Interdosage fluctuations in plasma carbamazepine concentration determine intermittent side effects.

Fluctuations in plasma carbamazepine concentrations were related to side effects in five epileptics. One patient was receiving only carbamazepine; four were receiving carbamazepine plus phenobarbital sodium or phenytoin sodium. The patients were studied during two 12-hour periods: carbamazepine given (1) twice daily or (2) four times daily. Concomitant medication regimens were kept constant; administration was single-blind. Plasma concentrations of carbamazepine, carbamazepine's epoxide metabolite, phenobarbital, and phenytoin were determined hourly; side effects were assessed simultaneously. Fluctuations in carbamazepine concentrations were 79% +/- 29% higher than trough levels on a twice-daily dosage schedule and 40% +/- 13% higher during four-times-a-day administration. The appearance and intensity of side effects followed the fluctuations in carbamazepine levels and were thus substantially reduced during the four-times-daily regimen. The intrapatient reproducibility of the side effects was good, whereas the thresholds of carbamazepine concentrations at which side effects appeared ranged from 17 to 37 mumole/L.