Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study.

OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.

Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients with epilepsy.

Effectiveness and safety of adjunctive cenobamate for focal seizures in adults with developmental disability treated in clinical practice.

Effectiveness and tolerability of adjunctive cenobamate for uncontrolled focal seizures in adults living with a developmental disability are not defined. Retrospective medical record review included adults ≥18 years old living with a developmental disability, either in a group home or with parents, and experiencing uncontrolled focal seizures despite stable doses of ≥1 antiseizure medication (ASM). Effectiveness was examined as percentage change in focal seizure frequency per month from the 2-month average before cenobamate to the average of months 5 and 6 while receiving cenobamate. Percentages of patients achieving responder rates in focal seizure frequency at 6 months of cenobamate treatment were examined. Adverse effects and concomitant ASM dosage adjustments were assessed. Of the 28 included patients, 26 (92.9%) continued cenobamate beyond 6 months. The responder rate of 100% seizure reduction (seizure-free) occurred in 48.2% of the patients who continued cenobamate for 6 months. Ten adverse effects were reported in 9 patients (32.1%), and 80% (8/10) were resolved by reducing concomitant ASM dosages. Two patients (7.1%) discontinued cenobamate due to adverse effects. Cenobamate resulted in substantial reduction in focal seizure frequency and was well tolerated.

The importance of drug titration in the management of patients with epilepsy.

The variable response to antiseizure medication (ASM) treatment and the numerous drug- and patient-related factors that must be considered when initiating therapy make drug titration to an optimal and tolerable dose an essential component in the pharmacologic treatment of patients with epilepsy. When initiating a new ASM, a "start low, go slow" titration approach is generally recommended and has been shown to reduce the risk of severe idiosyncratic reactions with certain medications and improve tolerability with regard to many frequently occurring central nervous system-related adverse effects (e.g., somnolence, dizziness). Many patients with epilepsy will require medication changes due to lack of efficacy or intolerability of the initial regimen. When this occurs, patients may be switched from one monotherapy to another or receive adjunctive therapy. When transitioning a patient from one ASM to another (referred to as monotherapy conversion or transitional polytherapy), there are several strategies for tapering the baseline ASM depending on the clinical scenario. Regardless of the particular strategy, the goal should be to discontinue the baseline ASM in order to prevent increased toxicity due to drug load. When adding on ASM therapy, flexible titration of the new ASM and adjustment of concomitant ASMs to achieve disease control with the lowest possible drug load (lowest numbers and lowest doses) may help improve tolerability of the add-on therapy. Communication with patients during the initiation of a new therapy may help patients adhere to the titration schedule, allowing them to reach their optimal maintenance dose.

Topiramate in essential tremor: findings from double-blind, placebo-controlled, crossover trials.

OBJECTIVE: To evaluate topiramate in adults with essential tremor. METHODS: This report represents the combined results of 3 randomized, double-blind, placebo-controlled, crossover trials that followed a common protocol. Study subjects were adults (> or =18 years old) who had untreated or treated moderate to severe essential tremor involving upper extremities. Patients were randomized to a double-blind sequence of topiramate (400 mg/d or maximum tolerated dose) then placebo (n = 30) or placebo then topiramate (n = 32). A 2-week washout period separated 10-week double-blind treatment phases. Upper extremity tremor was assessed using the Fahn-Tolosa-Marin tremor rating scale (TRS). The primary efficacy measure was the TRS total score at the final visit for patients providing on-treatment data in both double-blind treatment periods. Secondary efficacy measures included change from baseline in TRS total score and in TRS subscale scores for tremor severity, motor task performance, and functional disability. RESULTS: A total of 62 patients were enrolled. Total tremor score was significantly (P < 0.0001) lower with topiramate (28.7 +/- 1.0) vs placebo (37.0 +/- 1.0). The change from baseline in TRS total and subscale scores was significantly greater (P < or = 0.005) with topiramate treatment (mean score reduction, 7.7-11.8 vs 0.08-2.0). Of the 28 patients who discontinued without completing both treatment periods, adverse events accounted for 13 of 18 discontinuations during topiramate treatment and 5 of 10 discontinuations during placebo exposure. Adverse events reported by 2 or more patients discontinuing topiramate were nausea (n = 3), paresthesia (n = 3), and concentration/attention difficulty (n = 2). CONCLUSIONS: Topiramate was associated with overall tremor reduction and improvements in tremor severity, motor task performance, and functional disability in patients with moderate to severe essential tremor.

A double-blind placebo-controlled trial of topiramate treatment for essential tremor.

The safety and efficacy of topiramate (400 mg/d or maximum tolerated dose) as monotherapy or adjunctive treatment of essential tremor were investigated in a placebo-controlled, crossover study (n = 24). Topiramate resulted in significantly greater reductions from baseline based on normalized scores for a clinical rating of tremor location/severity, specific motor tasks/functional disabilities, and tremor-resultant functional disabilities. Most common adverse events were appetite suppression/weight loss and paresthesias.