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5.3       Preclinical safety data

In preclinical murine studies there was at least a two fold increase in teratogenic birth defects at dose levels of 3, 9 and 18 times the human therapeutic dose compared to the controls.

Carcinogenicity

Conventional 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.

Mutagenicity

Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.

Impairment of Fertility

Studies 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.

Teratogenicity

No 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.

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Undesirable effects

The side-effectsfollowing have been observed: consist of fatigue, muscle weakness, dizziness, ataxia, light-headedness, somnolence, occasional muscular hypotonia and co-ordination disturbances.  Such effects are usually transitory and disappear spontaneously as treatment continues or with dosage reduction.  They tend to occur early in treatment and can be greatly reduced, if not avoided, by commencing with low dosages followed by progressive increases.

Poor concentration, restlessness, confusion and disorientation have been observed.  Anterograde amnesia may occur using benzodiazepines at therapeutic dosage, the risk increasing at higher dosages.  Amnestic effects may be associated with inappropriate behaviour.

Depression may occur in patients treated with Rivotril, but it may be also associated with the underlying disease.

In rare cases, urticaria, pruritus, transient hair loss, pigmentation changes, nausea, gastrointestinal symptoms, headache, decrease in sexual drive (loss of libido), impotence and urinary incontinence may occur.  Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.  Allergic reactions and a very few cases of anaphylaxis and angioedema have been reported to occur with benzodiazepines.

Particularly in long-term or high-dose treatment, reversible disorders such as a slowing or slurring of speech (dysarthria), reduced co-ordination of movements and gait (ataxia) and disorders of vision (double vision, nystagmus) may occur.

Rarely respiratory depression may occur with intravenous Rivotril, particularly if other depressant drugs have been administered.  As a rule, this effect can be avoided by careful adjustment of the dose in individual requirements.

Immune System Disorders

Allergic reactions and very few cases of anaphylaxis have been reported to occur with benzodiazepines.   Angioedema may occur in rare cases.

Endocrine Disorders

Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.

Psychiatric Disorders and Paradoxical Reactions

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.

Nervous System Disorders

Somnolence, 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.

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 Disorders

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.

Increased salivation or bronchial secretion may occur in infants or young children (see also section 4.4)..

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 and 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 Disorders

In rare cases urinary incontinence may occur.

Reproductive System and Breast Disorders

In rare cases erectile dysfunction or loss of libido 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.

Injury, Poisoning and Procedural Complications

An increased risk for falls and fractures has been reported in elderly benzodiazepine users.

Investigations

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.

Dependence

Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products.  The risk of dependence increases with dose and duration of treatment; it and is particularly pronouncedalso greater in predisposed 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, 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.

In infants and small children, and particularly those with a degree of mental impairment, Rivotril may give rise to salivary or bronchial hypersecretion with drooling.  Supervision of the airway may be required.

With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.

As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.

Rivotril generally has a beneficial effect on behaviour disturbances in epileptic patients.  In certain cases, paradoxical effects such as aggressiveness, excitability, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams, irritability, agitation, 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.

Although Rivotril has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.

An increased risk of falls and fractures has been recorded in elderly benzodiazepine users.

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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 antiepileptic 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.  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).

RivotrilBenzodiazepines 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 (see section 4.5).

Clonazepam is considered to be probably nonporphyrinogenic at low doses, although there is some conflicting evidence of porphyrinogenicity at higher doses.   Therefore, in patients with porphyria, clonazepam must 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).

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.

Interaction with other medicinal products and other forms of interaction

Not recommended

Since alcohol can provoke epileptic seizures, irrespective of therapy, patients must under no circumstances drink alcohol while under treatment.  In 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).

Take into account

Centrally acting drugs: Enhanced effects on sedation, respiration and haemodynamics may occur when Rivitrol 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. This requires extra care in adjusting dosage 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 induce the metabolismincrease the clearance of clonazepam causing higher clearance and lowerthereby 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 serotonine 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.

Concurrent use of Rivotril and other centrally acting medications, e.g. other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle-relaxants may result in mutual potentiation of drug effects.  This is especially true in the presence of alcohol.  In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.

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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.

Patients with a history of depression and/or suicide attempts should be kept under close supervision.

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QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

Interaction with other medicinal products and other forms of interaction

The antiepileptic drugs phenytoin, phenobarbital, carbamazepine and valproate may induce the metabolism of clonazepam causing higher clearance and lower plasma concentrations of the latter during combined treatment.

The selective serotonine reuptake inhibitors sertraline and fluoxetine do not affect the pharmacokinetics of clonazepam when administered concomitantly.

Undesirable effects

An increased risk of falls and fractures has been recorded in elderly benzodiazepine users.

Overdose

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.  Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone.  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 usually lasts only a few hours but in elderly people it may be more protracted and cyclical.  Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease.

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PHARMACEUTICAL FORM

Tablets.

Rivotril 0.5mg Tablets:  Round, dull pinkish-buff tablets with Roche 0.5 ‘ROCHE 0,5’ imprinted on one face and two a single break bars mark on the other.

The Tablets can be broken into equal halves to facilitate dosing.

Rivotril 2mg Tablets:  Round, white tablets with Roche 2 ‘ROCHE ·2·’imprinted on one face and two cross break bars marks on the other.

The tablets can be broken into equal halves or quarters to facilitate dosing.

Special precautions for storage

Store in the original container and in the outer carton, in order to protect from light.

Nature and contents of container

Rivotril 0.5mg Tablets:

Rivotril tablets are available in plastic HDPE bottles with polyethylene snap closures, or aAmber glass bottles with aluminium polyethylene screw closures, containing either 50, 100 or 500 150 tablets and PVC blister packs containing 100 tablets.

Rivotril 2mg Tablets:

Rivotril tablets are available in plastic HDPE bottles with polyethylene snap closures, or aAmber glass bottles with aluminium polyethylene screw closures, containing either 30 or 100 or 500 tablets and PVC blister packs containing 100 tablets.

Not all pack sizes may be marketed.

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Update to Section 4.9 Overdose

4.9       Overdose

As with other benzodiazepine drugs, overdosage should not present undue problems of management or threat to life.  Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present.  Treatment is symptomatic and may include the need to maintain an airway.  Gastric lavage may be useful if performed soon after ingestion.

Symptoms:

The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response.  They range from drowsiness and light-headedness to ataxia, somnolence and stupor, and finally to coma with respiratory depression and circulatory collapse.  Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly. Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus.  Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone.  Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical.  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:

In the management of overdose it should be borne in mind, that multiple agents may have been taken. In addition to monitoring of respiration, pulse rate and blood pressure, IV fluid replacement with general supportive measures is indicated.  Hypotension may be treated with sympathomimetic agents.

The value of dialysis has not been determined.

1.   Maintain a clear airway and adequate ventilation if indicated.

2.   The benefit of gastric decontamination is uncertain.  Consider activated charcoal (50g for an adult, 10-15g for a child) in adults or children who have taken more than 0.4mg/kg within 1 hour, provided they are not too drowsy.

3.   Gastric lavage is unnecessary if these drugs have been taken alone.

4.   Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

5.   Supportive measures as indicated by the patient’s clinical state.

6.   Flumazenil (Anexate), a benzodiazepine antagoinist is available but should rarely be required.  It has a short half-life (about an hour).  Flumazenil is NOT TO BE USE IN MIXED OVERDOSE OR AS A “DIAGNOSTIC TEST” (see separate prescribing information).

Overdosage in non-epileptic patients may be treated with Anexate, a specific IV antidote for use in emergency situations.  Patients requiring such intervention should be monitored closely in hospital (see separate prescribing information).

Warning

The use of Anexate flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period.  Although Anexate 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.