Abstracts

Oral contraceptives have been shown to increase the apparent clearance of lamotrigine (LTG). In addition, the effect of the oral contraceptives on LTG clearance diminished during the [ldquo]pill free[rdquo] week, resulting in a transient approximate two-fold increase in LTG plasma concentrations. Based on these results, data from two large open-label studies were examined to characterize the safety of LTG at higher concentrations beyond that associated with the current recommended maximum of 500 mg/day., Study US17 and study US26 were open-label treatment protocols.In both trials, adjustment of concomitant antiepileptic drugs (AEDs) was permitted, including conversion to monotherapy with LTG and data were obtained every 6 months for the duration of the subject[apos]s participation in the study, including a single LTG concentration.
Demographics, adverse events (AEs) and exposure were summarized by study and by plasma concentration ([lt]10mg/mL, [gt]10mg/mL), which is the equivalent of 600 mg of lamotrigine as monotherapy. Only subjects with a plasma sample were analyzed for safety. Only AEs that were reported during the period that a patient was exposed to the dose recorded at the time of the PK sample were included in the safety analysis in order to examine the dose-response relationship., A total of 1602 subjects participated in the 2 trials, with 624 included in the safety analysis. Demographic characteristics were similar between studies. There were 492 patients with LTG concentrations [lt]10 [micro]g/mL (mean=5.4 [micro]g/mL, average exposure 15.4 months) and 132 patients [ge] 10 [micro]g/mL (mean=14.7 [micro]g/mL, average exposure 18.8 months).
Adverse events in US 17 and US 26 combined were reported slightly more frequently among the patients with LTG concentrations [ge] 10 [micro]g/mL (34%) than in those [lt] 10 [micro]g/mL (26%). AEs reported at a rate [ge] 5% and more frequently among those with concentrations [ge]10 [micro]g/mL are shown below:[table1]The term [ldquo]Any Rash[rdquo] (includes rash or urticaria) was slightly more frequent (5/132, 4%) at [ge]10 [micro]g/mL than [lt]10 [micro]g/mL (8/492, 2%). There were no cases of serious rash in either group. The rate of serious adverse events was comparable between groups. CNS adverse events were slightly more frequent at concentrations [gt] 10 [micro]g/ml., At mean concentrations of LTG of 14.7 approximating a LTG monotherapy dose of 900 mg qd non-serious CNS-related adverse events were slightly more frequent in comparison with a mean concentration of LTG of 5.4[micro]g/ml approximating a LTG dose of 600 mg qd. Doses increases of LTG up to 900 mg qd as monotherapy are well-tolerated., (Supported by GlaxoSmithKline Research and Development.)