Rivotril Dose
Rivotril Dose
Rivotril Dose
1. PRODUCT NAME
Caution: Never administer Rivotril drops directly into the mouth from the bottle.
After each opening, make sure the dropper is secured within the neck of the bottle.
Antiepileptic agent
3. PHARMACEUTICAL FORM
Rivotril 2.5 mg/mL oral solution (drops) are available as a clear, blue or colourless to slightly
green-yellow solution.
4. CLINICAL PARTICULARS
Rivotril is indicated for most clinical forms of epilepsy in infants and children, in particular
typical and atypical absences (Lennox-Gastaut syndrome), nodding spasms, primary or
secondary generalised tonic-clonic seizures.
In adults, Rivotril may be used in all varieties of generalised epilepsy (including absence,
myoclonic, akinetic, tonic and tonic-clonic seizures), and in partial (focal) epilepsy (including
psychomotor seizures).
The dosage of Rivotril must be individually adjusted according to the patient’s clinical
response, tolerance of the medicine and the patient’s age.
Before adding Rivotril to an existing anticonvulsant regimen, it should be considered that the
use of multiple anticonvulsants may result in an increase of undesirable effects.
To ensure optimum dosage adjustment, infants and children up to the age of 10 years should
be given the drops. The drops can also be used for titration.
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A single oral dose of Rivotril begins to take effect within 30 - 60 minutes and remains
effective for 6 - 8 hours in children and 8 - 12 hours in adults.
Dose
To avoid adverse reactions at the beginning of therapy, it is essential to start treatment with
Rivotril at a low dose and increase the daily dose progressively until the maintenance dose
suited to the individual patient has been reached.
The daily dose should be divided into 3 equal doses. If doses are not equally divided, the
largest dose should be given in the evening. The maintenance dose level is best attained after
1 - 3 weeks of treatment. Once the maintenance dose level has been reached, the daily
amount may be given in a single dose in the evening.
Adults
The initial dose should not exceed 1.5 mg/day divided into 3 doses. The dose may be
increased in increments of 0.5 mg every three days until either seizures are adequately
controlled or undesirable effects preclude any further increase.
The maintenance dose must be individualised for each patient depending upon response.
Usually a maintenance dose of 3 – 6 mg/day is sufficient. The maximum therapeutic dose for
adults is 20 mg/day and should not be exceeded.
Special populations
Elderly patients
The lowest possible dose should be used in the elderly and particular care should be taken
during up-titration (see section 4.4, Elderly).
Renal impairment
The safety and efficacy of clonazepam in patients with renal impairment has not been
studied, however based on pharmacokinetic considerations no dose adjustment is required in
these patients (see section 5.2, Pharmacokinetics in Special Populations).
Hepatic impairment
Patients with severe hepatic impairment should not be treated with clonazepam (see section
4.3). Patients with mild to moderate hepatic impairment should be given the lowest dose
possible.
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Paediatric population
See specific dosing recommendations.
Method of administration
Oral Treatment
Rivotril drops should be given with a spoon and may be mixed with water, tea or fruit juice.
Rivotril can be administered concurrently with one or several other antiepileptic agents, in
which case the dosage of each agent must be adjusted to achieve the optimum effect.
As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but
must be reduced in a stepwise fashion (see section 4.8).
4.3 Contraindications
General
Some loss of effect may occur during the course of clonazepam treatment.
Rivotril should be used with particular caution in patients with ataxia; in the event of acute
intoxication with alcohol or drugs; and in patients with severe liver damage (e.g. cirrhosis of
the liver).
Hepatic impairment
In patients in whom benzodiazepine therapy for periods of longer than 4 weeks is deemed
necessary, periodic liver function tests are recommended.
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Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Patients with a history of depression and/or suicide attempts should be kept under close
supervision.
Myasthenia gravis
As with any substance with CNS depressant and/or muscle-relaxant properties, particular care
should be taken when administering Rivotril to a patient with myasthenia gravis.
The concomitant use of Rivotril with alcohol and/or central nervous system (CNS)
depressants should be avoided. Such concomitant use 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 sections 4.5 and 4.9).
Rivotril should be used with extreme caution in patients with a history of alcohol or drug
abuse.
Patients should be advised that their tolerance for alcohol and other CNS depressants will be
diminished and that these medicines should either be eliminated or given in reduced dosage
in the presence of Rivotril.
Concomitant use of benzodiazepines, including Rivotril, and opioids may result in profound
sedation, respiratory depression, coma, and death. Because of these risks, reserve
concomitant prescribing of benzodiazepines and opioids for use in patients for whom
alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of opioids
alone. If a decision is made to prescribe Rivotril concomitantly with opioids, prescribe the
lowest effective dosages and minimum durations of concomitant use, and follow patients
closely for signs and symptoms of respiratory depression and sedation. Advise both patients
and caregivers about the risks of respiratory depression and sedation when Rivotril is used
with opioids (see section 4.5).
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adverse behavioral effects are known to occur when using benzodiazepines (see section 4.8).
Should this occur, the use of the drug should be discontinued. Paradoxical reactions are more
likely to occur in children and in the elderly.
Amnesia
Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk
increasing at higher dosages.
Sleep apnoea
Benzodiazepines are contraindicated for use in patients with sleep apnoea due to possible
additive effects on respiratory depression (see section 4.3). 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 is contraindicated in epileptic patients
with sleep apnoea, unless the expected benefit exceeds the potential risk.
Dosage
Like all medicines of this type, Rivotril may, depending on dosage, administration and
individual susceptibility, modify the patient’s reactions (e.g. driving ability, behaviour in
traffic).
Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine.
Porphyria
In patients with porphyria, Rivotril should be used with care because it may have a
porphyrogenic effect.
Epilepsy
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Abuse has been reported in poly-drug abusers. Rivotril should be used with extreme caution
in patients with a history of alcohol or drug abuse, dependence on CNS depressants, those
known to be addiction prone or those whose history suggests they may increase the dosage on
their own initiative.
Before prescribing and throughout treatment, assess each patient’s risk for abuse, misuse, and
addiction. Use of benzodiazepines, particularly patients at elevated risk, necessitates
counselling about the risks and proper use. Repeat prescriptions should not be given without
medical review.
Withdrawal
Once physical dependence has developed, abrupt termination of treatment or rapid dosage
reduction will be accompanied by withdrawal symptoms. The likelihood and degree of
severity of withdrawal symptoms is dependent on the duration of treatment, dose level and
degree of dependency. Withdrawal symptoms may occur with abrupt cessation of
benzodiazepines following normal therapeutic doses given for short periods of time. 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, diarrhoea, muscle pain, extreme anxiety, tension, restlessness, mood changes,
confusion, irritability and epileptic seizures which may be associated with the underlying
disease. In severe cases, the following symptoms may occur: derealisation, depersonalisation,
hyperacusis, hallucinations, numbness and tingling of the extremities and hypersensitivity to
light, noise and physical contact. Since the risk of withdrawal symptoms is greater after
abrupt discontinuation of treatment, abrupt withdrawal of Rivotril should therefore be
avoided and treatment - even if only of short duration - should be terminated by gradually
reducing the daily dose.
More serious manifestations of withdrawal are more common in patients who have received
excessive doses over a prolonged period, or in patients who have been dependent on alcohol
or other narcotic drugs in the past. An individualised withdrawal timetable needs to be
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planned for each patient in whom dependence is known or suspected. Patients should be
advised to consult their physician before either increasing the dose or abruptly discontinuing
the medication.
Rebound phenomena have been described in the context of benzodiazepine use. In some
cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with
withdrawal symptoms lasting weeks to more than 12 months.
Tolerance
Tolerance to benzodiazepines may develop from continued therapy. There is evidence that
tolerance develops to the sedative effects of benzodiazepines.
Paediatric population
In infants and young children, Rivotril may cause increased production of saliva and
bronchial secretions. Therefore, special attention must be paid to maintaining patency of the
airways.
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.
Rivotril can be administered concurrently with one or more antiepileptic agents. The
probability of pharmacokinetic interactions with these other medicines is low. Nevertheless,
adding an extra medicine to the patient’s regimen should involve a careful evaluation of the
response to the treatment because unwanted effects, such as sedation and apathy are more
likely to occur. In such cases, the dosage of each medicine must be adjusted to achieve the
optimum desired effect.
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The combination of Rivotril with valproic acid may occasionally cause petit mal status
epilepticus.
Rivotril may potentiate the anticholinergic effects of atropine and similar medicines,
antihistamines and antidepressants.
Rivotril itself does not induce the enzymes responsible for its own metabolism. The enzymes
involved in the metabolism of Rivotril have not been clearly identified but include CYP3A4.
Inhibitors of CYP3A4 (e.g. fluconazole) may impair the metabolism of Rivotril and lead to
exaggerated concentrations and effects.
The selective serotonin reuptake inhibitors (SSRIs) sertraline (weak CYP3A4 inducer),
fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbmate (CYP2C19) do not affect
the pharmacokinetics of clonazepam when administered concomitantly.
Rivotril has the potential to influence concentrations of phenytoin. Due to the bi-directional
nature of the clonazepam-phenytoin interaction, phenytoin levels have been found to be
unchanged, increased or decreased upon coadministration with Rivotril depending on dosing
and patient factors.
Enhanced side effects such as sedation and cardio-respiratory depression may also occur
when Rivotril is co-administered with any centrally acting depressants including alcohol.
Alcohol should be avoided in patients receiving Rivotril (see section 4.4, Concomitant use of
alcohol and/or CNS depressants).
See sections 4.4 and 4.9 for warning of other CNS depressants, including alcohol.
The concomitant use of benzodiazepines and opioids increases the risk of respiratory
depression because of actions at different receptor sites in the CNS that control respiration.
The potential for benzodiazepines to significantly worsen opioid-related respiratory
depression exists. Limit dosage and duration of concomitant use of benzodiazepines and
opioids, and follow patients closely for respiratory depression and sedation.
In combination therapy with centrally-acting medications, the dosage of each medicine must be
adjusted to achieve the optimum effect.
Pregnancy – Category B3
From preclinical studies it cannot be excluded that clonazepam might cause congenital
malformations. From epidemiological evaluations there is evidence that anticonvulsants act
as teratogens. However, it is difficult to determine from published epidemiological reports
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which medicine or combination of medicines is responsible for defects in the newborn. The
possibility also exists that other factors e.g. genetic factors or the epileptic condition itself
may be more important than the medication in leading to birth defects. Under these
circumstances, Rivotril should only be administered to pregnant women if the potential
benefits outweigh the risk to the foetus.
Overall, the risk of having an abnormal child is far outweighed by the dangers to the mother
and foetus of uncontrolled convulsions. It is therefore recommended that:
Breastfeeding
Although the active ingredient of Rivotril has been found to pass into the maternal milk in
small amounts only, mothers undergoing treatment with Rivotril should not breastfeed. If
there is a compelling indication for Rivotril, breastfeeding should be discontinued.
Fertility
Preclinical studies showed a reduced pregnancy rate and impaired pup survival (see
section 5.3).
Even if taken as directed, Rivotril 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 (see section 4.4).
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Post-Marketing
The adverse reactions listed in the table below have been reported during the post-marketing
period. Adverse reactions are presented according to the MedDRA system organ
classification. The frequency is “not known” (cannot be estimated from the available data).
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1
Paradoxical reactions are more likely to occur in children and in the elderly.
2
These effects 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.
3
Anterograde amnesia may occur with use of benzodiazepines at therapeutic dosages, the
risk increasing at higher dosages. Amnesic effects may be associated with inappropriate
behaviour.
4
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.
Paediatric population
Respiratory, thoracic and mediastinal disorders: In infants and young children, Rivotril may
cause increased production of saliva or of bronchial secretions. Particular attention should
therefore be paid to maintaining patency of the airways.
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4.9 Overdose
Symptoms
Treatment
Monitor the patient’s vital signs and institute supportive measures as indicated by the
patient’s clinical state. In particular, patients may require symptomatic treatment for cardio-
respiratory effects or central nervous system effects.
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.
Warning
The benzodiazepine antagonist flumazenil is not indicated in patients with epilepsy who
have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in
such patients may provoke seizures.
For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800764766).
5. PHARMACOLOGICAL PROPERTIES
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There are also animal data showing in addition an effect of clonazepam on serotonin. Animal
data and electroencephalographic (EEG) investigations in man have shown that clonazepam
rapidly suppresses many types of paroxysmal activity including the spike and wave discharge
in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with
temporal or other locations as well as irregular spikes and waves.
Generalised EEG abnormalities are more regularly suppressed than focal abnormalities.
According to these findings clonazepam has beneficial effects in generalised and focal
epilepsies.
Absorption
Clonazepam is quickly and almost completely absorbed after oral administration of Rivotril.
Peak plasma concentrations are reached in most cases within 1 - 4 hours after an oral dose.
The absorption half-life is around 25 minutes. The absolute bioavailability is around 90%
with large differences between individuals.
Plasma concentrations of clonazepam at steady state for a once-daily dosage regimen are 3-
fold higher than those after a single oral dose; the predicted accumulation ratios for two times
and three times daily regimens are 5 and 7, respectively. Following multiple oral doses of
2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged
55 ng/mL.
The plasma concentrations of clonazepam, which achieve the optimum effect are between 20
and 70 ng/mL (average 55 ng/mL). Severe toxic effects including increased frequency of
seizures developed in the majority of patients with steady state plasma concentrations above
100 ng/ml.
Distribution
Clonazepam distributes very rapidly to various organs and body tissues with preferential
uptake by brain structures.
The distribution half-life is approximately 0.5 – 1.0 hours. The volume of distribution of
clonazepam is estimated at about 3 L/kg. The plasma protein binding of clonazepam is
approximately 85%. Clonazepam must be assumed to cross the placental barrier and has been
detected in maternal milk.
Biotransformation
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Elimination
The mean elimination half-life is 30 - 40 hours and is independent of the dose. The clearance
is close to 55 mL/min irrespective of gender, but weight-normalised values declined with
increasing body weight.
50 - 70% of the 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. The urinary excretion of
unchanged clonazepam is usually less than 2% of the administered dose.
Renal impairment
Hepatic impairment
Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that
in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%).
Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been
further investigated, experience with another closely related nitrobenzodiazepine
(nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver
cirrhosis.
Elderly patients
Paediatric patients
Overall, the elimination kinetics in children are similar to those observed in adults. After
therapeutic doses to children (0.03-0.11 mg/kg) the serum concentrations were in the same
range (13-72 ng/ml) as effective concentrations in adults.
In neonates 0.10 mg/kg doses led to concentrations between 28-117 ng/ml at the end of a
short infusion, dropping to 18 – 60 ng/ml 30 minutes later; these were tolerated with no
appreciable side effects. In neonates clearance values are dependent on post-natal age.
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Elimination half-life values in neonates are of the same magnitude as those reported for
adults.
In children clearance values of 0.42 +/- 0.32 ml/min/kg (ages 2-18 years [104]) and 0.88 +/-
0.4 ml/min/kg (ages 7-12 years were reported; these values decreased with increasing body
weight. Ketogenic diet in children does not affect clonazepam concentrations.
Carcinogenicity
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 300 mg/kg/day.
Genotoxicity
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 100 mg/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 40
mg/kg/day, respectively.
6. PHARMACEUTICAL PARTICULARS
Oral solution: peach flavouring PHL-014725, saccharin sodium, glacial acetic acid,
propylene glycol and brilliant blue FCF (E133, CI42090).
6.2 Incompatibilities
In the absence of compatibility studies, this medicine must not be mixed with other
medicines.
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Rivotril 2.5 mg/mL oral solution is contained in a 10 mL amber glass bottle with controlled
release dropper in neck of bottle. Packs contain 1 bottle.
The release of medicines into the environment should be minimised. Medicines should not be
disposed of via wastewater and disposal through household waste should be avoided. Unused
or expired medicine should be returned to a pharmacy for disposal.
7. MEDICINE SCHEDULE
7. SPONSOR
08 August 2022
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