Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK
Perizam must not be used:
Benzodiazepines must not be given to children without careful assessment of the need for their use.
Perizam should not be used in children from 6 months to 2 years old, unless under exceptional situations as an anticonvulsivant treatment, when there is a clear epilepsy indication.
Before treatment of anxiety states associated with emotional instability, it must first be determined whether the patient suffers from a depressive disorder requiring adjunctive or different treatment. Indeed, in patients with anxiety associated with depression, Perizam must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepine (such as Perizam) alone, can precipitate suicide in such patients.
In some individuals taking Perizam, the drug reaches higher plasma levels than the same dose taken as a tablet. This may lead to an increased risk of respiratory depression and sedation which may be most noticeable when switching to this medicine from tablets. Therefore, caution must be taken when switching between clobazam products as the mean Cmax on single dose administration for the suspension is higher than that observed for the tablet formulation.
There is a lack of data regarding the use of the product in patients under 2 years old. For this reason, careful assessment and monitoring is required by the treating physician for use in children under 2 years for anticonvulsant treatment.
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 Perizam 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 Perizam with opioids should be reserved for patients for whom alternative treatment options are not possible.
If a decision is made to prescribe Perizam 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 anxiolytic 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.
As with other antiepileptic medicines, some patients may experience an increase in the frequency of seizures or the appearance of new types of seizures with clobazam. These phenomena can be the consequence of an overdose, a decrease in the plasma concentrations of antiepileptics used in combination, a progression of the disease or a paradoxical effect.
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.
Withdrawal syndrome can also occur when abruptly changing from a long-lasting benzodiazepine (e.g. LIKOZAM) to a short-acting benzodiazepine.
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.
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 Perizam) it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Abuse of benzodiazepines has been reported.
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.
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).
They are more likely to occur in children and the elderly.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
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.
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)
Respiratory function should be monitored in patients with chronic or acute severe respiratory insufficiency and a dose reduction of clobazam 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.
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
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)).
Perizam contains 2.3 mg of sodium per ml, equivalent to 0.12% of the WHO recommended maximum daily intake of 2g sodium for an adult. This should be taken into account by patients on a low sodium diet.
Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate. These may cause an allergic reaction. This allergy may happen some time after starting the medicine.
Liquid Maltitol (E965) 0.3g in 1 ml. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Propylene Glycol (E1520) 6.21mg in 1ml. Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates.
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 (please refer to 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 (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anticonvulsant drugs, anaesthetics and sedative antihistamines. Special caution is also necessary when clobazam is administered in cases of intoxication with such substances or with lithium.
Addition of clobazam to established anticonvulsant medication (eg, phenytoin, valproic acid) may cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dosage of Perizam 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.
Concomitant administration of drugs, inhibit the monooxygenase system, such as cimetidine and erythromycin, can enhance the effects of Clobazam.
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).
Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol may be necessary.
Clobazam must not be used in the first trimester of pregnancy or in breast-feeding women. If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become pregnant or suspects that she is pregnant.
Administration of clobazam before or during childbirth can result in the occurrence of respiratory depression (including respiratory distress and apnea), which may be associated with other disorders such as sedation signs, hypothermia, hypotonia, and feeding difficulties in the new born (signs and symptoms of the so-called “floppy infant syndrome”).
In the later stages of pregnancy, it must only be used if there are compelling indications.
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 for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.
Since benzodiazepines are found in the breast milk, benzodiazepines must not be given to breast feeding mothers.
No effects on fertility were observed in animals (see section 5.3).
Clobazam has major influence on the ability to drive and use machines. 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 behavior, 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 damage) (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 continuing 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.
In the absence of compatibility studies, this product must not be mixed with other medicinal products or beverages.
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