Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction.

Verapamil (120 mg three times a day) was given as adjunctive therapy to six patients with refractory partial epilepsy who were receiving carbamazepine (CBZ). Within a few days symptoms of CBZ neurotoxicity developed in all six patients. There was a mean rise of 46% in total and 33% in free plasma CBZ concentrations in five of these patients (p less than 0.01), and a simultaneous fall of 36% in the ratio of the principal metabolite, CBZ-10,11-epoxide, to CBZ (p less than 0.001). Two patients with mild symptoms were rechallenged with a lower verapamil dosage (120 mg twice a day) and showed similar rises in CBZ concentration and recurrent neurotoxic symptoms. Verapamil increased the area under the CBZ concentration/time curve during a dose interval by 42% in another patient. Withdrawal of verapamil was associated with a decline in circulating CBZ concentration from 12 mg/l to 7 mg/l and seizure breakthrough in a further patient who was receiving both drugs long term. These results suggest that verapamil inhibits the metabolism of CBZ to an extent likely to have important clinical repercussions.