Summary of Product Characteristics Updated 17-May-2018 | Rosemont Pharmaceuticals Limited
PosologyIf low doses are required, the 1mg/ml strength product the most suitable presentation. If high doses are required, the 2mg/ml strength product is the most suitable presentation.
Treatment of anxiety
AdultsThe usual anxiolytic dose for adults is 20-30 mg daily in divided doses or as a single dose given at night. Doses up to 60mg daily have been used in the treatment of adult in-patients with severe anxiety. The lowest dose that can control symptoms should be used. After improvement of the symptoms, the dose may be reduced. It should not be used for longer than 4 weeks. Long term chronic use as an anxiolytic is not recommended. In certain cases, extension beyond the maximum treatment period may be necessary; treatment must not be extended without re-evaluation of the patient's status using special expertise. It is strongly recommended that prolonged periods of uninterrupted treatment be avoided, since they may lead to dependence. Treatment should always be withdrawn gradually. Patients who have taken Perizam for a long time may require a longer period during which doses are reduced.Elderly: Doses of 10-20 mg daily in anxiety may be used in the elderly, who are more sensitive to the effects of psychoactive agents. Treatment requires low initial doses and gradual dose increments under careful observation.
Treatment of epilepsy in association with one or more other anticonvulsants
AdultsIn epilepsy a starting dose of 20-30 mg/day is recommended, increasing as necessary up to a maximum of 60 mg daily.
ElderlyTreatment requires low initial doses and gradual dose increments under careful observation.
Paediatric patients over 2 years:Perizam doses should be adapted individually. Doses can be taken once a day or divided in 2 3 times a day, keeping the same total dose.The patient must be re-assessed after a period not exceeding 4 weeks and every 4 weeks thereafter in order to evaluate the need for continued treatment. A break in therapy may be beneficial if drug exhaustion develops, recommencing therapy at a low dose. At the end of treatment (including in poor-responding patients), since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended to gradually decrease the dosage.When prescribed for children treatment requires low initial doses and gradual dose increments under careful observation. Clobazam is typically initiated at a low dose, often 5 mg/day or 0.1 mg/kg/day for younger patients, and increased by step of 0.1 to 0.2 mg/kg/day at 7 days intervals, until a minimum effective dose is reached or side effects occur. Studies have suggested that slow titration may help avoid adverse effects and that when present, side effects may be reduced or eliminated with dose reduction.The following up-titration regimen has been proposed in the literature in order to take into account the high metabolism variability linked to the P450 system maturation - especially in the presence of inducers and inhibitors - and should be used with increase of the dose by 0.1 to 0.2 mg/kg every week up to the targeted dose.A maintenance dose of 0.3 to 1mg/kg body weight daily is usually sufficient. The oral suspension is particularly recommended for children and adults with swallowing difficulties, as it allows a secure and precise dosage.Perizam should not be used as an anticonvulsivant treatment in children from 6 months to 2 years old, unless under exceptional situations, when there is a clear epilepsy indication. The starting dose in this exceptional circumstances should be the lowest one (0.1 mg/kg/day) and titration should be even more cautious, not more than 0.1 mg/kg/day as in this population the metabolic pathways for clobazam may not be fully mature. Up-to-date, no precise dosage recommendation can be made in this population.
Hepatic and renal failureTreatment requires low initial doses and gradual dose increments under careful observation regardless of the age group of the patient.
Method of administrationFor oral use onlyOnce titrated to an effective dose of Clobazam, patients should remain on their treatment and care should be exercised when changing between different formulations. (See section 4.4-Switching between formulations)This product may settle during storage. Please shake the bottle thoroughly before use.Perizam can be taken with or without food.
Switching between formulationsIn 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.
ChildrenThere 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.
AmnesiaAmnesia may occur with benzodiazepines. In case of loss or bereavement psychological adjustment may be inhibited by benzodiazepines. • Muscle weaknessClobazam can cause muscle weakness. Therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia or sleep apnoea, special observation is required and a dose reduction may be necessary. Clobazam is contraindicated in patients with myasthenia gravis.• Depression and personality disordersDisinhibiting 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. • DependenceUse of benzodiazepines - including clobazam - 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). 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, Perizam) to one with a short duration of action. • Respiratory DepressionRespiratory 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).• Renal and hepatic impairmentIn 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. • Elderly patientsIn 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.• Tolerance in epilepsyIn 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 anti-epileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used anti-epileptics, progress of the disease, or a paradoxical effect.• Psychiatric and paradoxical reactionsBenzodiazepines 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. (See section 4.8). Should this occur, use of the medicinal product should be discontinued.They are more likely to occur in children and the elderly. • Suicidal Ideation and behaviourSuicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for clobazam.Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.• CYP2C19 poor metabolisersIn 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 (please refer to section 5.2)).• AlcoholIt 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).
Excipient Warnings• Sodium contains 2.3mg/ml. 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.• Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Central nervous system depressant drugsEspecially 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. • AnticonvulsantsAddition 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.• MAOIsConcomitant administration of drugs, inhibit the monooxygenase system, such as cimetidine and erythromycin, can enhance the effects of Clobazam. • Narcotic analgesicsIf clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.• Muscle relaxantsThe effects of muscle relaxants, analgesics and nitrous oxide may be enhanced. • CYP 2C19 inhibitorsStrong 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).• CYP 2D6 substratesClobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol may be necessary.
PregnancyClobazam 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.
Breast-feedingSince benzodiazepines are found in the breast milk, benzodiazepines must not be given to breast feeding mothers.
FertilityNo effects on fertility were observed in animals (see section 5.3).
Reporting of suspected adverse reactionsReporting 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.
AbsorptionAfter oral administration, clobazam is rapidly and extensively absorbed.Time to peak plasma concentrations (Tmax) is achieved from 0.5 4.0 hrs.The peak plasma level of clobazam after oral administration of Clobazam Oral Suspension 2mg/ml was higher than that observed after administration of a reference 10mg tablet in a single dose, randomised, crossover bioequivalence study (mean Cmax 263.1 ± 54.38 ng and 224.00 ± 22.96 ng/ml, respectively).Concomitant intake of alcohol can increase the bioavailability of clobazam by 50%.
DistributionAfter a single dose of 20 mg clobazam, marked interindividual variability in maximum plasma concentrations (222 to 709 ng/ml) was observed after 0.25 to 4 hours. Clobazam is lipophilic and distributes rapidly throughout the body. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady-state was approximately 102 L, and is concentration independent over the therapeutic range. Approximately 80 90% of clobazam is bound to plasma protein.Clobazam accumulates approximately 2-3 fold to steady-state while the active metabolite N-desmethylclobazam (N-CLB) accumulates approximately 20-fold following clobazam twice daily administration. Steady state concentrations are reached within approximately 2 weeks.
MetabolismClobazam is rapidly and extensively metabolized in the liver. Clobazam metabolism occurs primarily by hepatic demethylation to N-desmethylclobazam (N-CLB), mediated by CYP3A4 and to a lesser extent by CYP2C19. N-CLB is an active metabolite and the main circulating metabolite found in human plasma.N-CLB undergoes further biotransformation in the liver to form 4-hydroxy-N-desmethylclobazam, primarily mediated by CYP2C19.CYP2C19 poor metabolizers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolizers.Clobazam is a weak CYP2D6 inhibitor. Co-administration with dextromethorphan led to increases of 90% in AUC and 59% in Cmax values for dextromethorphan.Concomitant administration of 400 mg ketoconazole (CYP3A4 inhibitor) increased Clobazam AUC by 54% with no effect on Cmax. These changes are not considered clinically relevant.
EliminationBased on a population pharmacokinetic analysis, plasma elimination half-lives of clobazam and N-CLB were estimated to be 36 hours and 79 hours respectively.Clobazam is cleared mainly by hepatic metabolism with subsequent renal elimination. In a mass balance study, approximately 80% of the administered dose was recovered in urine and about 11% in the faeces. Less than 1 % of unchanged clobazam and less than 10% of unchanged N-CLB are excreted through the kidneys.
• Populations at RiskElderlyHepatic metabolism decreases and total clearance with increasing concentrations at equilibrium, the free-fraction and half-lives. It is important to reduce the dose.
Hepatic ImpairmentThere is a decrease in total clearance.
Chronic toxicityIn chronic toxicity studies in rats with daily oral clobazam administration of 12-1000 mg/kg, spontaneous activity was dose-dependently reduced, whereas respiratory depression and hypothermia were observed at the high dose level. Dose-dependent sedation, somnolence, ataxia and tremor were initially evident in dogs receiving daily oral doses of 2.5-80 mg/kg clobazam, which almost completely reversed in the course of the study. Similar dose-dependent effects were noted in monkeys after daily oral administration of 2.5-20 mg/kg.
Reproduction toxicityIn fertility studies in mice with daily administration of 200 mg/kg clobazam and in rats receiving daily doses of 85 mg/kg, impairment of fertility and gravidity was observed. Reproduction toxicity studies in mice, rats and rabbits revealed no teratogenic potential after daily administration up to 100 mg/kg clobazam.Genotoxicty and carcinogenicityClobazam is not genotoxic or tumorigenic. Follicular cell adenoma were significantly increased in rats at the 100 mg/kg clobazam high dose. In contrast to other species (mouse, dog, monkey), clobazam is known to activate the thyroid gland in rats like other benzodiazepine-containing agents. No effects on human thyroid function were noted at clinically relevant doses (20-80 mg).
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