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 within 24 hours prior to breastfeeding.

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 has been 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 as 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 patient populations.

Elderly patients: although hepatic metabolism is somewhat reduced and the mean elimination half-life is 7 hours, studies have not shown accumulation of zopiclone in plasma after repeated dosing.

Patients with renal impairment: no accumulation of zopiclone or its metabolites has been observed during long-term treatment. Zopiclone crosses dialysis membranes. Hemodialysis is not effective in overdose management because zopiclone has a large volume of distribution.

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

Clinical Characteristics.

Indications.

Severe sleep disorders: situational and transient insomnia.

Contraindications.

The drug must never be administered to patients with:

• hypersensitivity to zopiclone or to any of the excipients of the medicinal product;
• severe 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).

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 produce additive central nervous system (CNS) depressant effects and reduce the patient's concentration ability. Impaired concentration ability may be hazardous when driving vehicles or operating machinery. Such substances include morphine derivatives (analgesics, antitussives, and opioid substitution 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.

Hypnotic agents. Currently prescribed hypnotics include either benzodiazepines and their derivatives (zolpidem, zopiclone) or H1-antihistamines. In addition to enhancing sedative effects, when co-administered with other CNS depressants or alcohol, potential potentiation of respiratory depression caused by benzodiazepines must be considered, especially when used concomitantly with morphine-like substances, other benzodiazepines, or phenobarbital, particularly in elderly patients.

Undesirable combination.

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

Patients should avoid consuming alcoholic beverages or taking medicinal products containing ethanol.

Sodium oxybate (gamma-hydroxybutyrate). Enhanced CNS depression. Impaired concentration ability may be hazardous when driving vehicles or operating machinery.

Combinations requiring precautions.

Rifampicin. Decreased plasma concentrations and reduced efficacy of zopiclone due to enhanced hepatic metabolism. Clinical monitoring of the patient is required. If necessary, an alternative hypnotic agent 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 hypnotic medicinal products. Enhanced CNS depression.

Other sedative medicinal products. Enhanced CNS depression.

Combinations to be considered.

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

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

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

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

Special precautions for use.

Warning. The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The 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.

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

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

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

Several factors may contribute to the development of dependence: duration of treatment, dose, history of dependence on drugs or other substances including alcohol, and presence of anxiety.

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

In rare cases, dependence on zopiclone has been observed with the 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 occurring very rarely: 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, nightmares, restlessness, hyperacusis, numbness, and tingling in the extremities.

Withdrawal symptoms may develop several days after discontinuation of treatment. With short-acting benzodiazepines, especially when used at high doses, withdrawal symptoms may occur between doses.

The risk of developing drug dependence may increase when multiple benzodiazepines are used simultaneously in the treatment of 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 all other sedative/hypnotic medicinal products, zopiclone causes CNS depressant effects. Psychomotor disturbances may occur several hours after taking the drug.

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

• administration of the 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 a dose higher than recommended;
• concomitant use with other CNS depressants, alcohol, illicit substances, or other medicinal products that increase zopiclone blood concentration (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, after taking zopiclone, especially within 12 hours after taking the drug.

Amnesia and impaired psychomotor function. Anterograde amnesia and impaired psychomotor function 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.

Symptoms that may develop include:

• worsening of insomnia, nightmares, 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 try to prevent the patient from doing what he or she wants;
• automatic behavior followed by amnesia.

The appearance of these symptoms requires 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 ability and concentration. The risk of these complications is higher in patients with cerebral disorders.

Some patients may experience daytime restlessness or anxiety.

Sleepwalking and related behavior. In patients receiving zopiclone treatment, episodes of complex behaviors such as driving while asleep (e.g., driving while the patient has taken a hypnotic-sedative drug and is not fully awake), followed by complete amnesia, have been observed. Although behavioral disturbances associated with sleepwalking may occur with zopiclone monotherapy at therapeutic doses, concomitant alcohol use and use 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 discontinue zopiclone, as this may be dangerous for the patients themselves and their surroundings (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

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

In elderly patients and patients 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.

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").

No accumulation of zopiclone was observed in patients with renal insufficiency during studies (see section "Pharmacokinetics").

Elderly patients. Caution should be exercised when treating elderly patients with benzodiazepines or related drugs due to the increased risk of behavioral disturbances and the risk of developing sedative and/or myorelaxant effects, which may lead to falls that often have serious consequences in this patient group.

Precautionary measures in use. Special caution is recommended when prescribing to patients with a history of alcoholism or other types of dependence on drugs or other substances (see section "Interaction with other medicinal products and other types of interactions").

Before prescribing a hypnotic, a comprehensive assessment is required in all cases of insomnia to identify and eliminate underlying causes.

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 indication and 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 used as monotherapy, as they do not treat depression, which may therefore continue to progress, accompanied by unchanged or increased suicide risk.

Since suicide risk may exist in such patients, the amount of zopiclone tablets available to them (prescribed and dispensed) should be minimized to reduce 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 occur due to withdrawal symptoms, even with gradual discontinuation.

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

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

Elderly patients – renal insufficiency. Although no accumulation of zopiclone was detected after long-term 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 the drug to patients with depression.

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

It is not recommended at the initial stage of psychosis treatment.

Use during pregnancy or breastfeeding.

Pregnancy. A large amount of data collected from cohort studies has not shown any evidence that the use of benzodiazepines during the first trimester of pregnancy leads to any congenital malformations. However, some case-control epidemiological studies have reported an increased incidence of cleft lip and palate associated with benzodiazepine use. According to these data, the incidence of cleft lip and palate was less than 2 per 1000 newborns exposed to benzodiazepines during intrauterine development, compared to an expected rate of 1 per 1000 in the general population.

Reduced fetal movements and changes in fetal heart rate have been reported with high-dose benzodiazepine use during the second and third trimesters of pregnancy. Use of benzodiazepines near the end of pregnancy, even at low doses, may cause effects of zopiclone on the newborn such as axial hypotonia and difficulty sucking, leading to poor weight gain. Although these effects are reversible, they may persist for 1–3 weeks depending on the elimination half-life of the prescribed benzodiazepine. Use of high doses of zopiclone may cause respiratory depression or apnea and hypothermia in the newborn. In addition, the newborn may develop a withdrawal syndrome, even in the absence of signs of zopiclone exposure. Characteristic symptoms include excessive excitability, psychomotor agitation, and tremor in the newborn, appearing some time after delivery. The time to onset of these symptoms depends on the drug's elimination half-life and may be substantial in the case of a long half-life.

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

Women of reproductive age receiving zopiclone treatment should be instructed to contact their physician if they plan to become pregnant or if they are in early pregnancy, so that their need for treatment can be reassessed.

If zopiclone treatment is absolutely necessary during pregnancy, high doses should be avoided shortly before the expected delivery date, and the above-described effects should be considered during newborn monitoring.

Lactation period.

During lactation, Normason should not be used.

Ability to affect reaction speed when driving or operating machinery.

Zopiclone may have a marked 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, reduced concentration, and impaired ability to drive, especially within the first 12 hours after taking zopiclone (see section "Adverse reactions"). To minimize this risk, an interval of at least 12 hours between taking zopiclone and driving, operating machinery, or working at heights is recommended.

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 use 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 medication should be taken immediately before bedtime.

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

Usual doses:

Adults under 65 years of age – 7.5 mg once daily;

Patients aged 65 years and older – 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 Normason must not exceed 7.5 mg.

Treatment duration.

Treatment should be as short-term as possible. The treatment course 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 for:

• transient insomnia – 2–5 days (e.g., during travel),
• short-term insomnia – 2–3 weeks (e.g., due to a significant life event).

In certain cases, an extension of the recommended treatment duration may be necessary. In such situations, the patient's condition should be re-evaluated thoroughly.

Children.

The use of zopiclone in children has not been studied; therefore, the medication is not recommended for this patient group.

Overdose.

Overdose may be life-threatening, especially in cases of concomitant overdose with multiple CNS depressants (including ethanol).

Following ingestion of a large amount of zopiclone, overdose primarily manifests as CNS depression, ranging from drowsiness to coma, depending on the ingested dose. Mild overdose is characterized by confusion and lethargy.

In more severe cases, ataxia, hypotonia, arterial hypotension, methemoglobinemia, respiratory depression, and occasionally death may occur. Concomitant medical conditions may act as additional risk factors that exacerbate overdose symptoms.

Treatment. If oral overdose occurred less than 1 hour ago, emesis may be induced in a conscious patient; otherwise, gastric lavage should be performed with airway protection. Administration of activated charcoal thereafter may help reduce drug absorption.

Close 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.

In cases of accidental or intentional benzodiazepine overdose, intravenous flumazenil may be useful for diagnosis and/or treatment.

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

Adverse Reactions

Adverse effects depend on the dose and individual patient sensitivity.

The most frequently observed adverse effect is a bitter taste in the mouth.

Neurological and psychiatric adverse effects (see section "Special Warnings and Precautions for Use"):

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

Cardiovascular system: palpitations.

Skin: skin rash and itching, which may be symptoms of hypersensitivity; sweating. If these reactions occur, the drug should be discontinued.

General disorders: muscle hypotonia, asthenia, chills, increased fatigue.

Immune system: urticaria, angioneurotic edema, anaphylactic reactions, Stevens–Johnson syndrome, toxic epidermal necrolysis/Lyell’s syndrome, erythema multiforme.

Eye disorders: diplopia, amblyopia.

Respiratory system: dyspnea, shortness of breath.

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

Laboratory findings: elevated levels of transaminases and/or alkaline phosphatase, which in isolated cases may lead to clinical signs of impaired liver function.

Metabolic disorders: weight loss.

Musculoskeletal system: heaviness in limbs.

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

Post-marketing surveillance: anger, behavioral disturbances associated with amnesia.

Withdrawal syndrome has been reported upon discontinuation of zopiclone (see section "Special Warnings and Precautions for Use"). Symptoms of withdrawal syndrome vary and include rebound insomnia, muscle pain, anxiety, tremor, increased sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, night terrors, irritability. In severe cases, symptoms may include derealization, depersonalization, hyperacusis, numbness and tingling in limbs, increased sensitivity to light, noise, and physical contact, hallucinations.

Seizures may occur very rarely.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via national reporting systems.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 1, 2, or 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

LLC "ASTRAFARM"

Manufacturer's address and location of business activity.

6 Kyivska St., Vyshneve, Buchanskyi district, Kyiv region, 08132, Ukraine