Each tablet contains 500 micrograms (0.5 mg) clonazepam.
Excipients: Also contains 40 mg lactose monohydrate.
The tablets can be broken into equal halves to facilitate dosing.
All clinical forms of epileptic disease and seizures in infants, children and adults, especially absence seizures (petit mal) including atypical absence; primary or secondarily generalised tonic-clonic (grand mal), tonic or clonic seizures; partial (focal) seizures with elementary or complex symptomatology; various forms of myoclonic seizures, myoclonus and associated abnormal movements.
Posology and method of administration
The scored 0.5 mg tablets facilitate the administration of lower daily doses in the initial stages of treatment.
Initial dosage should not exceed 1 mg/day. The maintenance dosage for adults normally falls within the range 4 to 8 mg.
The elderly are particularly sensitive to the effects of centrally depressant drugs and may experience confusion. It is recommended that the initial dosage of Rivotril should not exceed 0.5 mg/day.
These are total daily dosages which should be divided into 3 or 4 doses taken at intervals throughout the day. If necessary, larger doses may be given at the discretion of the physician, up to a maximum of 20 mg daily. The maintenance dose should be attained after 2 to 4 weeks of treatment.
Infants and children
To ensure optimum dosage adjustment, children should be given the 0.5 mg tablets.
Initial dosage should not exceed 250 micrograms/day for infants and small children (1 to 5 years) and 500 micrograms/day for older children. The maintenance dosage normally falls within the ranges:
School children (5 to 12 years)
3 to 6 mg
Small children (1 to 5 years)
1 to 3 mg
Infants (0 to 1 year)
500 micrograms to 1 mg
In some forms of childhood epilepsy, certain patients may cease to be adequately controlled by Rivotril. Control may be re-established by increasing the dose, or interrupting treatment with Rivotril for 2 or 3 weeks. During the interruption in therapy, careful observation and other drugs may be needed.
Mode of administration
Treatment should be started with low doses. The dose may be increased progressively until the maintenance dose suited to the individual patient has been found.
The dosage of Rivotril must be adjusted to the needs of each individual and depends on the individual response to therapy. The maintenance dosage must be determined according to clinical response and tolerance.
The daily dose should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before retiring. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.
Simultaneous administration of more than one anti-epileptic drug is a common practice in the treatment of epilepsy and may be undertaken with Rivotril. The dosage of each drug may be required to be adjusted to obtain the optimum effect. If status epilepticus occurs in a patient receiving oral Rivotril, intravenous Rivotril may still control the status. 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.
Patients with known sensitivity to benzodiazepines or any of the drug's excipients; acute pulmonary insufficiency, severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency.
Rivotril must not be used in patients in a coma, or in patients known to be abusing pharmaceuticals, drugs or alcohol.
Special warnings and precautions for use
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for clonazepam.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Patients with a history of depression and/or suicide attempts should be kept under close supervision.
Rivotril should be used with caution in patients with chronic pulmonary insufficiency, or with impairment of renal or hepatic function, and in the elderly or the debilitated. In these cases dosage should generally be reduced.
As with all other anti-epileptic drugs, treatment with Rivotril even if of short duration, must not be abruptly interrupted, but must be withdrawn by gradually reducing the dose in view of the risk of precipitating status epilepticus. In such cases a combination with other antiepileptics is indicated. This precaution must also be taken when withdrawing another drug while the patient is still receiving Rivotril therapy.
Prolonged use of benzodiazepines may result in dependence development with withdrawal symptoms on cessation of use.
Rivotril may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver).
The concomitant use of Rivotril with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Rivotril possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see 4.5).
Rivotril should be used with extreme caution in patients with a history of alcohol or drug abuse.
In infants and small children Rivotril may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways.
The dosage of Rivotril must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system (e.g. chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents. Effects on the respiratory system 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.
Clonazepam is considered to be probably nonporphyrinogenic, although there is some conflicting evidence. Therefore in patients with porphyria, clonazepam should be used with care.
Like all drugs of this type, Rivotril may, depending on dosage, administration and individual susceptibility, modify the patient's reactions (e.g. driving ability, behaviour in traffic).
As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on Rivotril, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients' reactions, depending on individual susceptibility.
In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. In particular long-term or high-dose treatment, may lead to reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia), nystagmus and vision (diplopia). Furthermore, the risk of anterograde amnesia, which may occur using benzodiazepines at therapeutic dosages, increases 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.
The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcoholism and/or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop after a lengthy period of use, especially with high doses or if the daily dose is reduced rapidly or abruptly discontinued.
Effects on ability to drive and use machines
As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on Rivotril, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients' reactions, depending on individual susceptibility. Even if taken as directed, clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This effect is aggravated by consumption of alcohol. Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient's physician and should be based on the patient's response to treatment and the dosage involved.
The following have been observed:
Immune System Disorders
Allergic reactions and very rare cases of anaphylaxis have been reported to occur with benzodiazepines.
Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.
Impaired concentration, restlessness, 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: excitability, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams and psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue Rivotril therapy. In rare cases loss of libido may occur.
Nervous System Disorders
Somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia and co-ordination disturbance. 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. Causing of generalised fits was observed very rarely.
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.
Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur.
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, particularly those with a degree of mental impairment, Rivotril may cause increased production of saliva or of bronchial secretion. Particular attention should therefore be paid to maintaining patency of the airways.
The following effects have been reported in rare cases: nausea, gastrointestinal and epigastric symptoms.
Skin and Subcutaneous Tissue Disorders
The following effects may occur in rare cases: urticaria, pruritus, rash, transient hairloss, pigmentation changes and angioedema.
Musculoskeletal and Connecting 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 Disorders
In rare cases urinary incontinence may occur.
Reproductive System and Breast Disorders
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).
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.
In rare cases decreased platelet count may occur. As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.
The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response. Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Rivotril is seldom life-threatening if the drug is taken alone, but may lead to coma, areflexia, apnoea, hypotension and cardiorespiratory depression. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease.
Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.
1. Maintain a clear airway and adequate ventilation if indicated.
2. Supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.
3. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients.
4. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure.
5. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.
6. Flumazenil, a benzodiazepine antagonist is available but should rarely be required. If CNS depression is severe consider the use of flumazenil. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug. Flumazenil is NOT TO BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC TEST”
The use of flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.
If excitation occurs, barbiturates should not be used.
Clonazepam is quickly and completely absorbed after oral administration of Rivotril. Peak plasma concentrations are reached in most cases within 1 - 4 hours after an oral dose. Bioavailability is 90% after oral administration.
Routine monitoring of plasma concentrations of Rivotril is of unproven value since this does not appear to correlate well with either therapeutic response or side-effects.
The mean volume of distribution of clonazepam is estimated at about 3 l/kg. Clonazepam must be assumed to cross the placental barrier and has been detected in maternal milk.
The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not.
The elimination half-life is between 20 and 60 hours (mean 30 hours).
Within 4 - 10 days 50 - 70% of the total radioactivity of a radiolabeled oral dose of clonazepam is excreted in the urine and 10 - 30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged clonazepam in the urine.
Pharmacokinetics in special clinical situations
Based on kinetic criteria no dose adjustment is required in patients with renal failure.
List of excipient(s)
Iron oxide red E172
Iron oxide yellow E172
Special precautions for storage
Store in the original package and in the outer carton, protected from light.
Nature and contents of container
Amber glass bottles with polyethylene screw closures, containing 50, 100 or 150 tablets.
Not all pack sizes may be marketed.