Interactions of clobazam with conventional antiepileptics in children

Clobazam is a 1,5-benzodiazepine effective in antiepileptic therapy of children and adults. Presently it is mainly used as adjuvant therapy for intractable seizures. Our objective was to evaluate the effect of clobazam on the apparent clearance of other antiepileptic drugs at steady state, and to determine the factors that determine the plasma levels of clobazam and its active metabolite N-desmethylclobazam. Patients were 74 children with intractable seizures who received treatment with clobazam at our institution as part of the Canadian Cooperative Clobazam Study Group during the years 1987 to 1991. Serum concentrations of clobazam, N-desmethylclobazam, and of concomitant antiepileptic drugs were monitored and prospectively collected. The effect of clobazam treatment on the apparent clearance steady state of the other antiepileptic drugs was determined by statistical comparison of the clearances of each drug before and after initiation of clobazam treatment using Wilcoxon's signed rank test. The effects of dosage, age, and concomitant antiepileptic therapy on the levels of clobazam and N-desmethylclobazam was assessed by multivariate analysis. Response to treatment and incidence of adverse effects were evaluated for each conventional antiepileptic drug to possibly identify favorable or unfavorable combinations with clobazam. Whereas the clearances of most conventional antiepileptics are not affected by cotherapy with clobazam, the apparent clearances of valproic acid and primidone are significantly reduced in the presence of clobazam. Serum concentrations of clobazam increased with dosage and age, and decreased with phenobarbital cotherapy. Serum concentrations of N-desmethylclobazam significantly correlated with clobazam serum levels, age, or clobazam dosage and were significantly increased by cotherapy with phenytoin or carbamazepine. None of the concomitantly used drugs were associated with increased or decreased rate of seizure control. Twelve patients experienced mild adverse drug effects that were not associated with particular cotherapy, clobazam dose, or plasma concentrations. When clobazam is added to a therapy regimen that includes valproic acid, the patient should be closely followed for possible adverse drug reactions caused by elevated valproic acid serum concentrations, and monitoring of valproate serum levels should be considered. When clobazam doses are gradually increased to achieve an optimal clinical effect, the interactions with phenobarbital, carbamazepine, and phenytoin do not necessitate therapeutic drug monitoring of clobazam or N-desmethylclobazam, because there is a large therapeutic window and a poor correlation between plasma concentrations and therapeutic efficacy.