Generic

Clonazepam

Therapeutic Class

Central nervous system (CNS)

Pack Size

Rivotril 0.5 mg tablet: Each box contains 80 tablets (8 x 10’s) in Alu-PVC / PVDC blister pack.
Rivotril 2 mg tablets: Each box contains 60 tablets (6 x 10’s) in Alu-PVC / PVDC blister pack.

Indications

Rivotril is indicated, primarily as an adjunct or in refractory cases, in most forms of epilepsy especially absence seizures including atypical absence seizures; Lennox-Gastaut syndrome; myoclonic and atonic seizures. For infantile spasms (including West-Syndrome) and tonic-clonic seizures it is only indicated as an adjunct or in refractory cases. Rivotril is indicated for the treatment of Panic Disorder, with or without agoraphobia.

Therapeutic Class

Central nervous system (CNS)

Dosage & Administration

The dosage of Rivotril must be individually adjusted according to the patient’s clinical response and tolerance. Rivotril tablets 0.5 mg can be divided into equal halves to facilitate dosing. Rivotril tablets 2 mg can be divided into equal halves or quarters to facilitate dosing. Tablets are scored to allow administration of lower doses. To break the tablet, hold it with the score facing up and apply downward pressure. Standard dosage in Epilepsy Before adding Rivotril to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesired effects. To ensure optimum dosage adjustment, infants should be given the drops. The 0.5 mg tablets facilitate the administration of lower daily doses to adults in the initial stages of treatment. A single oral dose of Rivotril begins to take effect within 30-60 minutes and remains effective for 6-8 hours in children and 8-12 hours in adults. Oral treatment To avoid adverse reactions at the beginning of therapy, it is essential to start treatment with Rivotril at a low dose and increase the daily dose progressively until the maintenance dose suited to the individual patient has been reached. The initial dose for infants and children up to the age of 10 years (or up to 30 kg bodyweight) is 0.01-0.03 mg/kg daily given in 2-3 divided doses. The dose should be increased by no more than 0.25-0.5 mg every third day until either a daily maintenance dose of approximately 0.1 mg/kg of bodyweight daily has been reached or seizures are controlled or undesired effects preclude further increase. The daily maximum dose in children is 0.2 mg/kg of bodyweight and should not be exceeded. Based on established dosages for children up to 10 years (see above) and those for adults (see below) the following can be recommended for children between 10 and 16 years: The initial dose is 1-1.5 mg/day given in 2-3 divided doses. The dose may be increased by 0.25-0.5 mg every third day until the individual maintenance dose (usually 3-6 mg/day) is reached. The initial dose for adults should not exceed 1.5 mg/day divided into 3 doses. The dose may be increased in increments of 0.5 mg every three days until either seizures are adequately controlled or undesired effects preclude any further increase. The maintenance dose must be individualized for each patient depending upon response. Usually a maintenance dose of 3-6 mg per day is sufficient. The maximum therapeutic dose for adults is 20 mg daily and should not be exceeded. The daily dose should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before retiring. The maintenance dose level is best attained after 1-3 weeks of treatment. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening. Dosage in Panic Disorder Adults: The initial dose for adults with Panic Disorder is 0.25 mg twice daily (0.5 mg/day). An increase to 0.5 mg twice daily (1 mg/day) may be made after 3 days. Subsequent up-titration should be made at intervals of 3 days until Panic Disorder is controlled or until limited by side effects. The usual maintenance dose is 1 mg twice daily (2 mg/day). A maximum dose of 2 mg twice daily (4 mg/day) may be prescribed in exceptional cases. Once a stable dose is achieved, patients may switch to a once daily dose, usually taken at bedtime. Duration of treatment: Maintenance treatment is recommended for at least 12-24 months, and in some cases, indefinitely. After at least 1 year of response gradual discontinuation should be attempted, with down-titration of 0.25 mg every 3 days, until the drug is completely withdrawn and close follow-up of the patient. Relapsing patients should begin taking medication again. Special Dosage Instructions Elderly Patients: The lowest possible dose should be used in the elderly and particular care should be taken during up-titration. Renal Impairment: The safety and efficacy of clonazepam in patients with renal impairment has not been studied, however based on pharmacokinetic considerations no dose adjustment is required in these patients. Hepatic Impairment: Patients with severe hepatic impairment should not be treated with Rivotril. Patients with mild to moderate hepatic impairment should be given the lowest dose possible. Epilepsy Rivotril can be administered concurrently with one or several other antiepileptic agents, in which case the dosage of each drug must be adjusted to achieve the optimum effect. As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion. Panic disorder Pediatric Patients: The safety and efficacy of clonazepam for the treatment of Panic Disorder in children has not been studied.

Contraindications

Rivotril is contraindicated in patients with known hypersensitivity to clonazepam or any of the drug’s excipients, and in patients with severe respiratory insufficiency or severe hepatic impairment as benzodiazepines may precipitate hepatic encephalopathy Rivotril tablets are contraindicated in patients with a medical history of sleep apnoea for the treatment of panic disorders.

Side Effects

Undesirable Effects Clinical Trials Epilepsy No text. Panic Disorder Data from 3 placebo-controlled clinical trials including 477 patients on active treatment in total are presented in the table below. Adverse Events occurring in ≥ 5% of patients in at least one of the Active Treatment Groups are included. Laboratory Abnormalities No text. Post Marketing Immune system Disorders: Allergic reactions and very few cases of anaphylaxis have been reported to occur with benzodiazepines. Endocrine Disorders: Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported. Psychiatric Disorders: Emotional and mood disturbances, confusional state, disorientation have been observed. Depression may occur in patients treated with Rivotril, but it may be also associated with the underlying disease. The following paradoxical reactions have been observed: restlessness, agitation, irritability, aggressiveness, nervousness, hostility, anxiety, sleep disturbances, delusion, anger, nightmares, abnormal dreams, hallucinations, psychoses, hyperactivity, inappropriate behavior and other adverse behavioral effects are known to occur. Should this occur, the use of the drug should be discontinued. Paradoxical reactions are more likely to occur in children and in the elderly. In rare cases changes in libido may occur. Nervous system Disorders: impaired concentration, somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia. These undesirable effects occur relatively frequently and are usually transient and generally disappear spontaneously in the course of the treatment or on reduction of the dosage. They can be partially prevented by increasing the dose slowly at the start of treatment. Headache was observed in rare cases. Particularly in long-term or high-dose treatment, reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia) and nystagmus may occur. Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour. With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible. Eye Disorder: Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur. Cardiac disorders: Cardiac failure including cardiac arrest has been reported. Respiratory Thoracic and Mediastinal System Disorders: Respiratory depression may occur, particularly on i.v. administration of clonazepam. This effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements. In infants and young children, Rivotril may cause increased production of saliva or of bronchial secretion. Particular attention should therefore be paid to maintaining patency of the airways. Gastrointestinal Disorders: The following effects have been reported in rare cases: nausea and epigastric symptoms. Skin and Subcutaneous Tissue Disorders: The following effects may occur in rare cases: urticaria, pruritus, rash, transient hairloss, pigmentation changes. Musculoskeletal and Connective Tissue Disorders: muscle weakness, this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment. Renal and Urinary Disorder: In rare cases urinary incontinence may occur. Reproductive System and Breast Disorder: In rare cases erectile dysfunction may occur. General Disorders and Administration Site Conditions: Fatigue (tiredness, lassitude), this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment. Paradoxical reactions including irritability have been observed (see also psychiatric disorders). If the injection is rapid or the calibre of the vein insufficient, there is a risk of thrombophlebitis, which may in turn lead to thrombosis. Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly. Investigations: In rare cases decreased platelet count may occur.

Pregnancy & Lactation

Use in Special Populations Pregnancy From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens. However, it is difficult to determine from published epidemiological reports which drug or combination of drugs is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. Under these circumstances, the drug should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus. During pregnancy, Rivotril may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Withdrawal symptoms in newborn infants have occasionally been reported with benzodiazepines. Labour and Delivery Pregnancy. Nursing Mothers Although the active ingredient of Rivotril has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for Rivotril, breastfeeding should be discontinued.

Precautions

General Some loss of effect may occur during the course of clonazepam treatment. Hepatic impairment / Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in severe hepatic impairment. Special caution should be exercised when administering clonazepam to patients with mild to moderate hepatic impairment. CNS, psychosis and depression Clonazepam should be used with particular caution in patients with ataxia. Benzodiazepines are not recommended for the primary treatment of psychoic illness. Patients with a history of depression and/or suicide attempts should be kept under close supervision. Myasthenia gravis As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering clonazepam to a patient with myasthenia gravis. Concomitant use of alcohol / CNS depressants The concomitant use of Rivotril with alcohol or/and CNS depressants should be avoided, as this has the potential to increase the clinical effects of Rivotril possibly including severe sedation that could result in coma or death, clinically relevant respiratory and/or cardio-vascular depression (see 2.4.5 Interactions with other Medicinal Products and other Forms of Interactions and 2.7 Overdose). Rivotril should be used with particular caution in the event of acute intoxication with alcohol or drugs.

Storage Conditions

This medicine should not be used after the expiry date (EXP) shown on the pack. Tablets in blister: keep blister in the outer carton in order to protect from light.