Sympazan (clobazam)

Clobazam, a 1,5-benzodiazepine, is an anticonvulsant that also demonstrates anxiolytic properties.

Clobazam is a 1,5-benzodiazepine that has anticonvulsant as well as anxiolytic properties. The exact mechanism of clobazam's anticonvulsant and anxiolytic actions has not been fully elucidated, but is thought to involve allosteric binding of the drug to the benzodiazepine site of the gamma-aminobutyric acid type A (GABAA) receptor, which in turn potentiates the inhibitory effects of GABA. Although structurally similar to the 1,4-benzodiazepines (e.g., clonazepam, diazepam, lorazepam), clobazam appears to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects), which have been attributed to differences in binding affinity for the GABAA receptor.

Clobazam is rapidly and almost completely absorbed following oral administration; peak plasma concentrations of the drug are achieved within 0.5-4 hours after single- or multiple-dose administration of the tablets and within 0.5-2 hours following single-dose administration of the oral suspension under fasting conditions. Bioavailability of the oral suspension is similar to that of the tablets under fasting conditions. Clobazam oral film and tablets are bioequivalent following administration of single doses of 10 or 20 mg.

After the oral film is placed on the tongue, the median time to disintegration is 82 seconds (range: 18-245 seconds) for the 10-mg film and 105 seconds (range: 45-300 seconds) for the 20-mg film. Food does not appear to substantially affect absorption of clobazam tablets; although not evaluated, bioavailability of the oral suspension and oral film also are unlikely to be altered by food. Because clobazam is highly lipophilic, it distributes rapidly throughout the body.

Clobazam is extensively metabolized in the liver where it undergoes N-demethylation and hydroxylation; approximately 2% and 1% of an orally administered dose is present in urine and feces, respectively, as unchanged drug. At least 14 metabolites of clobazam have been identified. The main circulating metabolite, N-desmethylclobazam, is pharmacologically active with potency estimates ranging from one-fifth to equal potency of the parent drug; therefore, the active metabolite may contribute to the efficacy and safety of the drug.

At therapeutic dosages, plasma concentrations of N-desmethylclobazam are approximately 3-5 times higher than those of clobazam. Biotransformation of clobazam to N-desmethylclobazam is mediated by the cytochrome P-450 (CYP) enzyme system, principally by CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6; N-desmethylclobazam is further metabolized by CYP2C19 to an inactive derivative. Both clobazam and N-desmethylclobazam are substrates of P-glycoprotein, but do not inhibit the transport protein.

Both the drug and its active metabolite also exhibit a high degree of protein binding (80-90 and 70%, respectively). Clobazam is eliminated mainly through renal excretion; following administration of a single radiolabeled dose of clobazam, approximately 82% of the dose was recovered in urine and 11% in feces. The mean elimination half-life of clobazam is approximately 36-42 hours and the mean elimination half-life of N-desmethylclobazam is approximately 71-82 hours.

Genetic polymorphism of the CYP2C19 isoenzyme can affect the metabolism of N-desmethylclobazam and result in possible increased concentrations of the active metabolite. Individuals with 2 copies of the CYP2C19*2 allele (the *2/*2 genotype) are described as poor metabolizers, those with 1 copy (the *1/*2 genotype) are intermediate metabolizers, and those homozygous for the wild-type CYP2C19*1 allele (the *1/*1 genotype) are described as extensive metabolizers. Systemic exposure to N-desmethylclobazam is approximately 3-5 and 2 times higher in poor and intermediate CYP2C19 metabolizers, respectively, than in extensive metabolizers.

Systemic exposure of clobazam is similar for both poor and extensive metabolizers of CYP2C19 substrates. The prevalence of poor CYP2C19 metabolizers in the general population varies depending on ethnic and racial background and has been reported to be as high as 15-30% among Asians, with a lower prevalence in Caucasians.

USES: This medication is used to treat seizures. It belongs to a class of medications called benzodiazepines. It works by calming the brain and nerves.

Generic name: clobazam
Pronunciation: (KLOE-ba-zam)

The following indications are listed for Sympazan:

• Lennox-Gastaut Syndrome Treatment Adjunct

Also known as: Lgs Treatment Adjunct.

No ICD codes are available for this drug.