LAMOTRIGINE HIGH-DOSE TOLERABILITY AND SAFETY IN PATIENTS WITH EPILEPSY - A DOUBLE-BLIND, PLACEBO-CONTROLLED, 11-WEEK STUDY

Purpose: This study was undertaken to evaluate the dose tolerability a nd safety of a chronic ascending twice-daily (b.i.d.) dosage regimen o f less than or equal to 700 mg/day lamotrigine (LTG) and to include de termination of the LTG pharmacokinetic profile at doses greater than o r equal to 500 mg/day in patients receiving concomitant enzyme-inducin g antiepileptic drugs (AEDs). Methods: Twelve adult male epileptic pat ients treated with enzyme-inducing AEDs received less than or equal to 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). Fo r 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients rece ived regimens of 500, 600, and 700 mg/day for 1 week each. Controls re ceived matching placebo in the same sequence. At study end, dosages we re tapered in 2 weeks. Follow-up evaluations were made 7 days later. R esults: Five LTG patients tolerated 700 mg/day for 1 week. LTG was red uced to 600 mg/day in a patient with mild diplopia and to 500 mg/day i n a patient with mild oscillopsia and diplopia. One patient discontinu ed 300-mg/day therapy with a moderately intense diffuse papular skin r ash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity a nd occurred in 50-75% of patients in both groups (except for diplopia, occurring only with LTG), Concomitant AED plasma concentrations were not markedly changed by LTG, LTG pharmacokinetics were linear over the range of 500-700 mg/day. Conclusions: LTG doses less than or equal to 700 mg/day can be tolerated in patients receiving concomitant enzyme- inducing AEDs.