What is the role of clobazam in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Answer

Clobazam has a 1,5 substitution instead of the usual 1,4-diazepine. This change results in an 80% reduction in its anxiolytic activity and a 10-fold decrease in its sedative effects. It has been licensed in Europe since 1975 but is not available in the United States. In addition to its agonist action at the GABA-A receptor, clobazam may affect voltage-sensitive conductance of calcium ions and the function of sodium channels.

Clobazam is relatively insoluble in water; therefore, no IV or intramuscular (IM) preparations are available. Its oral bioavailability is about 90%. Time to peak plasma concentration (Tmax) is 1-4 hours. The absorption rate is decreased when clobazam is taken with meals, but total absorption is not affected.

Plasma protein binding of clobazam is approximately 83% with the proportion of bound to unbound drug independent of clobazam concentration. Very low plasma protein levels are associated with increases in the unbound (ie, free) fraction, for example, in renal or hepatic disease. Brain and saliva concentrations are proportional to the unbound fraction. A good correlation exists between dosage and plasma levels; significant interindividual variations exist.

Clobazam is metabolized by oxidation in the liver to norclobazam (N -desmethylclobazam). This metabolite has a very long half-life (ie, 50 h), but it has a low affinity for the benzodiazepine receptor, and its antiepileptic effect is unclear. The elimination half-life usually is in the range of 10-50 hours. Norclobazam is conjugated in the liver and excreted in the bile as glucuronate and in the urine as sulfate. The clobazam plasma level is 20-350 ng/mL Norclobazam levels typically are 10 times higher than clobazam levels at usual clinical dosage.

No significant clinical interactions are reported for clobazam. Minor interactions are common.

Clobazam is a potent anticonvulsant for partial epilepsy. No double-blind, controlled studies have been reported, but the trials performed showed a striking benefit. In 1 study, the mean reduction of seizures was 50% in more than 50% of patients. These patients had partial epilepsy and were taking other antiepileptic drugs (AEDs). In 1 Canadian study in drug-naïve children, clobazam monotherapy was found to be as effective as CBZ or PHT.

The major clinical problem with clobazam is the development of tolerance; sedation tolerance is more evident than antiepileptic tolerance. No clear correlation between plasma levels and seizure control has been found. No measures have been effective against the development of tolerance. The anxiolytic effect (mild) may be beneficial for some patients. Clobazam is effective in a wide range of epilepsies and should be considered as adjunctive therapy. It can be used in patients with Lennox-Gastaut syndrome or primary or secondarily generalized seizures.

Clobazam is administered orally at a dose 10-20 mg/d, taken at night or twice daily. No parenteral preparations are available.

Essentially, the adverse effects of clobazam are similar to those of other benzodiazepines. The most common effect is sedation. Other adverse effects include dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue, and weakness. Idiosyncratic reactions are very rare and no fatal reactions have been reported so far.

Clobazam is useful in intermittent treatments (eg, catamenial epilepsy) and as prophylaxis for some situations, such as traveling, celebrations, and other occasions.


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