Drug Interactions between divalproex sodium and ethosuximide

MONITOR: Coadministration with valproic acid may alter the serum concentrations of ethosuximide. The exact mechanism of interaction is unknown. Data from a couple of small pharmacokinetic studies suggest that valproic acid may inhibit the metabolism of ethosuximide, although there have also been reports of decreases or no change in ethosuximide levels during concomitant valproic acid use. In a study of six healthy volunteers, administration of a single 500 mg oral dose of ethosuximide during treatment with valproic acid 800 mg to 1600 mg/day resulted in a 23% mean increase in elimination half-life and 15% mean decrease in total clearance of ethosuximide compared to administration alone. Other pharmacokinetic parameters were unchanged and similar to those reported in the literature. A high interindividual variability was observed in the interaction's occurrence, including two subjects who showed no evidence of interaction. In another study, the addition of valproic acid to ethosuximide treatment led to a 53% increase in serum ethosuximide concentration in four of five patients observed. These patients experienced sedation, and a reduction in ethosuximide dosage was necessary. By contrast, a different pharmacokinetic study reported no changes in total or nonrenal clearance of ethosuximide in six healthy volunteers during coadministration with valproic acid, and a retrospective study investigating the effects of concomitant antiepileptic therapy on ethosuximide plasma concentrations found that the mean ethosuximide level/dose ratio was significantly lower in patients who also took valproic acid.

MONITOR: Coadministration with ethosuximide may decrease the plasma concentrations of valproic acid. The exact mechanism of interaction is unknown. The interaction was reported in a study of 13 pediatric patients with epilepsy. In nine patients who had been receiving valproic acid with ethosuximide and in whom the latter was felt to be ineffective or unnecessary, mean serum valproic acid concentrations increased by 36% following the abrupt discontinuation of ethosuximide. No toxic clinical symptoms such as gastrointestinal problems, sedation, or tremor occurred. In four patients who had ethosuximide added to stable valproic acid therapy, mean serum valproic acid concentrations decreased by 30% following the addition of ethosuximide. The interaction was observed in every patient studied, although there was a high degree of interindividual variability in the magnitude of interaction.

MANAGEMENT: Caution is advised if ethosuximide and valproic acid are used in combination. Pharmacologic response and serum drug levels should be monitored more closely whenever either drug is added to or withdrawn from stabilized antiepileptic therapy, and the dosage(s) adjusted as necessary.