Safety of retigabine in adults with partial-onset seizures after long-term exposure: focus on unexpected ophthalmological and dermatological events.

BACKGROUND: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. METHODS: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. RESULTS: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. CONCLUSIONS: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

Survey of Physicians' Understanding of Specific Risks Associated with Retigabine.

BACKGROUND: Following reports of discoloration, including retinal pigmentation, in addition to known significant risks of urinary retention, central nervous system effects, and QTc prolongation, the retigabine indication was restricted to adjunctive treatment of partial onset seizures where other appropriate drug combinations have proved inadequate or have not been tolerated. OBJECTIVE: To ascertain the effectiveness of educational initiatives as reflected in physicians' understanding of retigabine-associated risks, management, and patient selection. METHODOLOGY: An online, cross-sectional survey, designated a post-authorization safety study (24/9/2014-30/1/2015), recruited retigabine prescribers (RP) and retigabine non-prescribers (RNP) in seven countries, who had been sent a retigabine Dear Health Care Professional letter (June 2013). Questions tested understanding of the significant risks associated with retigabine. RESULTS: 414/467 participants completed all questions (RP, n = 141; RNP, n = 273) and were included in the analysis. 74.2 % of these participants (RP, 77.3 %; RNP, 72.5 %) correctly identified the label indication. 81.9 % of participants (RP, 86.5 %; RNP, 79.5 %) recognized that specific retigabine-associated risks included pigment changes of ocular tissues, including the retina. 81.6 % of participants (RP, 87.2 %; RNP, 78.8 %) recognized that a comprehensive ophthalmologic examination is required. 99.8 % of participants (RP, 100.0 %; RNP, 99.6 %) acknowledged the requirement for action in case of retinal pigmentation or vision changes. RP and RNP results were similar to the overall participants' analysis, with a trend toward stronger understanding among RP. CONCLUSION: Most participants recognized the appropriate population for retigabine treatment and the requirement to monitor for adverse events including retinal pigmentation and vision changes. Understanding was satisfactory among RNP but stronger among RP.

Efficacy and safety of ezogabine/retigabine as adjunctive therapy to specified single antiepileptic medications in an open-label study of adults with partial-onset seizures.

PURPOSE: To assess efficacy/tolerability of ezogabine (EZG)/retigabine (RTG) in combination with specified monotherapy antiepileptic drug (AED) treatments in adults with uncontrolled partial-onset seizures using a flexible dosing regimen. METHODS: NCT01227902 was an open-label, uncontrolled study of flexibly dosed EZG/RTG. Adults with partial-onset seizures must have been taking either carbamazepine/oxcarbazepine (CBZ/OXC), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). The study comprised a screening/baseline phase, a 4-week titration phase (initiation on 150mg/day [50mg three times daily (TID)] with weekly increases of 150mg/day [50mg TID] over 4 weeks to 600mg/day), and a flexible dose evaluation (FDE) phase (optional weekly dose changes of 50-150mg/day, to an optimal daily dosage [300-1200mg/day]). The primary efficacy endpoint was percentage of patients experiencing a ≥50% reduction from baseline in partial seizure frequency (responder rate) during the treatment phase (titration and FDE phases). Safety and tolerability were also assessed. RESULTS: Patients (N=203) were enrolled and received ≥1 dose of EZG/RTG. The dose of EZG/RTG prescribed most frequently during the treatment phase was 600mg/day for all AED groups. Responder rates during the treatment phase were: 40.0% (CBZ/OXC), 32.0% (LTG), 50.0% (LEV), and 56.9% (VPA). Treatment-emergent adverse events occurred in 82% (CBZ/OXC), 76% (LTG), 73% (LEV), and 67% (VPA) of patients; most were of mild-to-moderate intensity. CONCLUSIONS: EZG/RTG was effective as adjunctive therapy to CBZ/OXC, LTG, LEV, and VPA, using a flexible dosing regimen, in adults with partial-onset seizures; safety and tolerability were consistent with that previously observed.

Current status of epilepsy health care for adult patients from central and eastern European Union countries--a survey of members of the Central Europe Epilepsy Experts Working Group.

PURPOSE: The aim of this survey was to review and compare the current approaches to epilepsy management in central and eastern EU (CEEU) countries. METHOD: The questionnaire was sent to ten invited experts from Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, and Slovenia. It focused on the treatment of adults. RESULTS: The number of neurologists and epilepsy reference centers is highly variable in CEEU countries. None of the analyzed states has a formal specialization in epileptology. No universal state-approved criteria for reference centers exist in Czech Republic, Estonia, Hungary, Latvia, and Slovenia. Generally, the protocols for epilepsy treatment in CEEU countries, including drug-resistant epilepsy, are in accordance with international guidelines; however, most countries have their own national standards of care and some have local clinical guidelines. Also, the reimbursement systems for antiepileptic drugs in CEEU countries are highly variable. Seven countries have epilepsy surgery centers. The costs of epilepsy surgeries are fully reimbursed, procedures performed abroad may also be covered. The length of time spent on waiting lists for surgery following the completion of preoperative investigations varies from two weeks to three years. The fraction of patients who qualified and were operated on within 12 months ranges from 20% to 100%. CONCLUSION: The lack of unified procedures pertaining to the evaluation and therapy of epilepsy is reflected by marked differences in access to treatment modalities for patients from CEEU countries.