Abstracts

Rationale: Ezogabine/retigabine (EZG/RTG) is a neuronal potassium channel opener developed as an adjunctive treatment for partial-onset seizures. Available in the EU in May 2011, EZG/RTG became generally available in the USA in May 2012. In the Fall of 2012, evaluation of adverse event (AE) reports from long-term open-label extension studies revealed that EZG/RTG may cause discoloration of the lips, nails, skin, and/or mucosa. Eye examinations have since shown EZG/RTG may be associated with pigmentation of ocular tissue. Methods: Since late 2012, GlaxoSmithKline has been investigating (including summary statistics and Kaplan-Meier analyses) the EZG/RTG-associated findings and AEs of discoloration/pigmentation of the retina, non-retinal ocular tissue, lips, nails, skin, and/or mucosa reported in subjects enrolled in the clinical trials (both ongoing and previously discontinued subjects) and spontaneous reports from patients. These data were reviewed by external experts and included in a series of periodic update reports to regulatory authorities. Results: As of March 28, 2014, lips, nails, skin, and/or mucosa discoloration events: of 365 study subjects examined, 108 have been reported to have discoloration of the lips, nails, skin, and/or mucosa (median time to onset: 4.4 years). 17% of subjects reported lips, nails, skin, and/or mucosa discoloration AEs after 5 years of exposure. The event rate of AEs of lips, nails, skin, and/or mucosa discoloration per patient-year of exposure is 0.036. There is no preponderance of Fitzpatrick Skin Phototypes (I-VI), ethnicity backgrounds, or specific geographic areas. Biopsy samples from 9 study subjects were obtained for histopathological evaluation and/or chemical extraction for measurement of potential drug-related material. There are limited data on reports of discoloration/pigmentation with an outcome of improved/resolved. Eye findings: after a review of 323 initial and 132 follow-up comprehensive eye examination worksheets completed for subjects in the clinical studies, there were 53 subjects for whom the examination included reported findings of retinal pigmentation. 19 of the 53 subjects had worse than 20/20 visual acuity in at least one eye. A review conducted by an external retinal specialist found that, based on available ophthalmic data to date, it was not possible to conclude that there is definite EZG/RTG-induced retinopathy. Continued vigilance with 6-monthly comprehensive eye examinations in patients taking EZG/RTG was advised. Conclusions: The presence of lips, nails, skin, and/or mucosa discoloration is causally associated with EZG/RTG exposure and appears to be related to duration of exposure. There is possible EZG/RTG-induced retinopathy, but evidence to date is insufficient to draw a conclusion regarding the characteristics and/or impact on visual function. Periodic comprehensive eye examinations are recommended as there is a need to continue to evaluate for potential EZG/RTG-induced retinal pigmentary changes and any associated impact on visual function. This research was fully funded by GlaxoSmithKline.