- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal status
Rivotril 0.5mg Tablets:Each tablet contains 0.5mg clonazepam.Excipients: Also contains 40mg lactose monohydrate.
Rivotril 2mg Tablets:Each tablet contains 2mg clonazepam.Excipients: Also contains 121.5mg lactose anhydrous.For a full list of excipients, see section 6.1.
Rivotril 0.5mg Tablets:Round, dull pinkish-buff tablets with 'ROCHE 0,5' imprinted on one face and a single break mark on the other.The Tablets can be broken into equal halves to facilitate dosing.
Rivotril 2mg Tablets:Round, white tablets with 'ROCHE ·2·' imprinted on one face and cross break marks on the other.The tablets can be broken into equal halves or quarters to facilitate dosing.
AdultsInitial dosage should not exceed 1mg/day. The maintenance dosage for adults normally falls within the range 4 to 8mg.
ElderlyThe 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 0.5mg/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 20mg daily. The maintenance dose should be attained after 2 to 4 weeks of treatment.
Infants and childrenTo ensure optimum dosage adjustment, children should be given the 0.5mg tablets.Initial dosage should not exceed 0.25mg/day for infants and small children (1 to 5 years) and 0.5mg/day for older children. The maintenance dosage normally falls within the ranges:
|School children (5 to 12 years)||3 to 6mg|
|Small children (1 to 5 years)||1 to 3mg|
|Infants (0 to 1 year)||0.5 to 1mg|
Mode of administrationTreatment 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 antiepileptic 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.
DependenceUse of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see 4.8). 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 (see 4.8) 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 alcohol 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. The symptoms include tremor, sweating, agitation, sleep disturbances and anxiety, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability and epileptic seizures which may be associated with the underlying disease. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact or hallucinations. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should therefore be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose. The risk of withdrawal symptoms is increased when benzodiazepines are used together with day-time sedatives (crossed tolerance).
Not recommendedIn combination with Rivotril, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects (see also section 4.4).See section 4.9 Overdose for warning of other central nervous system depressants, including alcohol.
Take into accountCentrally acting drugs: Enhanced effects on sedation, respiration and haemodynamics may occur when Rivotril is co-administered with any centrally acting depressants e.g. alcohol, and other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle relaxants and may result in mutual potentiation of drug effects (see also section 4.9).In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.Antiepileptic drugs: When Rivotril is used in conjunction with other antiepileptic drugs, side-effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. In such cases, the dosage of each drug must be adjusted to achieve the optimum desired effect, particularly in the initial stages of treatment. The combination of Rivotril and sodium valproate has, rarely, been associated with the development of absence status epilepticus. Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered.The antiepileptic drugs phenytoin, phenobarbital, carbamazepine and valproate may increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.Pharmacokinetic interactions: Clonazepam itself does not induce the enzymes responsible for its own metabolism.The selective serotonin reuptake inhibitors sertraline and fluoxetine do not affect the pharmacokinetics of clonazepam when administered concomitantly.Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.In concurrent treatment with phenytoin or primidone, a change, usually a rise in the serum concentration of these two substances has occasionally been observed.
Immune System DisordersAllergic reactions and very rare cases of anaphylaxis have been reported to occur with benzodiazepines. Angioedema may occur in rare cases.
Endocrine DisordersIsolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.
Psychiatric Disorders and Paradoxical ReactionsImpaired 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.
Nervous System DisordersSomnolence, slowed reaction, muscular hypotonia, dizziness and ataxia. These undesirable effects occur relatively frequently and may disappear gradually 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. Although Rivotril has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.
Eye DisordersParticularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur. Common: nystagmus
Cardiac DisordersCardiac failure including cardiac arrest has been reported.
Respiratory, Thoracic and Mediastinal System DisordersRespiratory 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.Increased salivation or bronchial secretion may occur in infants or young children (see also section 4.4).
Gastrointestinal DisordersThe following effects have been reported in rare cases: nausea, gastrointestinal and epigastric symptoms.
Skin and Subcutaneous Tissue DisordersThe following effects may occur in rare cases: urticaria, pruritus, rash, transient hair loss and pigmentation changes.
Musculoskeletal and Connective Tissue DisordersMuscle 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 DisordersIn rare cases urinary incontinence may occur.
Reproductive System and Breast DisordersIn rare cases erectile dysfunction or loss of libido may occur.
General Disorders and Administration Site ConditionsFatigue (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.
Injury, Poisoning and Procedural ComplicationsAn increased risk for falls and fractures has been reported in elderly benzodiazepine users.
InvestigationsIn rare cases decreased platelet count may occur. As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.
Dependence and withdrawal, (see 4.4).Paediatric populationFor paediatric specific events please refer to the information listed under headings: Endocrine Disorders and Respiratory, Thoracic and Mediastinal System Disorders in section 4.8.
Symptoms: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.
Management: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
WarningThe 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.
AbsorptionClonazepam 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.
DistributionThe 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.
MetabolismThe 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.
EliminationThe elimination half-life is between 20 and 60 hours (mean 30 hours).Within 4 - 10 days 50 - 70% of the total radioactivity of a radiolabelled 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 situationsBased on kinetic criteria no dose adjustment is required in patients with renal failure.
CarcinogenicityConventional studies of carcinogenic potential have not been conducted with clonazepam. No 2-year carcinogenicity studies have been conducted with clonazepam. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300mg/kg/day.
MutagenicityGenotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
Impairment of FertilityStudies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100mg/kg/day.
TeratogenicityNo adverse maternal or embryo-foetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40mg/kg/day, respectively.In several rabbit studies following doses of clonazepam of up to 20mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused sternebrae and limb defects) was observed (see section 4.6).As toxicokinetic evaluations have not been performed with clonazepam, it is not possible to determine the safety margin for the adverse effects observed in the non-clinical studies. The relevance of these findings to the patient population is unclear therefore a potential risk to man cannot be ruled out.
Rivotril 0.5mg tablets:Lactose (monohydrate) Maize starchPregelatinised potato starchTalcMagnesium stearateDeionised waterDye iron oxide red E172Dye iron oxide yellow E172.
Rivotril 2mg tablets:Lactose (anhydrous) Pregelatinised maize starch Magnesium stearateMicrocrystalline cellulose.
Rivotril 0.5mg Tablets:Amber glass bottles with polyethylene screw closures, containing 50, 100 or 150 tablets.
Rivotril 2mg Tablets:Amber glass bottles with polyethylene screw closures, containing 30 or 100 tablets.Not all pack sizes may be marketed.
|Rivotril 0.5mg Tablets:||PL 00031/0076R|
|Rivotril 2mg Tablets:||PL 00031/0077R|
Roche Products Limited
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