Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Sanofi-Aventis Ireland Limited T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland
Myasthenia gravis.
Hypersensitivity to clobazam, benzodiazepines or any of the excipients.
Severe respiratory insufficiency.
Sleep apnoea syndrome.
Severe hepatic insufficiency.
In breast-feeding women.
Benzodiazipines must not be given to children without careful assessment of the need for their use. Frisium must not be used in children between the ages of 6 months and 3 years, other than in exceptional cases for anticonvulsant treatment where there is a compelling indication. As there is no age appropriate formulation to enable safe and accurate dosing, no dosage recommendations can be made in children under 6 years of age (see section 4.2).
It is recommended that patients abstain from drinking alcohol during treatment with clobazam (increased risk of sedation and other adverse effects (please refer to section 4.5 Interactions with other Medicinal Products and other forms of Interaction)).
Benzodiazepines including clobazam, should be used with extreme caution in patients with a history of alcohol or drug abuse.
Concomitant use of Frisium and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Frisium with opioids should be reserved for patients for whom alternative treatment options are not possible.
If a decision is made to prescribe Frisium concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2). The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms (see section 4.5).
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
In the treatment of epilepsy with benzodiazepines – including clobazam – consideration must be given to the possibility of a decrease in anticonvulsant efficacy (development of tolerance) in the course of treatment.
Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Therefore the duration of treatment should be as short as possible (see Posology).
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (or rebound phenomena). These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur; derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.
Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
The duration of treatment should be as short as possible (see Posology). Extension beyond these periods should not take place without revaluation of the situation.
It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. When benzodiazepines with a long duration of action are being used (for example Frisium) it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also Undesirable Effects).
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued. They are more likely to occur in children and the elderly.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Benzodiazepines must not be given to children without careful assessment of the need for their use. Frisium must not be used in children between the ages of 6 months and 3 years, other than in exceptional cases for anticonvulsants treatment where there is a compelling indication.
The duration of treatment must be kept to a minimum.
In the elderly, due to the increased sensitivity to adverse reactions such as drowsiness, dizziness, muscle weakness, there is an increased risk of fall that may result in serious injury. A dose reduction is recommended.
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing experience. A majority of the reported cases involved the concomitant use of other drugs, including antiepileptic drugs, that are associated with serious skin reactions.
SJS/TEN could be associated with a fatal outcome. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment. Clobazam should be immediately discontinued when SJS/TEN is suspected. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered (see Section 4.8).
A lower dose is also recommended for patients with chronic or acute respiratory insufficiency due to the risk of respiratory depression (respiratory functions must be monitored and a dose reduction may be necessary). Clobazam is contraindicated in patients with severe respiratory insufficiency (please refer to section 4.3 Contraindications).
In patients with impairment of renal or hepatic function, responsiveness to clobazam and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long term treatment renal and hepatic function must be checked regularly. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.
Clobazam may cause muscle weakness, therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia, special observation is required and a dose reduction may be necessary. Clobazam is contraindicated in patients with myasthenia gravis.
Some epidemiological studies suggest an increased incidence of suicidal ideation, suicide attempt and suicide in patients with or without depression, and treated with benzodiazepines and other hypnotics, including clobazam. However, a causal relationship has not been established (see section 4.8).
In patients who are CYP2C19 poor metabolisers, levels of the active metabolite N-desmethylclobazam are expected to be increased as compared to extensive metabolizers. Dosage adjustment of clobazam may be necessary (e.g. low starting dose with care dose titration (please refer to section 5.2)).
The concomitant use of clobazam with cannabidiol-containing medicinal and nonmedicinal products may result in increased exposure to N-desmethylclobazam, leading to increased incidence of somnolence and sedation. Dosage adjustment of clobazam may be necessary. Nonmedicinal products containing cannabidiol must not be taken in combination with clobazam as they contain unknown quantities of cannabidiol and are of variable quality (see Section 4.5, and 5.2).
Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% (please refer to Section 5.2) and therefore increase the effects of Clobazam e.g. sedation. This affects the ability to drive or use machines.
Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics , hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines. Special caution is also necessary when clobazam is administered in cases of intoxication with such substances or with lithium.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Frisium with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
Addition of clobazam to established anticonvulsant medication (e.g phenytoin, valproic acid) might cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dose of Frisium should be determined by monitoring the EEG and the plasma levels of the other drugs checked.
Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N–desmethyl clobazam which may result in adverse reactions.
Stiripentol increases plasma levels of clobazam and its active metabolite N-desmethylclobazam, through inhibition of CYP3A and CYP2C19. Monitoring of blood levels is recommended, prior to initiation of stiripentol, and then once new steady-state concentration has been reached, i.e. after 2 weeks approximately.
If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.
The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced.
Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam (N-CLB), the active metabolite of clobazam. Dosage adjustment of clobazam may be necessary when co-administered with strong (e.g. fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C19 inhibitors (please refer to Section 5.2).
When cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on a healthy volunteer study, elevated levels (3-to 4-fold) of N-desmethylclobazam (an active metabolite of clobazam) can occur when combined with cannabidiol, likely mediated by CYP2C19 inhibition. Increased systemic levels of these active substances may lead to enhanced pharmacological effects and to an increase in adverse drug reactions. Concomitant use of cannabidiol and clobazam increases the incidence of somnolence and sedation. Reduction in dose of clobazam should be considered if somnolence or sedation are experienced when clobazam is co-administered with cannabidiol.
Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol may be necessary.
There are limited amount of data from the use of clobazam in pregnant women. Nevertheless, a large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of major malformations following exposure to benzodiazepines during the first trimester of pregnancy, although incidences of cleft lip and palate were reported in certain case-control studies.
Clobazam is not recommended during pregnancy and in women of childbearing potential not using contraception. Clobazam crosses the placenta. Animal studies have demonstrated reproductive toxicity (see section 5.3).
Women of childbearing potential should be informed of the risks and benefits of the use of clobazam during pregnancy.
Women of childbearing potential should be informed to contact her physician regarding discontinuation of the product if they are pregnant or intend to become pregnant. If clobazam treatment is continued, it should be used at the lowest effective dose.
Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during the second and/or third trimester of pregnancy.
If clobazam is administered during the late phase of pregnancy or during childbirth, effects on the neonate, such as respiratory depression (including respiratory distress and apnea), sedation signs, hypothermia, hypotonia, and feeding difficulties in the newborn (so-called “floppy infant syndrome”) are to be expected.
Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk of developing a withdrawal syndrome in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.
Since benzodizepines are found in the breast milk, clobazam must not be used in breast-feeding women.
There is insufficient information to assess effects of clobazam on fertility in humans.
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also Interactions).
Common: decreased appetite
Common: irritability, aggression, restlessness, depression (pre-existing depression may be unmasked), drug tolerance (especially during prolonged use), agitation
Uncommon: abnormal behaviour, confusional state, anxiety, delusion, nightmare, loss of libido (particularly with high doses or in long-term treatment and is reversible)
Not known: dependence (especially during prolonged use), initial insomnia, anger, hallucination, psychotic disorder, poor quality sleep, suicidal ideation
Very common: somnolence, especially at the beginning of treatment and when higher doses are used
Common: sedation, dizziness, disturbance in attention, slow speech/dysarthria/ speech disorder (particularly with high doses or in long-term treatment, and are reversible), headache, tremor, ataxia
Uncommon: emotional poverty, amnesia (may be associated with abnormal behaviour), memory impairment, anterograde amnesia (in (in the normal dose range, but especially at higher dose levels)
Not known: cognitive disorder, altered state of consciousness (particularly in elderly patients, may be combined with respiratory disorders), nystagmus (particularly with high doses or in long-term treatment), gait disturbance (particularly with high doses or in long-term treatment and is reversible)
Uncommon: diplopia (particularly with high doses or in long-term treatment and is reversible)
Not known: respiratory depression respiratory failure (particularly in patients with pre-existing compromised respiratory function e.g. in patients with bronchial asthma or brain damage) (see Sections 4.3 Contraindications and 4.4 Warnings and Precautions)
Common: dry mouth, nausea, constipation
Uncommon: rash
Not known: urticaria; Steven-Johnson syndrome, toxic epidermal necrolysis (including some cases with fatal outcome);
Not known: muscle spasms, muscle weakness
Very common: fatigue, especially at the beginning of treatment and when higher doses are used
Not known: slow response to stimuli, hypothermia
Uncommon: weight increased (particularly with high doses or in long-term treatment) Injury poisoning and procedural complications
Uncommon: fall
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/rick balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance. Website: www.hpra.ie.
Not applicable.
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