A Post Marketing Surveillance Study to Monitor the Risk of Urinary Retention in Retigabine Users

Epilepsy is one of the most common neurological disorders, with a prevalence of active disease between 0.3 and 1.8% based on population-based studies across the world (0.7% in US) using medical record reviews. These studies have estimated approximately 1.4 million current epilepsy patients in the US alone. Effective seizure control often requires long-term exposure and compliance to various AEDs. Despite the advent of many new AEDs over the past 15 years, approximately 30% of epilepsy patients continue to experience recurrent seizures due to lack of treatment efficacy and discontinuation of therapy due to undesirable side effects or poor treatment compliance. Therefore, an unmet need remains for treatments that can reduce seizure frequency and severity as well as improvements in AED tolerability and safety.

In January 2010, the FDA accepted the new drug application (NDA) for EZG for adjunctive treatment of epilepsy in adults with partial-onset seizures. US market entry is anticipated by 2011. EZG is the first potassium channel opener to reach late stage clinical development for the treatment of epilepsy. EZG's anticonvulsant properties are primarily mediated by opening or activating neuronal voltage-gated potassium channels. The efficacy and safety of EZG as part of polytherapy AED regimens in adults with refractory partial-onset seizures has been demonstrated in one Phase II and two Phase III double-blind, placebo-controlled trials: RESTORE 1 and 2.

In the Phase II study, 399 patients were randomized to four treatment arms (placebo, 600, 900, and 1200 mg/day EZG). The median change from baseline seizure frequency was 13.1% for the placebo group; in comparison, the median change was 23.4% for 600 mg/day, 29.3% for 900 mg/day (p=0.0387), and 35.2% for 1200 mg/day (p=0.0024). RESTORE 1 was conducted in the US and had two arms (placebo and 1200 mg/day EZG), while RESTORE 2 was conducted mainly in Europe and Australia with three different arms (placebo, 600, and 900 mg/day EZG). In RESTORE 1 (n=301), the median reduction in seizure frequency among patients using 1200 mg/day EZG (n=151) was 44% compared with 18% among placebo users (n=150; p<0.001). In RESTORE 2, a significant reduction in partial seizure frequency was found in both EZG doses vs. placebo (p<0.001): 28% for 600 mg/day, 40% for 900 mg/day, and 16% for placebo.During these trials EZG was generally well tolerated; most adverse events (AEs) were mild or moderate with central nervous system (CNS) related AEs (dizziness, somnolence and fatigue) being most common. However, among non-CNS events, an increased incidence of bladder-related AEs, including UR, relative to placebo was observed with EZG, primarily with 1200 mg/day. Among the patients in EZG arms from all trials (n=813), 0.9% experienced UR compared with 0.5% in the placebo arms (n=427). In addition 5% of patients in the EZG arms compared with 3% of patients in the placebo arms experienced urinary symptoms, including dysuria, urinary hesitancy, and UR.

There are concerns that these AEs may reflect the inhibition of bladder contractility secondary to EZG's effects on KCNQ (Kv7) voltage-gated potassium channels in the detrusor muscle of the bladder. However, the limited number of patients exposed to EZG during trials suggests that the risk of UR associated with exposure to EZG has to date been poorly quantified.

A post-marketing safety surveillance study using a US health insurance claims database coupled with medical records review will be implemented to determine the risk of UR associated with exposure to AED polytherapy regimens containing EZG in a real-world setting. The risk of UR among epilepsy patients treated with EZG AED polytherapy will be compared to the risk among epilepsy patients treated with non-EZG AED polytherapy. In addition, both EZG and non-EZG AED polytherapy users will be described in terms of their demographic characteristics, concomitant AED use, co-morbidities, use of medications potentially associated with UR, and medical conditions pre-disposing to UR. Secondarily, off-label usage of EZG will be monitored and described. In addition, the risk of UR among epilepsy patients treated with non-EZG AED monotherapy will be determined.