Current and Emerging Adjunctive Antiepileptic Therapies
Current and Emerging Adjunctive Antiepileptic Therapies
Although monotherapy is the preferred treatment for people with epilepsy, many patients require adjunctive therapy or polytherapy if their seizures do not respond to single-drug treatment. For a variety of reasons, antiepileptic drugs (AEDs) seeking approval from the US Food and Drug Administration (FDA) are often evaluated as adjunctive or "add-on" therapy in phase 3 clinical trials, and the results of these trials for carisbamate, eslicarbazepine acetate, lacosamide, and retigabine are summarized below. Adjuvant trials addressing special populations such as infants taking topiramate and the effect of eslicarbazepine acetate on quality of life and depressive symptoms are also described.
Retigabine 600 mg/day and 900 mg/day were evaluated as adjunctive therapy in 538 adult patients with refractory partial-onset seizures in this multicenter, randomized, double-blind, placebo-controlled trial. Administered 3 times daily, retigabine significantly reduced overall median seizure frequency at both the 600-mg/day dose (27.9%) and the 900-mg/day dose (39.9%), compared with the placebo response of 15.9%. The most common adverse effects were dizziness, somnolence, headache, and fatigue.
Retigabine 1200 mg/day was evaluated in 305 adults with inadequately controlled partial-onset seizures who were taking 1 to 3 AEDs. After an 8-week baseline, retigabine was titrated in 153 of 305 patients from 300 mg/day to 1200 mg/day over 6 weeks, and seizure frequency was evaluated over a 12-week maintenance phase. The remaining 152 patients received placebo. In the maintenance phase, the 28-day median partial seizure frequency was significantly reduced by 55% in the retigabine group compared with 19% in the placebo group. Seizure freedom was significantly greater in the retigabine group (8%) compared with the placebo group (2%). Discontinuations were 36.6% in the retigabine group compared with 17.1% in the placebo group. The most common adverse events were dizziness (40%), somnolence (31%), fatigue (16%), and confusion (14%). Adverse events resulted in retigabine discontinuation in 28.6% of patients.
Lacosamide was recently approved by the FDA for adjunctive treatment of partial seizures. Three studies pooled retrospective analyses of the 3 pivotal phase 2/3 trials (SP667-phase 2, N = 418; SP754-phase 3, N = 405; SP755-phase 3, N = 485). These were fixed-dose, randomized, double-blind, placebo-controlled trials with a 12-week maintenance phase studying adults with refractory partial-onset seizures. Subjects began lacosamide at 50 mg twice a day, which was increased by 100 mg each week to the target dose of 200, 400, or 600 mg/day. Early onset of lacosamide effectiveness occurred at 1 week when all patients were receiving 100 mg/day (lacosamide 33% vs placebo 19.4%, P < .01) and at 2 weeks at 200 mg/day (lacosamide 34% vs placebo 20%, P < .01).
In the safety and tolerability analysis of the 3 pooled lacosamide trials, 944 subjects taking lacosamide and 364 patients receiving placebo were exposed to lacosamide for a median of 111 days (N = 1308). Adverse events that occurred in > 10% of the lacosamide group compared with the placebo group were dizziness (31% vs 8%), headache (13% vs 9%), nausea (11% vs 4%), and diplopia (11% vs 2%). Additional adverse events occurred in > 10% of patients in the 600-mg/day lacosamide treatment group, including vomiting, fatigue, ataxia, blurred vision, tremor, and nystagmus. The number of patients discontinuing treatment because of toxicity increased with lacosamide dosage (8% at 200 mg/day, 17% at 400 mg/day, and 29% at 600 mg/day).
From the 3 pooled studies, Rosenfeld and coworkers compared 466 patients taking lacosamide 400 mg/day with 359 patients taking placebo with respect to efficacy and concomitant AEDs. The median percent reduction per 28 days in seizure frequency was significantly greater in patients taking lacosamide compared with those taking placebo (36.8% vs 18.4%). The most commonly used concomitant AEDs were lamotrigine (33%), carbamazepine (33%), levetiracetam (30%), valproate (23%), topiramate (23%), and oxcarbazepine (17%). The concomitant drugs did not appear to affect lacosamide efficacy.
Postmarketing Studies
Introduction
Although monotherapy is the preferred treatment for people with epilepsy, many patients require adjunctive therapy or polytherapy if their seizures do not respond to single-drug treatment. For a variety of reasons, antiepileptic drugs (AEDs) seeking approval from the US Food and Drug Administration (FDA) are often evaluated as adjunctive or "add-on" therapy in phase 3 clinical trials, and the results of these trials for carisbamate, eslicarbazepine acetate, lacosamide, and retigabine are summarized below. Adjuvant trials addressing special populations such as infants taking topiramate and the effect of eslicarbazepine acetate on quality of life and depressive symptoms are also described.
Retigabine 600 mg/day and 900 mg/day were evaluated as adjunctive therapy in 538 adult patients with refractory partial-onset seizures in this multicenter, randomized, double-blind, placebo-controlled trial. Administered 3 times daily, retigabine significantly reduced overall median seizure frequency at both the 600-mg/day dose (27.9%) and the 900-mg/day dose (39.9%), compared with the placebo response of 15.9%. The most common adverse effects were dizziness, somnolence, headache, and fatigue.
Retigabine 1200 mg/day was evaluated in 305 adults with inadequately controlled partial-onset seizures who were taking 1 to 3 AEDs. After an 8-week baseline, retigabine was titrated in 153 of 305 patients from 300 mg/day to 1200 mg/day over 6 weeks, and seizure frequency was evaluated over a 12-week maintenance phase. The remaining 152 patients received placebo. In the maintenance phase, the 28-day median partial seizure frequency was significantly reduced by 55% in the retigabine group compared with 19% in the placebo group. Seizure freedom was significantly greater in the retigabine group (8%) compared with the placebo group (2%). Discontinuations were 36.6% in the retigabine group compared with 17.1% in the placebo group. The most common adverse events were dizziness (40%), somnolence (31%), fatigue (16%), and confusion (14%). Adverse events resulted in retigabine discontinuation in 28.6% of patients.
Lacosamide was recently approved by the FDA for adjunctive treatment of partial seizures. Three studies pooled retrospective analyses of the 3 pivotal phase 2/3 trials (SP667-phase 2, N = 418; SP754-phase 3, N = 405; SP755-phase 3, N = 485). These were fixed-dose, randomized, double-blind, placebo-controlled trials with a 12-week maintenance phase studying adults with refractory partial-onset seizures. Subjects began lacosamide at 50 mg twice a day, which was increased by 100 mg each week to the target dose of 200, 400, or 600 mg/day. Early onset of lacosamide effectiveness occurred at 1 week when all patients were receiving 100 mg/day (lacosamide 33% vs placebo 19.4%, P < .01) and at 2 weeks at 200 mg/day (lacosamide 34% vs placebo 20%, P < .01).
In the safety and tolerability analysis of the 3 pooled lacosamide trials, 944 subjects taking lacosamide and 364 patients receiving placebo were exposed to lacosamide for a median of 111 days (N = 1308). Adverse events that occurred in > 10% of the lacosamide group compared with the placebo group were dizziness (31% vs 8%), headache (13% vs 9%), nausea (11% vs 4%), and diplopia (11% vs 2%). Additional adverse events occurred in > 10% of patients in the 600-mg/day lacosamide treatment group, including vomiting, fatigue, ataxia, blurred vision, tremor, and nystagmus. The number of patients discontinuing treatment because of toxicity increased with lacosamide dosage (8% at 200 mg/day, 17% at 400 mg/day, and 29% at 600 mg/day).
From the 3 pooled studies, Rosenfeld and coworkers compared 466 patients taking lacosamide 400 mg/day with 359 patients taking placebo with respect to efficacy and concomitant AEDs. The median percent reduction per 28 days in seizure frequency was significantly greater in patients taking lacosamide compared with those taking placebo (36.8% vs 18.4%). The most commonly used concomitant AEDs were lamotrigine (33%), carbamazepine (33%), levetiracetam (30%), valproate (23%), topiramate (23%), and oxcarbazepine (17%). The concomitant drugs did not appear to affect lacosamide efficacy.
Postmarketing Studies
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