Rivotril (Tablets, Solution) Instructions for Use

ATC Code

N03AE01 (Clonazepam)

Active Substance

Clonazepam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

An antiepileptic drug from the group of benzodiazepine derivatives. It has a pronounced anticonvulsant effect, as well as central muscle relaxant, anxiolytic, sedative and hypnotic effects.

It enhances the inhibitory effect of GABA on the transmission of nerve impulses. It stimulates benzodiazepine receptors located in the allosteric center of postsynaptic GABA receptors of the ascending activating reticular formation of the brainstem and interneurons of the lateral horns of the spinal cord. It reduces the excitability of subcortical structures of the brain (limbic system, thalamus, hypothalamus), inhibits postsynaptic spinal reflexes.

The anxiolytic effect is due to the influence on the amygdala complex of the limbic system and is manifested in a decrease in emotional stress, weakening of anxiety, fear, and restlessness.

The sedative effect is due to the influence on the reticular formation of the brainstem and nonspecific nuclei of the thalamus and is manifested by a decrease in neurotic symptoms (anxiety, fear).

The anticonvulsant action is realized by enhancing presynaptic inhibition. This suppresses the spread of epileptogenic activity arising in epileptogenic foci in the cortex, thalamus and limbic structures, but does not relieve the excited state of the focus.

It has been shown that in humans, Clonazepam rapidly suppresses paroxysmal activity of various types, including spike-wave complexes in absences (petit mal), slow and generalized spike-wave complexes, temporal and other localization spikes, as well as irregular spikes and waves.

Generalized type EEG changes are suppressed to a greater extent than focal ones. According to these data, Clonazepam has a beneficial effect in generalized and focal forms of epilepsy.

The central muscle relaxant effect is due to the inhibition of polysynaptic spinal afferent inhibitory pathways (and to a lesser extent, monosynaptic ones). Direct inhibition of motor nerves and muscle function is also possible.

Pharmacokinetics

When taken orally, the bioavailability is more than 90%. Plasma protein binding is more than 80%. V_d is 3.2 L/kg. T_1/2 is 23 hours. It is excreted mainly in the form of metabolites.

Indications

First-line agent – epilepsy (adults, infants and young children): typical absences (petit mal), atypical absences (Lennox-Gastaut syndrome), nodding spasms, atonic seizures (drop attacks or drop attacks).

Second-line agent – infantile spasms (West syndrome).

Third-line agent – tonic-clonic seizures (grand mal), simple and complex partial seizures and secondarily generalized tonic-clonic seizures.

Status epilepticus (IV administration).

Somnambulism, muscle hypertonia, insomnia (especially in patients with organic brain lesions), psychomotor agitation, alcohol withdrawal syndrome (acute agitation, tremor, impending or acute alcoholic delirium and hallucinations), panic disorders.

ICD codes

Dosage Regimen

Tablets, Solution

Individual. For oral administration, the initial dose for adults is recommended not to exceed 1 mg/day. The maintenance dose is 4-8 mg/day.

For infants and children aged 1-5 years, the initial dose should not exceed 250 mcg/day, for children aged 5-12 years – 500 mcg/day. Maintenance daily doses for children under 1 year of age are 0.5-1 mg, 1-5 years – 1-3 mg, 5-12 years – 3-6 mg.

For elderly patients, an initial dose not exceeding 500 mcg is recommended.

The daily dose should be divided into 3-4 equal doses. Maintenance doses are prescribed after 2-3 weeks of treatment.

IV (slowly) for adults – 1 mg, for children under 12 years of age – 500 mcg.

Adverse Reactions

From the nervous system at the beginning of treatment – pronounced inhibition, feeling of fatigue, drowsiness, lethargy, dizziness, stupor, headaches; rarely – confusion, ataxia. When used in high doses, especially with long-term treatment – articulation disorders, diplopia, nystagmus; paradoxical reactions (including acute states of agitation); anterograde amnesia. Rarely – hyperergic reactions, muscle weakness – depression. With long-term treatment of some forms of epilepsy, an increase in the frequency of seizures is possible.

From the digestive system rarely – dry mouth, nausea, diarrhea, heartburn, nausea, vomiting, decreased appetite, constipation or diarrhea, impaired liver function, increased activity of hepatic transaminases and alkaline phosphatase, jaundice. In infants and young children, increased salivation is possible.

From the cardiovascular system decreased blood pressure, tachycardia.

From the endocrine system change in libido, dysmenorrhea, reversible premature sexual development in children (incomplete precocious puberty).

From the respiratory system with IV administration, respiratory depression is possible, especially against the background of treatment with other drugs that cause respiratory depression; in infants and young children, bronchial hypersecretion is possible.

From the hematopoietic system leukopenia, neutropenia, agranulocytosis, anemia, thrombocytopenia.

From the urinary system urinary incontinence, urinary retention, impaired renal function.

Allergic reactions urticaria, skin rash, itching, extremely rarely – anaphylactic shock.

Dermatological reactions transient alopecia, pigmentation changes.

Other habituation, drug dependence; with a sharp dose reduction or discontinuation of use – withdrawal syndrome.

Contraindications

Respiratory center depression, severe COPD (progression of the degree of respiratory failure), acute respiratory failure, myasthenia gravis, coma, shock, angle-closure glaucoma (acute attack or predisposition), acute alcohol intoxication with weakening of vital functions, acute poisoning with narcotic analgesics and hypnotics, severe depression (suicidal tendencies may be noted), pregnancy, lactation period, hypersensitivity to clonazepam.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation. Clonazepam crosses the placental barrier. Clonazepam may be excreted in breast milk.

Use in Hepatic Impairment

Use with particular caution in patients with severe liver diseases.

Pediatric Use

With prolonged use of clonazepam in children, the possibility of an adverse effect on physical and mental development should be taken into account, which may not manifest itself for many years.

Geriatric Use

Use with caution in elderly patients, as they may have delayed elimination of clonazepam and reduced tolerance, especially in the presence of cardiopulmonary insufficiency.

Special Precautions

Use with particular caution in patients with ataxia, severe liver diseases, severe chronic respiratory failure, especially in the stage of acute deterioration, with episodes of nocturnal apnea.

Use with caution in elderly patients, as they may have delayed elimination of clonazepam and reduced tolerance, especially in the presence of cardiopulmonary insufficiency.

With long-term use, the development of drug dependence is possible. With abrupt withdrawal of clonazepam after long-term treatment, the development of withdrawal syndrome is possible.

With prolonged use of clonazepam in children, the possibility of an adverse effect on physical and mental development should be taken into account, which may not manifest itself for many years.

During treatment, alcohol consumption is not allowed.

Effect on the ability to drive vehicles and operate machinery

During treatment, a slowdown in the speed of psychomotor reactions is observed. This must be taken into account by persons engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Drug Interactions

With simultaneous use with drugs that have a depressant effect on the central nervous system, ethanol, ethanol-containing drugs, an increase in the depressant effect on the central nervous system is possible.

With simultaneous use, Clonazepam enhances the effect of muscle relaxants; with sodium valproate – weakening of the effect of sodium valproate and provocation of convulsive seizures.

With simultaneous use, a case of a twofold decrease in the plasma concentration of desipramine and its increase after discontinuation of clonazepam has been described.

With simultaneous use with carbamazepine, which causes induction of liver microsomal enzymes, an increase in metabolism and, as a result, a decrease in the plasma concentration of clonazepam, a decrease in its T_1/2 is possible.

With simultaneous use with caffeine, a decrease in the sedative and anxiolytic effect of clonazepam is possible; with lamotrigine – a decrease in the plasma concentration of clonazepam is possible; with lithium carbonate – the development of neurotoxicity.

With simultaneous use with primidone, the plasma concentration of primidone increases; with tiapride – the development of neuroleptic malignant syndrome is possible.

With simultaneous use with toremifene, a significant decrease in the AUC and T_1/2 of toremifene is possible due to the induction of liver microsomal enzymes under the influence of clonazepam, which leads to an acceleration of toremifene metabolism.

A case of headache with localization in the occipital region with simultaneous use with phenelzine has been described.

With simultaneous use, an increase in the plasma concentration of phenytoin and the development of toxic reactions, a decrease in its concentration, or the absence of these changes is possible.

With simultaneous use with cimetidine, the side effects from the central nervous system are enhanced, however, the frequency of convulsive seizures in some patients decreased.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.