Clonazepam ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLOPANEZEPAM IC (CLONAZEPAM IC)

Composition:

Active substance: clonazepam;

One tablet contains 0.5 mg or 1 mg or 2 mg of clonazepam;

Excipients: lactose monohydrate, potato starch, calcium stearate, gelatin, colorants (tartrazine (E 110) – for the 0.5 mg dosage; purple [ponceau 4R (E 124), indigo carmine (E 132)] – for the 1 mg dosage).

Pharmaceutical form. Tablets.

Main physicochemical characteristics: tablets of pale orange color (0.5 mg dosage), pale violet color (1 mg dosage), white color (2 mg dosage), flat cylindrical shape with bevelled edges. The company trademark is printed on one side of the tablet, and a dividing line on the other side.

Pharmacotherapeutic group.

Antiepileptic agents. Benzodiazepine derivatives. Clonazepam. ATC code N03A E01.

Pharmacological Properties

Pharmacodynamics

Clonazepam belongs to the group of benzodiazepine derivatives. The mechanism of action of clonazepam is closely related to the inhibitory endogenous neurotransmitter gamma-aminobutyric acid (GABA) and its receptors, through which it mediates most of its effects in the nervous system—GABA-A receptors. Like all benzodiazepines, clonazepam enhances the inhibitory effect of GABAergic neurons in the cerebral cortex, hippocampus, cerebellum, brainstem, and other structures of the central nervous system (CNS).

The clinical effect of the drug is characterized by strong and prolonged anticonvulsant activity; the drug also exerts anxiolytic, calming, sedative, mild hypnotic, and moderate muscle relaxant effects.

Animal studies and electroencephalographic (EEG) studies in humans have shown that clonazepam rapidly suppresses paroxysmal activity of various types, including spike-wave complexes in absence seizures (petit mal), slow and generalized spike-wave complexes, temporal spikes and those from other locations, as well as irregular spikes and waves.

Generalized EEG abnormalities are suppressed more effectively by clonazepam than focal abnormalities such as focal spikes. Clonazepam has a beneficial effect on both generalized and focal forms of epilepsy.

Pharmacokinetics

Absorption

After oral administration, clonazepam is rapidly and completely absorbed from the gastrointestinal tract. The oral bioavailability is 90%. After a single oral dose of 2 mg clonazepam, maximum serum concentration is reached within 1–4 hours, and in some cases within 4–8 hours. Steady-state blood concentration is achieved within 4–6 days.

Routine monitoring of plasma clonazepam concentrations is not considered necessary, as they do not correlate sufficiently with therapeutic or adverse effects.

Distribution

Due to its high lipid solubility, clonazepam rapidly distributes into tissues. Clonazepam crosses the placental and blood-brain barriers and is excreted into breast milk.

Metabolism

The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group in the liver, resulting in the formation of 7-amino or 7-acetylamino derivatives, along with a small amount of 3-hydroxy metabolites of all three compounds, as well as their glucuronic and sulfate conjugates. The nitro derivatives are pharmacologically active, whereas the amino derivatives are not.

Elimination

The elimination half-life ranges from 20 to 60 hours (on average, 30 hours).

Within 4–10 days, 50–70% of the total radioactivity of orally administered radiolabeled clonazepam is excreted in urine, and 10–30% is eliminated in feces, almost entirely as free or conjugated metabolites. Less than 0.5% of unchanged clonazepam is found in urine.

Pharmacokinetic data in specific clinical situations

According to pharmacokinetic data, dose adjustment is not required in patients with impaired renal function.

Clinical characteristics.

Indications.

Epilepsy in infants, preschool and school-age children (mainly typical and atypical absence seizures and primary or secondary generalized tonic-clonic seizures).

Epilepsy in adults (mainly focal seizures).

Paroxysmal anxiety syndrome, anxiety states in phobias, e.g. agoraphobia (not to be prescribed to children).

Psychomotor agitation associated with reactive psychoses.

Contraindications.

Hypersensitivity to benzodiazepine derivatives or to any other components of the medicinal product. Central origin respiratory disorders and severe states of respiratory insufficiency regardless of cause; sleep apnea syndrome, closed-angle glaucoma, impaired consciousness, myasthenia gravis, severe hepatic or renal insufficiency, acute porphyria, alcohol intoxication, alcohol abuse, drug or narcotic dependence.

Interaction with other medicinal products and other forms of interactions.

The CNS depressant effect of clonazepam is enhanced by all medicinal products with similar action, such as barbiturates, centrally acting antihypertensives, antipsychotics, tricyclic antidepressants and related antidepressants, anticonvulsants, opioid analgesics, and ethanol.

A significant sedative and hypotensive effect occurs when clonazepam is used concomitantly with α-blockers or moxonidine. A significant hypotensive effect occurs when clonazepam is used with angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-II receptor antagonists, adrenergic neuron blockers, β-blockers, clonidine, methyldopa, calcium channel blockers, diazoxide, hydralazine, minoxidil, diuretics, nitrates, or sodium nitroprusside.

When used in combination with other antiepileptic medicinal products, toxicity as well as signs and symptoms of CNS depression, particularly sedation and apathy, may be more pronounced, especially when used concomitantly with hydantoins or phenobarbital. This requires particular caution in selecting an adequate dose during the initial stages of treatment. The combination of clonazepam and sodium valproate may rarely lead to the development of absence status epilepticus. Although some patients tolerate this combination well and benefit from it, the potential danger should be kept in mind.

Alcohol may alter the effect of clonazepam, reduce therapeutic efficacy, or lead to the development of unpredictable adverse effects. Alcohol consumption during clonazepam treatment enhances the CNS depressant effect of clonazepam and may provoke paradoxical reactions such as epileptic seizures, psychomotor agitation, aggressive behavior, or pathological intoxication. Pathological intoxication does not depend on the type or amount of alcohol consumed; sometimes even a small dose is sufficient. Under no circumstances should alcohol be consumed during clonazepam treatment. In addition, alcohol enhances the sedative effect of clonazepam, which may lead to impaired motor coordination and loss of consciousness.

The sedative effect is enhanced when clonazepam is used concomitantly with general anesthetics, antihistamines (to a lesser extent for antihistamines lacking sedative effects, and generally not for antihistamines intended for topical use), baclofen, lofexidine, mirtazapine, nabilone, and tizanidine.

Concomitant use of sedatives such as benzodiazepines or medicinal products with benzodiazepine-like action increases the risk of sedation, respiratory depression, coma, and fatal outcome due to enhanced CNS depression (see section "Special precautions").

Concomitant use of clonazepam with muscle relaxants prolongs and enhances their effect.

Concomitant use with the class III antiarrhythmic agent amiodarone may enhance the toxicity of clonazepam (including CNS depression, impaired motor coordination).

Clonazepam may act as an antagonist to the effects of levodopa.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and fluoxetine do not affect the pharmacokinetics of clonazepam when used concomitantly.

Hepatic enzyme inducers increase the clearance of benzodiazepines.

Antiepileptic agents such as phenytoin, phenobarbital, carbamazepine, and valproate may increase the clearance of clonazepam, leading to decreased plasma concentrations of clonazepam and reduced intensity of its pharmacological effects. Plasma concentrations of clonazepam are often reduced when used concomitantly with primidone and possibly theophylline.

Rifampicin may accelerate the metabolism of clonazepam.

Tobacco smoking reduces the effect of the medicinal product.

Hepatic enzyme inhibitors reduce the clearance of benzodiazepines and may enhance their effects.

There is a risk of prolonged sedation and respiratory depression when clonazepam is used concomitantly with amprenavir.

Cimetidine, disulfiram, fluvoxamine, ritonavir, erythromycin, and ketoconazole inhibit the metabolism of clonazepam, thereby increasing its plasma concentration, which leads to enhanced CNS depressant effects of clonazepam.

Clonazepam does not induce the activity of enzymes involved in its metabolism.

Concomitant use of clonazepam with phenytoin or primidone may alter plasma concentrations of phenytoin or primidone (usually increasing them).

Special precautions for use.

Before initiating treatment with clonazepam, a careful benefit/risk assessment should be performed. Clonazepam must be used strictly under medical supervision.

Suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. Therefore, patients should be monitored for signs of suicidal ideation and behavior. Patients with a history of depression and/or suicide attempts must be under close surveillance.

Careful individual dose titration is required in patients with pre-existing liver or respiratory diseases (e.g., chronic obstructive pulmonary disease) and in patients receiving treatment with other centrally acting agents or anticonvulsant (antiepileptic) drugs (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of clonazepam with CNS depressants should be avoided due to the potential for enhanced clinical effects of clonazepam, including pronounced sedation, clinically significant respiratory depression, and/or cardiovascular depression (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory effects may be enhanced in the presence of existing airway obstruction or brain damage, or when other respiratory depressant drugs are used. Generally, this effect can be avoided by careful individual dose titration.

Like all drugs of this type, clonazepam may alter patient reactions depending on dose, route of administration, and individual sensitivity (see section "Effect on ability to drive and use machines"). Generally, patients with epilepsy are not permitted to drive motor vehicles. Even with adequate seizure control during clonazepam treatment, it should be remembered that any dose increase or change in dosing intervals may alter patient reactions depending on individual sensitivity.

Prolonged use of benzodiazepines may lead to dependence with withdrawal symptoms upon discontinuation. As with other antiepileptic drugs, clonazepam treatment should be discontinued gradually due to the risk of precipitating status epilepticus. Similar caution should be exercised when discontinuing other medicinal products while the patient continues clonazepam therapy.

Dependence

Use of clonazepam may lead to physical and psychological dependence (see section "Adverse reactions"). In particular, long-term therapy or high-dose treatment may result in reversible disorders such as dysarthria, impaired coordination of movement and gait (ataxia), nystagmus, and double vision (diplopia). Additionally, the risk of anterograde amnesia, which may occur with benzodiazepines at therapeutic doses, increases with higher doses. Amnestic effects may be associated with inappropriate behavior. In some forms of epilepsy, seizure frequency may increase during prolonged treatment (see section "Adverse reactions"). The risk of dependence increases with higher doses and longer duration of treatment; it is also higher in patients with a history of alcohol and/or drug dependence.

In cases of physical dependence, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. Withdrawal symptoms may develop after very long-term use of clonazepam, especially at high doses, or after rapid reduction of the daily dose or abrupt discontinuation of therapy. Withdrawal symptoms include tremor, increased sweating, agitation, sleep disturbances, anxiety, headache, muscle pain, severe anxiety attacks, tension, restlessness, confusion, irritability, and epileptic seizures, which may be related to the underlying disease. In severe cases, the following symptoms may occur: derealization, depersonalization, hallucinations, hyperacusis, numbness and tingling in the extremities, seizures, increased sensitivity to light and noise, and tactile hypersensitivity. Since the risk of withdrawal syndrome is greater after abrupt discontinuation, this should be avoided. Discontinuation (even for a short period) should be achieved by gradual reduction of the daily dose. The risk of withdrawal symptoms increases when benzodiazepines are used concomitantly with daytime sedative drugs (cross-tolerance).

Tolerance

Prolonged use of clonazepam may reduce its therapeutic effect.

Risks associated with concomitant use of opioids and sedative medicinal products such as benzodiazepines or drugs with benzodiazepine-like activity

Concomitant use of clonazepam and opioids may result in sedation, respiratory depression, coma, and death. Concomitant use of clonazepam with opioids or sedative medicinal products such as benzodiazepines or drugs with benzodiazepine-like activity should be considered only if no alternative treatment option is available. When clonazepam is prescribed together with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, patients and caregivers should be informed about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Anterograde amnesia

Clonazepam may cause anterograde amnesia. This condition usually occurs several hours after taking clonazepam, particularly at high doses.

Paradoxical reactions

Clonazepam may cause paradoxical reactions including restlessness, excitement, irritability, aggression, hostility, nightmares, sleepwalking, worsening of insomnia, hallucinations, psychoses, and personality disorders. These reactions are most commonly observed in elderly patients and patients with alcohol dependence. If such symptoms occur, clonazepam should be discontinued.

Depression

Clonazepam should be used with caution in patients with symptoms of endogenous depression, as such patients may exhibit suicidal behavior. Due to the risk of intentional overdose, these patients should receive the lowest effective dose of clonazepam.

Benzodiazepines and drugs with benzodiazepine-like activity should not be used as monotherapy for depression or anxiety associated with depression. Monotherapy with these drugs increases the risk of suicidal behavior.

Special patient groups

Clonazepam should be used with caution in patients with impaired liver or kidney function (see section "Contraindications"), in debilitated patients, particularly those with impaired balance and reduced mobility, due to increased risk of falls and fractures. In such cases, the dose of clonazepam is generally reduced.

Benzodiazepines are not recommended in patients with severe hepatic insufficiency, as they may accelerate the development of hepatic encephalopathy. Hepatic insufficiency may lead to enhanced adverse effects of benzodiazepines.

Clonazepam should be used with caution in patients with chronic respiratory insufficiency (see section "Contraindications"), as benzodiazepines may depress the respiratory center.

Clonazepam may cause increased salivation and bronchial secretion, especially in infants and young children. Airway patency should be monitored during treatment.

Clonazepam should be used with particular caution in patients with cerebellar or spinal ataxia.

Clonazepam should be used cautiously in patients with glaucoma (see section "Contraindications", closed-angle glaucoma).

Clonazepam is considered unlikely to have porphyrinogenic activity, although some conflicting data exist. Clonazepam in patients with porphyria may provoke seizures (see section "Contraindications").

Benzodiazepines should be used with caution in patients with a history of alcohol, drug, or substance dependence. These patients should be closely monitored during clonazepam treatment due to the risk of developing clonazepam dependence.

Reduced doses of clonazepam should be prescribed to elderly patients (see section "Dosage and administration") due to the severity of adverse reactions that may occur in this age group, primarily due to the risk of disorientation and impaired coordination, which may lead to falls and injuries.

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

During prolonged clonazepam therapy, liver function and peripheral blood picture should be monitored.

Tablets with strengths of 0.5 mg and 1 mg contain colorants (Yellow FCF (E 110) and Ponceau 4R (E 124), respectively), which may cause allergic reactions.

Alcohol consumption is prohibited during treatment and for 3 days after discontinuation of clonazepam.

Use during pregnancy or breastfeeding.

Animal studies with clonazepam have shown reproductive toxicity. Preclinical data indicate a teratogenic effect of clonazepam. In preclinical studies in mice, at least a two-fold increase in the frequency of teratogenic congenital malformations was observed compared to controls at doses 3-, 9-, and 18-fold higher than the therapeutic doses for humans.

Pregnancy

Clonazepam exerts harmful pharmacological effects on pregnancy and on the fetus/newborn.

Clonazepam should not be used during pregnancy. Use of clonazepam in pregnant women, especially during the first and third trimesters, may be considered only if such treatment is absolutely necessary and the use of a safer alternative drug is impossible or contraindicated. Clonazepam should be prescribed to pregnant women only if the potential benefit outweighs the risk to the fetus.

High-dose use in the last trimester of pregnancy or during labor may cause fetal arrhythmia and hypothermia, arterial hypotension, moderate respiratory depression, and weak sucking reflex in the newborn. In infants whose mothers have taken benzodiazepines for a prolonged period during late pregnancy, physical dependence may develop, and there is a risk of withdrawal syndrome after birth.

It should be noted that both pregnancy itself and abrupt discontinuation of therapy may exacerbate epilepsy.

Women of childbearing potential should be informed of the need to seek medical advice if they plan to become pregnant or suspect they are pregnant.

Period of breastfeeding

Clonazepam passes into breast milk and therefore should not be used in breastfeeding mothers. If clonazepam use is necessary, breastfeeding should be discontinued.

Effect on ability to drive and use machines.

Patients with epilepsy should avoid driving vehicles or operating machinery. Even with adequate seizure control during clonazepam treatment, dose increases or changes in dosing intervals may alter patient reactions depending on individual sensitivity. Clonazepam may slow reaction time to such an extent that the ability to drive vehicles or operate machinery is impaired.

Driving vehicles or operating machinery and other hazardous activities should be avoided during clonazepam treatment and for 3 days after its discontinuation.

Method of Administration and Dosage.

The medicinal product should be taken orally, without chewing, and washed down with a small amount of liquid. The dosage and duration of therapy should be determined individually for each patient, taking into account the nature, severity, and specific features of the disease course, stability of the achieved therapeutic effect, and the patient's tolerance to the medicinal product. Treatment should be initiated with the lowest effective dose, gradually increasing it until the desired therapeutic effect is achieved. If it is not possible to divide the daily dose evenly among administrations throughout the day, the highest dose should be taken at bedtime. Discontinuation of therapy should be performed gradually, with a slow reduction of the daily dose.

In Epilepsy

Adults

The initial dose is 1 mg/day, divided into 3 equal doses administered at regular intervals. The dose should be gradually increased by 0.5–1 mg every 3 days until the optimal effect is achieved.

The maintenance dose is individually adjusted for each patient depending on the therapeutic response (usually 4–8 mg/day in 3–4 divided doses) and is typically reached within 2–4 weeks. The maximum daily dose is 20 mg.

Elderly Patients

Elderly patients are particularly sensitive to the effects of central nervous system depressants; therefore, therapy should be initiated with a daily dose not exceeding 0.5 mg.

Children

The initial dose for infants and children aged 1 to 5 years is 0.25 mg/day; for children aged 6 years and older – 0.5 mg/day. The dose may be gradually increased every 3 days until a satisfactory therapeutic effect is achieved.

Maintenance daily dose:

• for infants under 1 year of age – 0.5–1 mg,
• for children aged 1 to 5 years – 1–3 mg,
• for children aged 6 to 12 years – 3–6 mg.

The maximum daily dose for children is 0.2 mg/kg body weight. The daily dose should be divided into 3–4 doses administered at regular intervals.

Temporary Discontinuation

In certain forms of childhood epilepsy, a reduction in the therapeutic effect of clonazepam may be observed in some patients. An adequate therapeutic response may be restored either by increasing the dose or by temporarily discontinuing clonazepam therapy for a period of 2 to 3 weeks. During this time, careful monitoring of the patient's condition is required, and alternative pharmacological therapy may be advisable.

For children under 3 years of age, the required number of tablets should be crushed into a fine powder, dissolved in a small amount of water, and administered as a suspension.

Patients with Impaired Renal and/or Hepatic Function

Caution is required when administering clonazepam to patients with impaired renal and/or hepatic function. Dose reduction may be necessary (see section "Pharmacological Properties").

In Paroxysmal Anxiety Syndrome

For adults, the initial dose is 0.5 mg/day, divided into 2 doses. The average dose is 1 mg/day. To reduce daytime drowsiness, the medicinal product may be taken once daily at bedtime. The maximum daily dose is 4 mg.

The safety and efficacy of clonazepam in children with paroxysmal anxiety syndrome have not been established.

Children.

The medicinal product may be used in pediatric practice. For children under 3 years of age, the required number of tablets should be crushed into a fine powder, dissolved in a small amount of water, and administered as a suspension.

The medicinal product is not indicated for children in the treatment of paroxysmal anxiety syndrome or anxiety states associated with phobias (e.g., agoraphobia).

Overdose.

As with other benzodiazepines, clonazepam overdose is generally not life-threatening. Patients who have ingested doses exceeding 60 mg have recovered without specific treatment. Symptoms of overdose include profound drowsiness and muscle hypotonia.

Symptoms

Symptoms of overdose or intoxication vary significantly depending on the patient's age, body weight, and individual response.

The most common symptoms are drowsiness, ataxia, dysarthria, and nystagmus. Other symptoms of clonazepam overdose include confusion, and in severe cases – loss of consciousness and coma. Coma, arterial hypotension, and respiratory depression may occur but are not life-threatening when benzodiazepines are taken alone. Coma usually lasts only a few hours, but in elderly patients it may be prolonged and cyclic. Respiratory depression caused by benzodiazepines is more serious in patients with severe chronic obstructive pulmonary disease.

Poisoning due to simultaneous intake of clonazepam with alcohol or other central nervous system depressants may be life-threatening.

Treatment

Management of clonazepam overdose involves rapid elimination of unabsorbed drug from the body or reduction of its gastrointestinal absorption.

Emergency Treatment Measures:

1. Maintain airway patency and ensure adequate ventilation, if necessary.
2. The benefit of gastric decontamination is uncertain. Activated charcoal (50 g for adults, 10–15 g for children) should be considered within 1 hour after ingestion of more than 0.4 mg/kg, provided the patient is not excessively drowsy.
3. Further absorption should be prevented using appropriate methods, such as administration of activated charcoal within 1–2 hours after overdose. When administering activated charcoal, airway patency must be ensured, especially in drowsy patients.
4. Gastric lavage is not routinely recommended if clonazepam alone was ingested. However, it may be considered in cases of mixed drug overdose.
5. If no symptoms of overdose develop within 4 hours after clonazepam ingestion, subsequent development of symptoms is unlikely.
6. Supportive measures should be based on the patient's clinical condition. Symptomatic treatment of cardiovascular, respiratory, or central nervous system effects may be required. Airway patency, heart rate, and blood pressure should be monitored, and appropriate symptomatic treatment applied as needed.
7. Flumazenil, a benzodiazepine receptor antagonist, may be beneficial but is rarely necessary. It has a short elimination half-life (approximately 1 hour). Flumazenil should be considered in cases of severe central nervous system depression. Close monitoring of the patient is required during and after flumazenil administration. Flumazenil should be used with extreme caution in patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants). Flumazenil is contraindicated in mixed drug overdose and should not be used as a diagnostic test.

Warning

Flumazenil is not recommended for patients with epilepsy who are receiving long-term benzodiazepine therapy. Although flumazenil has minimal direct anticonvulsant activity, sudden reversal of the protective effect of benzodiazepine agonists may precipitate seizures in epileptic patients.

Barbiturates should not be used in the presence of agitation.

Adverse Reactions

Adverse reactions associated with the use of clonazepam are classified by organ systems and frequency. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

The frequency and severity of adverse effects depend on individual patient sensitivity and dosage.

Serious adverse reactions, which lead to discontinuation of the drug, occur rarely.

Adverse effects marked with an asterisk (*) are usually transient and resolve spontaneously during treatment or upon dose reduction. They typically occur at the beginning of therapy; their intensity can be significantly reduced or avoided by starting treatment with low doses and gradually increasing them.

List of adverse reactions

Psychiatric disorders and paradoxical reactions

Anterograde amnesia may occur during treatment with benzodiazepines at therapeutic doses; the risk increases with higher doses. Amnestic effects may be associated with inappropriate behavior.

Depression may be caused by the treatment itself or may represent a symptom of the underlying disease. Signs and symptoms of latent depression may emerge during clonazepam therapy.

The use of clonazepam at therapeutic doses may lead to the development of physical and psychological dependence. The risk of dependence increases with higher doses and longer duration of treatment, and is particularly high in patients with a history of alcohol abuse or drug dependence (see section "Special precautions"). Abrupt discontinuation of treatment may result in withdrawal syndrome (see section "Special precautions").

Paradoxical reactions such as aggression, hostility, psychomotor agitation, increased excitability, nervousness, irritability, agitation, anxiety, sleep disturbances, nightmares, vivid dreams, insomnia, psychiatric disorders, personality disorders, tremor, and emergence of new seizure types may also occur. These paradoxical reactions occur most frequently after alcohol consumption, in elderly patients, and in patients with psychiatric disorders. If such paradoxical reactions occur, the benefit of continuing therapy should be weighed against the severity of the reactions. It may be necessary to introduce other medications into the treatment regimen or discontinue clonazepam therapy.

Nervous system disorders: dizziness*, feeling of emptiness or "light-headedness"*, somnolence*, increased fatigue*, slowed reaction time*, ataxia*, impaired motor coordination*, muscle hypotonia, muscle weakness, reduced concentration, memory impairment, impaired ability to absorb information, restlessness, headache*, confusion* and disorientation*, photophobia*; rarely – emotional lability.

Dysarthria and ataxia are reversible disorders and occur particularly during prolonged therapy or with high-dose administration.

These adverse effects occur relatively frequently and may gradually resolve during the course of treatment or upon dose reduction. Their occurrence can be partially prevented by slow dose escalation at the beginning of therapy.

Headache has been observed in rare cases.

Provocation of generalized seizures has been observed very rarely.

In certain forms of epilepsy, an increase in seizure frequency may occur during long-term treatment.

Eye disorders: diplopia and nystagmus are reversible disorders and occur particularly during prolonged therapy or with high-dose administration; reduced visual acuity.

Cardiovascular disorders: bradycardia, chest pain, slight decrease in blood pressure.

Cases of heart failure, including cardiac arrest, have been reported.

Respiratory, thoracic and mediastinal disorders

Respiratory depression may occur rarely, especially when clonazepam is used concomitantly with other drugs that have a depressant effect. This effect may be enhanced in the presence of existing airway obstruction or brain damage, or when other respiratory depressant drugs have been administered. This effect can usually be avoided by careful individual dose titration.

In infants and young children, particularly those with psychiatric disorders, increased salivation or bronchial secretion with drooling may occur. In such cases, monitoring of the airway may be required.

Symptoms of catarrhal inflammation of the upper respiratory tract may rarely occur.

Gastrointestinal disorders: rarely – nausea, gastric discomfort, dry mouth; increased salivation, vomiting, abdominal pain, constipation, gastrointestinal symptoms.

Hepatobiliary disorders: liver function abnormalities, jaundice.

Isolated cases of abnormal liver function tests (including mild elevations of transaminase levels) have been reported.

Nutritional and metabolism disorders: decreased or absent appetite.

Endocrine system disorders

Isolated cases of premature sexual development in children with the appearance of secondary sexual characteristics (incomplete precocious puberty) have been reported.

Renal and urinary disorders: rarely – urinary incontinence; urinary retention, frequent urination, involuntary urination; menstrual cycle disturbances, libido disorders, impotence.

Musculoskeletal and connective tissue disorders: muscle weakness*, episodic muscle hypotonia*; rarely – muscle pain.

Skin and subcutaneous tissue disorders: hypersensitivity reactions, including rash, urticaria, pruritus; eczema; rarely – temporary hair loss, changes in skin pigmentation.

Immune system disorders: hypersensitivity reactions; anaphylactic reactions and angioedema have been reported very rarely.

General disorders: weakness, syncope.

Injury, poisoning and procedural complications

An increased risk of falls and fractures has been reported in elderly patients taking benzodiazepines.

Investigations

A decrease in platelet count may be observed in rare cases. As with other benzodiazepines, isolated cases of blood dyscrasias are possible.

Children

See sections "Endocrine system disorders" and "Respiratory, thoracic and mediastinal disorders" above.

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 in a blister; 5 blisters (for 0.5 mg and 1 mg strengths), 3 blisters (for 2 mg strength) per carton.

Prescription status

Prescription only.

Manufacturer

"INTERKHIM" Limited Liability Company.

Manufacturer's address and place of business

40-A, 21st km of Starokyivska Road, Odessa, 65025, Ukraine.