Minimizing the Adverse effects of Epilepsy Therapies: Principles and Practice

Louis, Erik K. St.

doi:10.1002/9781118951026.ch10

Cited by 3 publications

(3 citation statements)

References 43 publications

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“…Because patients with refractory epilepsy often experience tolerability issues due to polypharmacy, reducing concomitant medications during the addition of new therapy is frequently necessary. Many patients with uncontrolled epilepsy have excessive drug load, most commonly through use of combination therapy, which can result in significant TEAEs, DDIs, and reduced quality of life 26–28 . The ultimate goal of treatment is to reach 100% seizure reduction with the fewest possible TEAEs.…”

Section: Discussionmentioning

confidence: 99%

“…Many patients with uncontrolled epilepsy have excessive drug load, most commonly through use of combination therapy, which can result in significant TEAEs, DDIs, and reduced quality of life. 26 , 27 , 28 The ultimate goal of treatment is to reach 100% seizure reduction with the fewest possible TEAEs. When initiating treatment, slowly reducing the concomitant ASM dose in patients who experience TEAEs while adding another drug may aid in reducing drug burden while allowing for optimal efficacy.…”

Section: Discussionmentioning

confidence: 99%

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Post hoc analysis of a phase 3, multicenter, open‐label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications

Rosenfeld

Abou‐Khalil

Aboumatar³

et al. 2021

Epilepsia

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Objective To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long‐term, open‐label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention. Methods Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2‐week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut‐off, on or after September 1, 2019. Results A total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut‐off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut‐off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)–related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months. Significance Concomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Post hoc analysis of a phase 3, multicenter, open‐label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications

Rosenfeld

Abou‐Khalil

Aboumatar³

et al. 2021

Epilepsia

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“…Dose-titration is often used to reduce the risk of adverse events and increase tolerability, allowing for the identification of the most appropriate maintenance dose for treatment success [10]. It also permits the evaluation of the doses of concomitant ASMs and the possibility of minimizing the total ASM load of the regimen [11].…”

Section: Introductionmentioning

confidence: 99%

Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures

Privitera

Richy

Schabert

2022

Epilepsy & Behavior

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Objective: The efficacy and safety of cenobamate relative to other antiseizure medications (ASMs) has not been evaluated. An indirect treatment comparison (network meta-analysis) was performed to determine if adjunctive cenobamate increases the odds ratio (OR) for 50% responder rate or for withdrawals due to treatment-emergent adverse events (TEAEs) leading to ASM discontinuation versus adjunctive therapy with other ASMs. Methods: A systematic literature review was conducted to identify randomized, double-blind, placebocontrolled trials (maintenance phase 12 weeks) assessing adjunctive ASMs in adults with uncontrolled focal seizures. Cenobamate was compared to a group of seven other ASMs, and to subgroups of branded (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel) and older (lamotrigine, levetiracetam, and topiramate) ASMs at FDA-recommended daily maintenance doses (FDA-RDMD), at all doses, and at maximum and minimum daily doses. Statistical significance was set at p < 0.05. Results: Twenty-one studies were eligible for analysis. The placebo-adjusted 50% responder rate for FDA-RDMD of cenobamate was superior (OR 4.200; 95% CI 2.279, 7.742) to FDA-RDMD of all seven assessed (OR 2.202 95% CI 1.915, 2.532; p = 0.044) and branded ASMs (OR 2.148; 95% CI 1.849, 2.494; p = 0.037). There was no significant difference for 50% responder rate between FDA-RDMD of cenobamate and FDA-RDMD of older ASMs (OR 2.617; 95% CI 1.767, 3.878; p = 0.202). No significant differences were identified for 50% responder rate when comparing all doses and maximum/minimum doses of cenobamate to all seven, branded, and older ASMs. Cenobamate demonstrated comparable TEAE withdrawal rates to all seven ASMs, branded ASMs, and older ASMs across each of the four dose ranges (all p > 0.05). Significance: Patients receiving FDA-RDMD of cenobamate were more likely to have 50% seizure reduction compared with FDA-RDMD of the seven assessed ASMs and branded ASMs, without an increase in treatment discontinuation due to TEAEs.

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