DAILY FLUCTUATION OF PLASMA-LEVELS WITH CONVENTIONAL AND CONTROLLED-RELEASE CARBAMAZEPINE - CORRELATION WITH ADVERSE-EFFECTS

The pharmacokinetics, tolerability, and efficacy of carbamazepine (CBZ ) and the pharmacokinetics of carbamazepine-10, Il-epoxide (CBZE) were studied after chronic administration of a conventional tablet formula tion or of the controlled-release (CR) formulation of CBZ 400 mg (Tegr etol 400) to 20 patients with epilepsy treated with carbamazepine and complaining of intermittent adverse effects. To compare the two formul ations at the same doses and dose schedules, the study design had to b e open, within-patient, with an initial 4 week period to individually adjust the dosage schedule with conventional CBZ followed by a 4 week period in which the CR formulation was substituted for conventional CB Z at the same daily dose and given by the same schedule. A further 4 w eek period was also studied to evaluate the same dosage of the CR form ulation but given b.i.d. In this latter period six patients required a n increase in dosage (200 mg/day). Before the beginning of the study a nd at the end of each period seizure frequency and tolerability were a ssessed. Tolerability was estimated with a specifically prepared scale that assesses the main items and with an overall rating scale. At the end of each treatment period, serum levels of CBZ and CBZE were deter mined at various times over a 10 h period. Peak plasma concentrations (C-max) of CBZ and the fluctuation index (FI) were significantly lower for the CR CBZ, although minimal and mean plasma concentrations were the same in the three periods of the study. The number of patients wit h and without seizures and the number of seizures in poorly controlled patients did not differ significantly in the three periods, but the n umber of patients with adverse effects decreased significantly with CR CBZ. The incidence and the severity of diplopia, vertigo and nystagmu s correlated with the FI and/or the C-max of CBZ, being greater in pat ients with a C-max over 8 mu g/ml or an FI over 25%.