Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures

- This double-blind study examined three titration rates for retigabine/ezogabine.
- Patients with partial-onset seizures received adjuvant retigabine/ezogabine.
- The slow titration rate (150 mg/day every 7 days) appeared to be the best tolerated.
- This titration rate is now recommended for clinical use.

SummaryRetigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N = 73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300 mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150 mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200 mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p = 0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p = 0.010) but not in the medium-titration group (p = 0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG.