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Clobazam

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Clobazamum; H-4723; HR-376; Klobatsaami; Klobazam; Klobazamas; LM-2717
BAN: Clobazam
USAN: Clobazam
INN: Clobazam [rINN (en)]
INN: Clobazam [rINN (es)]
INN: Clobazam [rINN (fr)]
INN: Clobazamum [rINN (la)]
INN: Клобазам [rINN (ru)]
Chemical name: 7-Chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione
Molecular formula: C16H13ClN2O2 =300.7
CAS: 22316-47-8
ATC code: N05BA09
Read code: y00Jo [Epilepsy Only]; y01yi

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Clobazam). A white or almost white crystalline powder. Slightly soluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane.

Dependence and Withdrawal

As for Diazepam.

Adverse Effects, Treatment, and Precautions

As for Diazepam.

Breast feeding. Benzodiazepines, such as clobazam, given to the mother may cause neonatal sedation and breast feeding should be avoided. For comments on antiepileptic therapy and breast feeding.

Driving. For a comment on antiepileptic drugs and driving.

Effects on menstruation. Occasionally the use of clobazam before menstruation for catamenial epilepsy appeared to delay the period.

Effects on mental function. For a review of the effects of antiepileptic therapy, including clobazam, on cognition and mood, including risk of suicidal ideation.

Effects on the skin. Report of toxic epidermal necrolysis that developed in light-exposed areas in a patient being treated with clobazam.

Porphyria. Clobazam is considered to be unsafe in patients with porphyria although there is conflicting evidence of porphyrinogenicity.

For comments on the use of benzodiazepines in porphyria.

Pregnancy. For comments on the management of epilepsy during pregnancy.

Interactions

As for Diazepam.

Antiepileptics. For reference to the interactions of clobazam withfelbamate and stiripentol, see under Diazepam.

Pharmacokinetics

Clobazam is well absorbed from the gastrointestinal tract and peak plasma concentrations are reached 1 to 4 hours after oral doses. It is about 85% bound to plasma proteins. Clobazam is highly lipophilic and rapidly crosses the blood-brain barrier. It is metabolised in the liver by demethylation and hydroxylation but unlike the 1,4-benzodiazepines such as diazepam, clobazam, a 1,5-benzodiazepine, ishydroxylatedatthe4-position rather than the 3-position (see also Metabolism under Diazepam). Clobazam is excreted unchanged and as metabolites mainly in the urine. Mean half-lives of 18 hours and 42 hours have been reported for clobazam and its main active metabolite N-desmethylclobazam, respectively.

Uses and Administration

Clobazam is a long-acting 1,5-benzodiazepine with uses similar to those of diazepam (a 1,4-benzodiazepine). It may be used as an adjunct in the treatment of epilepsy with other antiepileptics, although its use may be limited by the development of tolerance or sedation (but see below). It is also used in the short-term treatment of acute anxiety. As an adjunct in epilepsy usual oral doses in the UK are 20 to 30 mg daily, increased if necessary to a maximum of 60 mg daily. For doses in children, see below. As with other antiepileptics, withdrawal of clobazam therapy or transition to or from another type of antiep-ileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients and under Clonazepam, below.

For the short-term management of acute anxiety usual oral doses of 10 to 30 mg daily may be taken in divided doses or as a single dose at night; up to 80 mg daily has been used in hospitalised patients with severe anxiety states. Low initial doses and cautious increments to a usual daily dose of 10 to 20 mg are recommended in elderly or debilitated patients.

Administration in children. In the UK, clobazam is licensed for use as an adjunct in epilepsy in children over 3 years of age; no more than half the adult dose (see above) should be given. Alternatively, the BNFC suggests the following oral doses according to age:

• 1 month to 12 years: initially 125 micrograms/kg twice daily, increased every 5 days to a usual maintenance dose of 250 micrograms/kg twice daily. The maximum dose is 500 micrograms/kg twice daily and should not exceed 15 mg twice daily

• 12 to 18 years: initially 10 mg twice daily, increased every 5 days to a usual maintenance dose of 10 to 15 mg twice daily. The dose should not exceed 30 mg twice daily

The BNFC also suggests that clobazam may be given for cluster seizures and as monotherapy under specialist supervision for catamenial seizures (usually for 7 to 10 days each month just before and during menstruation).

Epilepsy. Benzodiazepines are sometimes used in the management of epilepsy, but their long-term use is limited by problems of sedation, dependence, and tolerance to the antiepileptic effects.

Clobazam, a 1,5-benzodiazepine, is considered to be somewhat better tolerated than conventional benzodiazepines, and has been widely used for adjunctive oral therapy in patients with epilepsy. Clobazam is active against partial and generalised seizures in epilepsy of widely differing aetiology in patients of all ages and has also been used for short-term cover in patients with intermittent seizures, including in women with catamenial epilepsy (seizures associated with menstruation) or patients whose epileptic attacks occur in clusters. Clobazam has also been tried with some success in children, including those with refractory epilepsy and epileptic encephalopathy. However, a recent systematic review concluded that although clobazam may reduce seizure frequency and may be most effective in partial onset seizures, it was not clear who would best benefit from its use and over what time-frame.

Neuropathic pain. There has been a mention of the complete relief of phantom limb pain refractory to other therapy in an elderly patient given clobazam 10 mg three times daily.

Preparations

British Pharmacopoeia 2008; Clobazam Capsules.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Karidium; Australia: Frisium; Austria: Frisium; Belgium: Frisium; Brazil: Frisium; Urbanil; Canada: Frisium; Chile: Frisin¤; Grifoclobam; Czech Republic: Frisium; Denmark: Frisium; Finland: Frisium; France: Urbanyl; Germany: Frisium; Greece: Frisium; Hong Kong: Frisium; Hungary: Frisium; India: Frisium; Ireland: Frisium; Israel: Frisium; Italy: Frisium; Malaysia: Frisium; Mexico: Frisium¤; Urbadan¤; Netherlands: Frisium; Urbadan¤; New Zealand: Frisium; Portugal: Castilium; Urbanil; South Africa: Urbanol; Singapore: Frisium¤; Spain: Clarmyl¤; Clopax¤; Noiafren; Sederlona¤; Switzerland: Urbanyl; Thailand: Frisium; United Kingdom: Frisium; Venezuela: Frisium

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