Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom
Patients with known sensitivity to benzodiazepines; or any of the drugs excipients; acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency.
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antiepileptic drugs, treatment with Rivotril even if of short duration, must not be abruptly interrupted, but must be withdrawn by gradually reducing the dose in view of the risk of precipitating status epilepticus.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).
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 (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.
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).
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.
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 increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.
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.
Preclinical studies in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data). From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens.
Rivotril has harmful pharmacological effects on pregnancy and the foetus/newborn child. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heart beat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor sucking in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. Therefore Rivotril should not be used in pregnancy unless clearly necessary.
The active ingredient of Rivotril has been found to pass into the maternal milk in small amounts. Therefore Rivotril should not be used in mothers who breastfeed unless clearly necessary.
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:
Allergic reactions and very few cases of anaphylaxis have been reported to occur with benzodiazepines. Angioedema may occur in rare cases.
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.
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.
Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur.
Cardiac failure including cardiac arrest has been reported.
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).
The following effects have been reported in rare cases: nausea and epigastric symptoms.
The following effects may occur in rare cases: urticaria, pruritus, rash, transient hair loss and pigmentation changes.
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.
In rare cases urinary incontinence may occur.
In rare cases erectile dysfunction or loss of libido may occur.
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.
An increased risk for falls and fractures has been reported in elderly benzodiazepine users.
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.
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 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, 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.
Not applicable.
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