Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Martindale Pharmaceuticals Ltd, Bampton Road, Harold Hill, Essex, RM3 8UG
Clobazam must not be used:
Benzodiazepines must not be given to children without careful assessment of the need for their use. Clobazam must not be used in children between the ages of 6 month to 2 years old, other than in exceptional cases for anticonvulsant treatment where there is a compelling indication.
Amnesia may occur with benzodiazepines. In case of loss or bereavement psychological adjustment may be inhibited by benzodiazepines.
Clobazam can cause muscle weakness.Special caution is necessary if clobazam is used in patients with pre-existing muscle weakness, spinal or cerebellar ataxia or sleep apnoea. 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).
Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed and aggressive behaviour towards self and others may be precipitated. Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders
Use of benzodiazepines – including clobazam – 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 history of alcohol or drug abuse. Therefore the duration of treatment should be as short as possible (see section 4.2 Posology).;
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (or rebound phenomena). Rebound phenomena are characterised by a recurrence in enhanced form of the symptoms which originally led to clobazam treatment. This may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness.
A withdrawal syndrome may also occur when abruptly changing over from a benzodiazepine with a long duration of action (for example, clobazam) to one with a short duration of action.
Respiratory function should be monitored in patients with chronic or acute severe respiratory insufficiency and a dose reduction of clobazam may be necessary.
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.
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 period. A majority of the reported cases involved the concomitant use of other drugs, including anti-epileptic 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).
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.
In the treatment of epilepsy with benzodiazepines – including clobazam – consideration must be given to the possibility of a decrease in anti-convulsant efficacy (development of tolerance) in the course of treatment.
In patients who are CYP2C19 poor metabolisers, levels of the active metabolite N-desmethylclobazam are expected to be increased as compared to extensive metabolisers. As this may lead to increased side effects, dosage adjustment of clobazam may be necessary (e.g. low starting dose with careful dose titration (see section 5.2).
It is recommended that patients abstain from drinking alcohol during treatment with clobazam (increased risk of sedation and other adverse effects) (see section 4.5).
Concomitant use of clobazam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of benzodiazepines such as clobazam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe clobazam 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 caregivers (where applicable) to be aware of these symptoms (see section 4.5).
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.
The concomitant use of clobazam with cannabidiol-containing medicinal and non-medicinal products may result in increased exposure to N-desmethylclobazam, leading to increased incidence of somnolence and sedation. Dosage adjustment of clobazam may be necessary. Non-medicinal products containing cannabidiol must not be taken in combination with clobazam as they contain unknown quantities of cannabidiol and are of variable quality (see sections 4.5 and 5.2).
Tapclob Oral Suspension contains sorbitol. Patients with a rare hereditary problems of fructose intolerance should not take this medicine.
The medicine also contains sodium methyl and propyl hydroxybenzoates which may cause allergic reactions. The signs may include a rash, swallowing or breathing problems and swelling of the lips, face, throat or tongue.
Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% (see section 5.2) and therefore increase the effects of clobazam e.g. sedation (see section 4.5).
Especially when clobazam is administered at higher doses, an enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics, hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-convulsant 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 benzodiazepines such as clobazam 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 anti-convulsant medication (e.g. phenytoin, valproic acid) may cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dosage 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.
Stiripentol increases plasma levels of clobazam and its active metabolite N-desmethylclobazam, through inhibition of CYP3A and CYP2C19. Monitoring of blood levels of clobazam and active metabolite is recommended, prior to initiation of stiripentol, and then once new steady-state concentration has been reached, i.e. after 2 weeks approximately. Clinical monitoring is recommended and dose adjustment may be necessary.
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 (see section 5.2).
Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol) may be necessary.
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.
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 benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast-feeding mothers.
No clinical data on fertility are available. In a fertility study in male and female rats no effect on fertility was observed (see section 5.3).
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).
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The following CIOMS frequency rating is used, when applicable: Very common (≥1/10); common (≥1/100 to ≤1/10);uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000); not known (cannot be estimated from the available data).
Common: decreased appetite
Common: irritability, aggression, restlessness, depression (pre-existing depression may be unmasked), drug tolerance (especially during prolonged use) (see section 4.4), 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) (see section 4.4), initial insomnia, anger, hallucination, psychotic disorder, poor sleep quality, 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 is reversible), headache, tremor, ataxia
Uncommon: emotional poverty, amnesia (may be associated with abnormal behaviour), memory impairment, anterograde amnesia (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 injury)) (see section 4.3 and 4.4)
Common: dry mouth, nausea, constipation
Uncommon: rash
Not known: photosensitivity reaction, urticaria, Stevens-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, and is reversible)
Uncommon: fall
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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