Brivaracetam effectiveness and tolerability in older and younger adults with epilepsy: EXPERIENCE, a pooled analysis of international data from retrospective studies.

This analysis assessed the effectiveness and tolerability of brivaracetam (BRV) in older (≥65 years of age) and younger (≥16 to <65 years of age) adults with epilepsy. This was a subgroup analysis from EXPERIENCE/EPD332, a pooled analysis of individual patient records from multiple independent, non-interventional studies of patients with epilepsy starting BRV in Australia, Europe, and the United States. Included patients had ≥6 months of follow-up data. Outcomes included responders (≥50 % reduction from baseline in seizure frequency), seizure freedom (no seizures within 3 months before the time point), and continuous seizure freedom (no seizures from baseline) at 12 months; BRV discontinuation during the whole study follow-up; and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were deemed non-responders/not seizure-free. Analysis populations included the Full Analysis Set (FAS; patients who received ≥1 BRV dose and had seizure type and age documented at baseline) and the modified FAS (FAS patients who had ≥1 seizure recorded during baseline). The FAS was used for all outcomes except seizure reduction. The FAS included 147 (8.9 %) patients aged ≥65 years and 1497 (91.1 %) aged ≥16 to <65 years. Compared with the younger subgroup, patients aged ≥65 years had a longer median epilepsy duration (33.0 years [n = 144] vs 17.0 years [n = 1460]) and lower median seizure frequency at index (2.0 seizures/28 days [n = 129] vs 4.0 seizures/28 days [n = 1256]), and less commonly had >1 prior antiseizure medication (106/141 [75.2 %] vs 1265/1479 [85.5 %]). At 12 months, a numerically higher percentage of patients aged ≥65 years versus the younger subgroup achieved ≥50 % seizure reduction (46.5 % [n = 71] vs 36.0 % [n = 751]), seizure freedom (26.0 % [n = 100] vs 13.9 % [n = 1011]), and continuous seizure freedom (22.0 % [n = 100] vs 10.7 % [n = 1011]). During the whole study follow-up, 43/147 (29.3 %) patients aged ≥65 years and 508/1492 (34.0 %) aged ≥16 to <65 years discontinued BRV. The incidence of TEAEs since the prior visit was similar in both subgroups at 3 months (≥65 years vs ≥16 to <65 years: 38/138 [27.5 %] vs 356/1404 [25.4 %]), 6 months (19/119 [16.0 %] vs 176/1257 [14.0 %]), and 12 months (8/104 [7.7 %] vs 107/1128 [9.5 %]). This real-world analysis suggests BRV was effective in patients aged ≥65 years and ≥16 to <65 years, with numerically higher effectiveness in the older subgroup. BRV was well tolerated in both subgroups.

Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy.

One third of patients with epilepsy will continue to have uncontrolled seizures despite treatment with antiseizure medications (ASMs). There is therefore a need to develop novel ASMs. Brivaracetam (BRV) is an ASM that was developed in a major drug discovery program aimed at identifying selective, high-affinity synaptic vesicle protein 2A (SV2A) ligands, the target molecule of levetiracetam. BRV binds to SV2A with 15- to 30-fold higher affinity and greater selectivity than levetiracetam. BRV has broad-spectrum antiseizure activity in animal models of epilepsy, a favorable pharmacokinetic profile, few clinically relevant drug-drug interactions, and rapid brain penetration. BRV is available in oral and intravenous formulations and can be initiated at target dose without titration. Efficacy and safety of adjunctive BRV (50-200 mg/day) treatment of focal-onset seizures was demonstrated in three pivotal phase III trials (NCT00490035/NCT00464269/NCT01261325), including in patients who had previously failed levetiracetam. Efficacy and safety of adjunctive BRV were also demonstrated in adult Asian patients with focal-onset seizures (NCT03083665). In several open-label trials (NCT00150800/NCT00175916/NCT01339559), long-term safety and tolerability of adjunctive BRV was established, with efficacy maintained for up to 14 years, with high retention rates. Evidence from daily clinical practice highlights BRV effectiveness and tolerability in specific epilepsy patient populations with high unmet needs: the elderly (≥ 65 years of age), children (< 16 years of age), patients with cognitive impairment, patients with psychiatric comorbid conditions, and patients with acquired epilepsy of specific etiologies (post-stroke epilepsy/brain tumor related epilepsy/traumatic brain injury-related epilepsy). Here, we review the preclinical profile and clinical benefits of BRV from pivotal trials and recently published evidence from daily clinical practice.

One in three people with epilepsy continue to have seizures despite treatment. Brivaracetam is a medicine used to treat seizures in people with epilepsy. It binds to a protein in the brain (synaptic vesicle protein 2A) and is effective in many different animal models of epilepsy. Brivaracetam enters the brain quickly. It has few interactions with other medicines, which is important because people with epilepsy may be taking additional medicines for epilepsy or other conditions. Brivaracetam is available as tablets, oral solution, and solution for intravenous injection, can be started at the recommended target dose, and is easy to use. In three phase III trials, people with uncontrolled focal-onset seizures taking brivaracetam 50­200 mg each day had fewer seizures than people taking a placebo. Brivaracetam was tolerated well. It also worked well in many people who had previously not responded to antiseizure medications. The efficacy of brivaracetam treatment is maintained for up to 14 years. Brivaracetam treatment reduces seizures in the elderly (≥ 65 years old), in children (< 16 years old), in people with cognitive or learning disabilities, in people with additional psychiatric conditions, and in people with different causes of epilepsy (post-stroke epilepsy, brain-tumor related epilepsy, and traumatic brain injury-related epilepsy). Here, we review brivaracetam characteristics and the results when people with epilepsy received brivaracetam in key clinical trials and real-world studies in daily clinical practice.

Time-course of drug-related psychiatric and behavioral treatment-emergent adverse events during brivaracetam treatment in adults with focal-onset seizures.

OBJECTIVE: We previously analyzed data from three phase lll trials of adjunctive brivaracetam (BRV) in adults showing that the incidence and prevalence of drug-related central nervous system treatment-emergent adverse events (TEAEs) quickly peaked and decreased over several weeks following BRV treatment initiation. However, that analysis did not assess psychiatric and behavioral side effects which can occur with antiseizure medication (ASM) treatment. Here, we investigate the time-course of psychiatric and behavioral TEAEs by week of BRV treatment and how these TEAEs were managed. METHODS: Data were pooled from three trials (N01252 [NCT00490035]; N01253 [NCT00464269]; N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal-onset seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the incidence and prevalence of drug-related psychiatric or behavioral TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) or placebo (PBO) during the 12-week treatment period. A logistic regression model was used to determine if psychiatric or behavioral comorbid conditions were predictors for drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. RESULTS: A total of 803 patients received BRV 50-200 mg/day, and 459 patients received PBO. Drug-related psychiatric or behavioral TEAEs were reported by 11.0 % of patients during adjunctive BRV treatment (PBO: 4.8 %) with onset early after BRV initiation (median time to onset of first drug-related psychiatric or behavioral TEAE: 15 days). Incidence peaked at week 1 and decreased over the first 4 weeks following BRV initiation. Prevalence peaked at week 4 and then remained stable between weeks 5-12. In an analysis excluding patients on concomitant levetiracetam (BRV: n = 744; PBO: n = 422), the incidence of drug-related psychiatric or behavioral TEAEs was similar to the incidence in the overall population. The most common drug-related psychiatric or behavioral TEAEs were irritability, insomnia, depression, and anxiety. Only 2 % of patients discontinued BRV due to psychiatric or behavioral TEAEs (PBO: 1.3 %), while most patients on BRV who reported drug-related psychiatric or behavioral TEAEs did not require a change in dose (84.1 %; PBO: 63.6 %). A history of psychiatric or behavioral comorbid conditions (not ongoing at BRV initiation) was not associated with an increased likelihood of drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. Ongoing psychiatric or behavioral comorbid conditions at BRV initiation increased the likelihood of drug-related psychiatric or behavioral TEAEs, but not the likelihood of BRV discontinuation due to psychiatric or behavioral TEAEs. CONCLUSIONS: Drug-related psychiatric and behavioral TEAEs occurred early during BRV treatment, and most patients did not require a change in BRV dose. These data can help guide clinician monitoring and patient expectations after starting BRV.

Effectiveness and tolerability of brivaracetam in patients with epilepsy stratified by comorbidities and etiology in the real world: 12-month subgroup data from the international EXPERIENCE pooled analysis.

OBJECTIVE: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies. METHODS: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE]). RESULTS: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively. CONCLUSIONS: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.

Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen. METHODS: This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation. RESULTS: Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups. CONCLUSION: BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.

Lacosamide and pregnancy: Data from spontaneous and solicited reports.

OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Asymptomatic Gastric Giant Polyp in a Boy with Peutz-Jeghers Syndrome Presented with Multiple Café Au Lait Traits.

We describe an asymptomatic case of PJS in a six-year-old boy with café au lait spots in several parts of his body, a large gastroduodenal polyp, two polyps near the ampulla of Vater, and another in the jejunum. This patient shows some unique aspects of PJS. No other such large gastric polyp in a Peutz-Jeghers child is reported in the literature. The large size of the gastric polyp with lack of symptoms is unusual and poses a unique challenge in terms of management and surgical resection.

Acute appendicitis in a child with swine influenza (H1N1).

Swine flu is a multisystemic disease and can affect the gastrointestinal system. There are only three published reports of swine flu cases with acute appendicitis; two of them in children under 16 years of age. We present an unusual case of acute appendicitis in a child already diagnosed with swine flu infection. A 9½-year-old girl presented with febrile illness and mild abdominal pain. PCR (+) was positive for H1N1. 3 days after hospital admission she developed acute appendicitis and was operated on. On the fourth postoperative day she developed right upper lobe atelectasis; she was started on antiviral treatment to which she responded very well. She was discharged on day 7 without further consequences in her postoperative course. Children with swine flu may be susceptible to rapidly deteriorating and complicated acute appendicitis. This calls for more caution especially in periods of epidemics.