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Lamotrigine Dosing and Titration in Bipolar Trials Key to Prevention of Rash: Presented at ECNP

By Bruce Sylvester
Special to DG News

BARCELONA, SPAIN -- October 9, 2002 -- A review of 11 controlled bipolar and unipolar clinical trials indicates that, at recommended dosing levels, lamotrigine therapy is associated with no statistically or clinically higher rate of serious rash than placebo.

The studies, all between three and 78 weeks' duration, were reported here October 7 at the 15^th Congress of the European College of Neuropsychopharmachology (ECNP).

"We saw data from early clinical use of lamotrigine for epilepsy suggesting a risk of rash," said lead investigator Joseph Calabrese, MD, professor of psychiatry at Case Western Reserve University Medical School in Cleveland, Ohio, United States. "We suspected that this had to do with high initial dosing levels and fast titration in those trials.

"This analysis of a large body of bipolar-related trial data confirms that the threat of rash can be generally managed with careful initial dosing and titration among these patients," he added.

Incidence for all types of rash for lamotrigine were 9 percent (108/1198), placebo 7.6 percent (80/1056), and active comparators, including lithium and desipramine, 6.1 percent (26/427).

The investigators reported that there were only two cases of serious rash in the lamotrigine groups (both in uncontrolled studies) and one in the placebo group. None of the rash cases were classified as Stevens-Johnson syndrome by the original researchers. One case of Stevens-Johnson syndrome, not requiring hospitalization, occurred in a patient on open-label lamotrigine.

The overall incidence of serious rash was below a rate of 1 in 1000 for all lamotrigine subjects," the investigators said.

"This paper provides information on rash incidence from all controlled trials conducted by the manufacturer in bipolar and unipolar depression to date," they noted. "Rash is further categorised as non-serious, serious and Stevens-Johnson Syndrome [SJS]. Any case reported as possible SJS or toxic epidermal necrolysis (TEN) is classified here as SJS. Any skin reaction associated with patient hospitalisation and double-blind treatment discontinuation is classified as 'serious'. The definition of 'serious rash' is a deliberately conservative one that can be reliably applied retrospectively to clinical trial data. By definition it can include rashes that are medically non-serious. All other cases of rash are reported here as 'non-serious"."

In light of the early rash-related problems in epilepsy treatment, the researchers also cited current dosing/titration levels for manufacturer bipolar clinical trials: weeks 1-2 at 25 mg/day; weeks 3-4 at 50 mg/day; increase dosage for one to two weeks by 50-100 mg/day, reaching a maintenance dose of 100-400 mg/day, the researchers said.

Funding for this study came form GlaxoSmithKline.

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