Abstracts

Neurobehavioral effects of TPM have been the subject of considerable discussion since early studies of high-dose TPM as add-on therapy in adults. However, such AEs were generally lower in children, perhaps due to the use of relatively lower doses and more gradual titration. TPM as monotherapy in newly diagnosed epilepsy allows neurobehavioral AEs to be evaluated without antiepileptic drug (AED) cotherapy as a confounder, albeit without placebo to control for background events. We focus on neurobehavioral AEs reported in children. AEs in TPM trials are coded with a WHOART dictionary modified to reflect symptoms reported in early add-on TPM studies. Such terms as concentration/attention or memory difficulty and speech/language problems are unique to the TPM dictionary compared with the conventional WHOART dictionary.
Three randomized double-blind trials evaluated TPM monotherapy in newly diagnosed epilepsy. In 2 studies, patients were randomized to 50 or 500 mg/day (25 or 200 if [le]50 kg) or to 50 or 400 mg/day. Dose reductions were allowed to manage AEs ([quot]flex[quot] dosing), although dose reductions before patients achieved 200 mg/day were not allowed in patients randomized to TPM 400. In a third study, patients were randomized to fixed doses of the investigator[apos]s choice of carbamazepine or valproate or to 100 or 200 mg TPM; dosage reductions were not allowed. Study duration was 4-6 mos after the last patient randomized. Data are reported for the intent-to-treat population.
Of 1131 patients, 245 were children/adolescents (6-15 yrs). The table presents mean doses, patient number, and neurobehavioral AEs of special interest. [table1]
Although Ns are relatively small in individual groups and subject to considerable variation by an event[rsquo]s chance occurrence in even 1 patient, as demonstrated by the variability in memory difficulty, data suggest a pattern in which higher doses, particularly if fixed, are less well tolerated. However, 50 and 200 mg TPM are generally associated with a low incidence of neurobehavioral AEs when doses are adjusted according to patient response. The recommended initial target dose, based on efficacy and tolerability, is 100 mg. Even in a fixed-dose study, 100 mg TPM was well tolerated. The incidence of neurobehavioral AEs with this initial target dose would be expected to be even lower with flex dosing. Studies in larger pediatric populations are warranted.
[Supported by: Johnson [amp] Johnson Pharmaceutical Research [amp] Development]