Adult: 20-30 mg daily in divided doses or as single dose preferably at bedtime. If necessary, may increase dose up to 60 mg daily in patients with severe anxiety. Duration of treatment: Not exceeding 4 weeks and patient must be re-assessed after. Use the lowest possible dose for the shortest possible time. Elderly: 10-20 mg daily. Observe carefully during gradual dose increments.
Oral Adjunct in epilepsy
Adult: Initially, 20-30 mg daily. Max: 60 mg daily. Child: ≥2 years As oral suspension: 0.1 mg/kg daily, may increase slowly in increments of 0.1-0.2 mg/kg daily at 7 days interval until adequate response is achieved or toxicity occurs; ≥6 years As tab or oral suspension: Initially, 5 mg daily. Maintenance: 0.3-1 mg/kg daily. Max: 60 mg daily. Initiate at low doses and observe carefully during gradual dose increments. Elderly: Initiate at low doses and observe carefully during gradual dose increments.
Special Patient Group
Clobazam is extensively metabolised in the liver by CYP3A and to a lesser extent by CYP2C19 and CYP2B6 to active metabolite, N-desmethylclobazam (NCLB). The active metabolite, NCLB, may substantially contribute to the safety and efficacy of long-term use of clobazam in adjunctive therapy in epilepsy. CYP2C19 is the major contributor for the hydroxylation of NCLB to inactive metabolite, 4-hydroxydesmethylclobazam; the CYP2C19 genotype is the main determinant of the serum concentration of NCLB. Therefore, genetic polymorphism of CYP2C19 may affect the pharmacokinetics of clobazam.
The activity of CYP2C19 is decreased in individuals with mutant alleles, which are CYP2C19*2 and CYP2C19*3. The allele frequencies of CYP2C19 varies among different ethnic backgrounds. The frequency of CYP2C19*2 and CYP2C19*3 is 30% and 5%, respectively, in the Japanese population which are higher than those of 15% and 0.04%, respectively, in Caucasians. CYP2C19*2 and CYP2C19*3 mutant alleles are associated with poor metaboliser phenotype, which may affect both the safety and effectiveness of a drug.
CYP2C19 extensive metabolisers
Carriers of homozygous alleles e.g. *1/*1 may have an increased metabolism of NCLB as compared to other groups and may lead to poorer response to treatment. The risk of adverse effects may also be lower in these individuals.
CYP2C19 immediate metabolisers
Carriers of heterozygous alleles e.g. *1/*2, *1/*3 may have an increased metabolism of NCLB as compared to poor metabolisers, and decreased metabolism but also a better response to treatment as compared to extensive metabolisers.
CYP2C19 poor metabolisers
Carriers of *2/*2, *3/*3, *2/*3 alleles. These patients lack the activity of CYP2C19 resulting in increased levels of NCLB as compared to extensive metabolisers. According to studies, although polymorphisms have no effect on the development of tolerance to or adverse reactions of clobazam, higher incidents of adverse effects were observed in poor metabolisers. Concomitant use of CYP3A4 inducers or CYP2C19 inhibitors in these individuals may also influence the serum concentration levels of NCLB. Product guidelines recommend dose adjustment.
Recommended dose in adjunctive therapy in epilepsy: Initially, 5 mg daily, may increase dose slowly according to weight or depending on patient tolerability and safety.
Adjunct in epilepsy: Mild to moderate: Initially, 5 mg daily for 1 week, may increase dose depending on patient response and tolerability. Max: 40 mg/day. Severe: Contraindicated.
May be taken with or without food.
Chống chỉ định
History of drug or alcohol dependence, myasthenia gravis, severe respiratory insufficiency, sleep apnoea syndrome. Severe hepatic impairment. Pregnancy (1st trimester) and lactation.
Patients with spinal or cerebellar ataxia, pre-existing muscle weakness, personality disorders (e.g. depression), at risk of falls. Avoid abrupt discontinuation and prolonged use. Renal and mild to moderate hepatic impairment. Children and elderly. Pregnancy (2nd-3rd trimester). CYP2C19 poor metabolisers. Concomitant use with opioids.
This drug may cause sedation, amnesia, impaired concentration and impaired muscular function, if affected, do not drive or operate machinery.
Monitor respiratory, renal and hepatic function; signs and symptoms of dermatological toxicities, depression or suicidal thoughts. Assess seizure control and ensure adequate tolerance of the medications.
Symptoms: CNS depression associated with drowsiness, confusion, lethargy, progressing to ataxia, hypotonia, hypotension, respiratory depression, rarely, coma or death. Management: Supportive treatment. Perform gastric lavage and/or administration of activated charcoal, IV fluid replenishment. Monitor vital signs and level of consciousness. Hypotension may be treated by replenishment with plasma substitutes and with sympathomimetic agents if necessary.
Concomitant use with opioids may result in sedation, respiratory depression, and coma. Enhanced CNS depressive effect with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, anticonvulsants, anaesthetics and sedative antihistamines. Increased serum concentration of phenytoin. Increased plasma concentrations with CYP2C19 and CYP3A inhibitors (e.g. stiripentol) or moderate to strong CYP2C19 inhibitors (e.g. fluconazole, fluvoxamine, ticlopidine, omeprazole). Enhanced effects of muscle relaxants, analgesics, and nitrous oxide. Decreased serum concentration of hormonal contraceptives (e.g. oestrogen).
Increased bioavailability of clobazam with alcohol and therefore enhances the CNS depressant effect.
Description: Clobazam is a long-acting 1,5-benzodiazepine that binds at the benzodiazepine site of the GABAA receptor within the central nervous system including the limbic system and reticular formation, thereby increasing neuronal membrane permeability to Cl ions and enhancing the inhibitory effect of GABA. The shift in Cl ion leads to hyperpolarisation (less excitable state) and stabilisation. Onset: Max effect: 5-9 days. Pharmacokinetics: Absorption: Rapidly and extensively absorbed from the gastrointestinal tract. Bioavailability: Approx 100% (tab). Time to peak plasma concentrations: 0.5-4 hours (tab); 0.5-2 hours (oral suspension). Distribution: Rapidly distributed throughout the body; crosses placenta and present in breast milk. Volume of distribution: 100 L. Plasma protein binding: 80-90% (clobazam); 70% (active metabolite). Metabolism: Extensively metabolised in the liver by CYP3A and to a lesser extent by CYP2C19 and 2B6 via N-demethylation to the active metabolite, N-desmethylclobazam (NCLB); and subsequently by CYP2C19 via hydroxylation to an inactive metabolite. Excretion: Via urine (approx 82%; approx 2% as unchanged drug, approx 94% as NCLB); faeces (approx 11%; 1% as unchanged drug). Elimination half-life: 36-42 hours (clobazam); 71-82 hours (NCLB).
N05BA09 - clobazam ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.
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