Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Some loss of effect may occur during the course of Rivotril treatment.
Use in Hepatic impairment
Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in severe hepatic impairment (see section 4.3 Contraindications). Special caution should be exercised when administering Rivotril to patients with mild to moderate hepatic impairment. In patients in whom benzodiazepine therapy for periods longer than 4 weeks is deemed necessary, periodic liver function tests are recommended.

Following the prolonged use of Rivotril at therapeutic doses, withdrawal from the medication should be gradual. An individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected. Periods from 4 weeks to 4 months have been suggested. As with other benzodiazepines, when treatment is suddenly withdrawn, a temporary increase in sleep disturbance can occur after use of Rivotril (see section 4.4 Special warnings and precautions for use, Dependence).


Only a small minority of patients with the common seizure types achieves a lasting remission with clonazepam. Tolerance to the anticonvulsant effect of clonazepam may occur after 4 weeks to 6 months of continuous treatment in the majority of patients leading to increased seizure frequency. Increasing the dose in this situation is rarely worthwhile. If seizures are no longer being adequately controlled, the medicine should be discontinued and alternative treatment implemented.

Porphyria
Rivotril should be used with care in patients with porphyria because it may have a porphyrogenic effect.

Concomitant use of alcohol and CNS depressants
The concomitant use of Rivotril with alcohol and/or CNS depressants 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 cardiovascular depression (see section 4.5 Interactions with other medicines and other forms of interactions and section 4.9
Overdose).

Since alcohol can provoke epileptic seizures irrespective of therapy and may potentiate the CNS depressant effects of clonazepam, it is imperative that patients should abstain from drinking alcohol while under treatment with Rivotril. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of Rivotril.

Rivotril should be used with particular care in patients with ataxia, in the event of acute intoxication with alcohol or drugs, other anti-epileptic medicines, hypnotics, analgesics, neuroleptic agents, antidepressants or lithium, or if the patient suffers from sleep apnoea.

As up to 70% of clonazepam metabolites are excreted via the kidneys, the pharmacodynamics of clonazepam and its metabolites might be altered.

Hypotension
Although hypotension has occurred rarely, Rivotril should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac or cerebral complications.
This is particularly important in elderly patients.

Amnesia
Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. The risk increases at higher doses.

Sleep apnoea
Benzodiazepines are not recommended for use in patients with sleep apnoea due to possible additive effects on respiratory depression. Sleep apnoea appears to be more common in patients with epilepsy and the relationship between sleep apnoea, seizure occurrence and post-ictal hypoxia needs to be considered in light of benzodiazepine-induced sedation and respiratory depression. Therefore, Rivotril should only be used in epileptic patients with sleep apnoea when the expected benefit exceeds the potential risk.


Myasthenia gravis
As with any substance with CNS depressant and / or muscle relaxant properties, Rivotril could increase the muscle weakness in myasthenia gravis and should be used with caution in this condition.

Acute narrow-angle glaucoma
Caution should be used in the treatment of patients with acute narrow-angle glaucoma (because of atropine-like side effects).

Impaired renal function and blood dyscrasias
Patients with impaired renal function should use benzodiazepine medication with caution and dosage reduction may be advisable. In rare instances patients on benzodiazepines have developed blood dyscrasias, and some have had elevations of liver enzymes. In patients in whom benzodiazepine therapy for periods longer than 4 weeks is deemed necessary, periodic blood counts are recommended.

Psychiatric and Paradoxical Reactions
Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, nervousness, hostility, anxiety, delusion, sleep disturbances, nightmares, hallucinations, psychoses, vivid dreams, acute rage, stimulation or excitement, inappropriate behaviour and other adverse behavioural effects may occur. Should such reactions occur, Rivotril should be discontinued.

Impaired Respiratory Function
Caution in the use of Rivotril is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease (COPD), benzodiazepines can cause increased arterial carbon dioxide tension and decreased oxygen tension. The dosage of Rivotril must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system.

Depression, Psychosis and Schizophrenia
Rivotril is not recommended as primary therapy in patients with depression and/or psychosis.
In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Suicidal tendencies may be present or uncovered and protective measures may be required. Patients with a history of depression and/ or suicide attempts should be kept under close supervision.

Epilepsy
The dosage of Rivotril must be carefully adjusted to individual requirements in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see section 4.5 Interactions with other medicines and other forms of interactions).

When Rivotril is administered to persons with convulsive disorders, an increase in the frequency and/or severity of grand mal seizures may occur, necessitating increased anticonvulsant medication. Abrupt withdrawal of benzodiazepines in persons with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures. When in the judgement of the clinician, the need for dosage reduction or discontinuation arises, this should be done gradually.


Abuse
Caution must be exercised in administering Rivotril to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative.
It is desirable to limit repeat prescription without adequate medical supervision.

Dependence
The use of benzodiazepines may lead to development of physical and psychological dependence, as defined by the presence of a withdrawal syndrome on discontinuation of the medicine. 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. Abuse has been reported in poly-drug users. Tolerance, as defined by a need to increase the dose in order to achieve the same therapeutic effect, seldom occurs in patients receiving recommended doses under medical supervision. Tolerance to sedation may occur with benzodiazepines, especially in those with drug seeking behaviour.

Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepines. These symptoms range from insomnia, anxiety, agitation, sleep disturbances, headaches, diarrhoea, irritability, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feeling of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyperreflexia and loss of short-term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating.
Such manifestations of withdrawal, especially the more serious ones, are more common in patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, Rivotril should be terminated by tapering the dose to minimise occurrence of withdrawal symptoms. Patients should be advised to consult with their physician before either increasing the dose or abruptly discontinuing the medication.

Rebound phenomena have been described in the context of benzodiazepine use. Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pre- treatment levels following cessation of benzodiazepines. Rebound phenomena in general possibly reflect re-emergence of pre-existing symptoms combined with withdrawal symptoms described earlier. Some patients prescribed benzodiazepines with very short half- lives (in the order of 2 – 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/rebound symptoms may follow high doses for relatively short periods.

Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see section 5.1- Pharmacodynamic Propreties - Clinical Trials), patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon. However, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.


Use in the Elderly
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.

Elderly or debilitated patients may be particularly susceptible to the pharmacologic effects of benzodiazepines such as giddiness, ataxia and confusion, which may increase the risk of a fall. Literature suggests that such effects appear to be greater in elderly patients than in younger patients even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms and organ function.

Elderly patients, patients with pre-existing disease of the respiratory system (e.g. chronic obstructive lung disease), liver or kidney disease, or those who are receiving treatment with other centrally acting medications or anticonvulsant agents, require very careful dosage adjustment.

Paediatric Use
Salivary and bronchial hypersecretion can occur in infants and small children and supervision is required to ensure that airways remain free, especially on commencing therapy or in the event of respiratory infection.

Safety and effectiveness in paediatric patients with panic disorder below the age of 18 have not been established.
Effects on laboratory tests
No data available.

Effects on Driving