Can you compare the clinical benefit of brivaracetam vs levetiracetam in pediatrics? What are the benefits? Any specific disease states that it is more beneficial. Why should we add this to formulary? How would we convert from IV to oral?

Comment by InpharmD Researcher

While there is a paucity of direct comparative evidence between brivaracetam and levetiracetam in pediatric patients, brivaracetam has demonstrated higher potency and more pronounced effect in seizure protection tests than levetiracetam. Additionally, the increased binding affinity of brivaracetam theoretically improves clinical tolerability compared to levetiracetam. Despite the lack of clinical comparative data in pediatric patients, brivaracetam has been found to be effective as a potential treatment alternative for patients with drug-refractory focal or generalized epilepsies, particularly for patients with recent exposure to levetiracetam or patients who switched from levetiracetam to brivaracetam. For this reason, the addition of brivaracetam to formulary would allow for alternative treatment options for patients with drug-refractory seizures who have exhausted other treatment options, primarily levetiracetam. The manufacturer states that dose conversions between brivaracetam formulations (oral solution, oral tablet, and injection solution) are 1:1.

Background

Brivaracetam (BRV) and levetiracetam (LEV) demonstrate a similar pharmacokinetic profile, conferring easy and immediate switching from LEV to BRV at a ratio of 10:1 to 20:1, or vice versa. Mechanistically, BRV has revealed higher potency than LEV in animal models, based on 15 to 30x increased affinity for binding to synaptic vesicle protein 2A (SV2A), which potentiates its anticonvulsant activity. Conversely, LEV has only moderate affinity to SV2A, although it also has several other mechanisms of action. Still, between the two, BRV has demonstrated a more pronounced effect for neuronal hypersynchronization in seizure protection tests. Numerous clinical trials have been performed with LEV and BRV as adjunct therapy, although fewer studies focus on monotherapy. Based on mechanism of action, the high selectivity of BRV theoretically suggests improved clinical tolerability compared to LEV; some studies have observed decreased adverse events when switching from LEV to BRV, including reduced behavioral disturbances. Thus, BRV may also present as a potential treatment alternative for patients with drug-refractory epilepsies, particularly for patients who are intolerant to LEV. [1], [2], [3]

Comparative data between LEV and BRV is lacking, particularly in children. Indirect comparisons via meta-analysis have been made based on adult data, however. One prominent analysis was published in 2016, and aimed to compare the efficacy and tolerability of LEV and BRV in adult patients with refractory focal seizures (RFS). Thirteen trials (LEV, n= 1,765 and BRV, n= 1,919) were included for analysis. The indirect comparison between LEV-treated vs. BRV-treated RFS patients showed that there were no statistical differences at all dose levels (low-dose levels: 5, 20, 25, 50 mg BRV vs 500 and 1,000 mg LEV; middle-dose levels: 100 mg BRV, 2,000 mg LEV; high-dose levels: 150 to 200 mg BRV, 3,000 mg LEV). However, most risk ratios (RR) at three dose levels were >1 for 50% response proportions (smallest p-value 0.08). Two adverse events, including headache (RR 0.41; 95% confidence interval [CI] 0.12 to 1.37; p= 0.02) and dizziness (RR 0.38; 95% CI 0.18 to 0.83; p= 0.03), were relatively lower in high-dose LEV vs. BRV. There were no statistically significant differences in other adverse events at the middle- and low-dose levels. The authors concluded that LEV might have slightly higher efficacy with a lower probability of dizziness compared with BRV for patients with RFS. [4]

Another 2016 meta-analysis evaluating the effect of BRV as an add-on for refractory focal epilepsy included six randomized controlled trials involving 2,399 participants. Seizures were considered drug-resistant if uncontrolled by one or more concomitant antiepileptic drugs at optimal stable dosages. The pooled RR for 50% responders and seizure freedom with brivaracetam were 1.79 (95% CI 1.51 to 2.12) and 4.74 (95% CI 2.00 to 11.25), respectively. Subanalysis by LEV status did not show a statistically significant difference in 50% responder rate when comparing BRV with placebo in patients with concomitant assumption of LEV. Analyses evaluating brivaracetam’s effect in patients refractory to LEV were not conducted. As such, it was suggested that further studies are needed to draw definitive conclusions about brivaracetam’s efficacy in non-levetiracetam-naive patients. [5]

On the Briviact® information page for healthcare workers, the manufacturer states that dose conversions between BRV formulations (oral solution, oral tablet, and injection solution) are 1:1. This is further supported by a 2016 randomized, single-dose phase 1 study, in which 25 healthy participants received five single doses of BRV (10, 50, 75, 100 mg tablet or intravenous [IV] bolus over 2 minutes) in a five-way crossover design, with drug administrations separated by a washout period of ≥7 days. Each dose of BRV was administered under fasting conditions, after which patients were monitored for 48 hours in the clinical pharmacology unit. Blood samples were taken at temporal points up to 48 hours postdose during each treatment period. The study observed bioequivalence between the 50 mg tablet and the 10, 75, and 100 mg tablets based on 90% CIs around geometric least squares mean (LSM) ratios, while BRV 100 mg IV was bioequivalent to 50 and 100 mg tablets, albeit with a higher Cmax during the first hour post-injection. Safety profiles of both IV and tablet formulations were also similar, with no new safety concerns identified. Thus, the investigators concluded no dose adjustment was required when switching between oral and IV formulations of BRV. [6], [7]

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-7 for your response.

Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany
Design	Multicenter, retrospective cohort study N= 262
Objective	To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice
Study Groups	Study participants (N= 262)
Inclusion Criteria	Records of epileptic patients exposed to at least one dose of brivaracetam
Exclusion Criteria	Patients who failed to achieve a 3-month follow-up
Methods	Medical records of epilepsy patients exposed to at least one dose of brivaracetam (ranging from 10 mg to 200 mg; mean 55.8 ± 27.7 mg) were collected with observation time between 3 to 12 months. Patients on levetiracetam were converted to brivaracetam without specific instructions. The patients were usually seen every 3 to 6 months and seizures were documented in diaries. Seizure-free status was defined as terminal remission of three months or more.
Duration	February to November 2016
Outcome Measures	50% responder rate or achieving seizure-free status at three months and six months
Baseline Characteristics		Study participants (N= 262)
	Age ranges, year < 18 18 to 40 41 to 64 65	9 128 109 16
	Female	133
	Epilepsy syndrome Idiopathic generalized epilepsy Symptomatic or cryptogenic focal epilepsy Symptomatic generalized epilepsy Unknown epilepsy syndrome	19 227 8 8
	Levetiracetam status Switched from levetiracetam to brivaracetam* Start of brivaracetam with previous exposure to levetiracetam Start of brivaracetam with no exposure to levetiracetam	133 103 26
	Patients were converted from levetiracetam to brivaracetam (n=133) at a median ratio of 15:1 (mean 14.8:1; range 2:1 to 40:1). The switch was performed directly between doses within a median of one day for 105 patients while 28 patients switched via overlapping within a median of 12 days.
Results	Endpoint	Study participants (N= 262)
	3-month status 50% response rate Seizure-free status	41.2% 14.9%
	6-month status 505 response rate Seizure-free status	40.5% 15.3%
Adverse Events	Treatment‐emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV‐induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53 to 7.95). There were no treatment-emergent adverse events (TEAEs) associated specifically with direct versus overlapping switch from LEV to BRV.
Study Author Conclusions	Brivaracetam in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to levetiracetam. An immediate switch from levetiracetam to brivaracetam at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of brivaracetam in patients not currently taking levetiracetam. The occurrence of brivaracetam during previous levetiracetam exposure predicted poor psychobehavioral tolerability of brivaracetam treatment. A switch to brivaracetam can be considered in patients with Levetiracetam-induced BAE.
InpharmD Researcher Critique	Retrospective reviews are limited by the accuracy of the available data. Seizure frequencies were self-reported via patient diaries.

References:

Steinig I, Von podewils F, Möddel G, et al. Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany. Epilepsia. 2017;58(7):1208-1216.

Tolerability, efficacy and retention rate of BRV in patients previously treated with LEV: a monocenter retrospective outcome analysis
Design	Single-center, retrospective analysis N= 102
Objective	To determine the potential for improvement of tolerability and efficacy by the use of brivaracetam (BRV) in patients previously treated with levetiracetam (LEV)
Study Groups	Seizure-free (n= 12) Improved seizure frequency (n= 19) Increased seizure frequency (n= 5) All patients switched from LEV to BRV (n= 60)
Inclusion Criteria	Patients treated with BRV for whom follow-up information on efficacy and/or tolerability were available
Exclusion Criteria	Excluded from efficacy analysis: under-report seizures due to postictal amnesia; if very high numbers of auras/partial seizures were documented; mentally disabled patients who were not sufficiently supervised by their caregivers to have all seizures documented across the day
Methods	Patients' charts were reviewed based on outpatient visits, and seizure counts as documented in seizure diaries were available for both a baseline period of at least three months prior to the introduction of BRV and for a BRV treatment period of at least six months. Patients who discontinued treatment earlier were also included to analyze tolerability and retention rate. One group (n= 60) underwent an overnight switch from levetiracetam (mean dosage: 2,161 mg/day), and 42 patients were add-treated with other baseline antiepileptic drugs (AED) but had LEV at some time in the past; 11 of them were gradually switched from another AED than LEV. Nine patients had BRV in monotherapy as off-label use. Patients switched directly from BRV to LEV were compared with patients who have had a history of a failed treatment with LEV, either due to ineffectiveness or intolerability.
Duration	March 2016 to December 2017 Treatment duration: 301.6 ± 156.8 days Follow up: six months
Outcome Measures	Mean prior LEV dose, mean starting BRV dose, mean final BRV dose, mean final BRV dose/LEV dose
Baseline Characteristics		All patients (n= 102)
	Age, years	42.5 ± 15.8
	Female	53 (52%)
	Epilepsy duration, years	17.6 ± 15.4
	Epilepsy etiology Focal and/or structural Genetic (idiopathic generalized) Progressive myoclonus Unknown	83 (81.4%) 9 (8.8%) 2 (2%) 8 (7.8%)
	Number of concomitant AEDs	1.6 ± 1.9
	Number of previous AEDs	4.5 ± 3.6
	Medical history Mental disability Psychiatric disease	16 (15.7%) 49 (48%)
	Direct switch from LEV to BRV	62 (60.8%)
	Past history of LEV treatment	40 (39.2%)
	Duration of treatment with BRV, months	301.6 ± 156.8
	In the efficacy analysis, only 61 patients with reliable seizure documentation (15 seizure free and 46 seizure active) are included.
Results		Mean prior LEV dose	Mean starting BRV dose	Mean final BRV dose	Mean final BRV dose/LEV dose
	Seizure-free patients (n= 12)	2,229.2 ± 1,058	147.9 ± 78	154.2 ± 74.9	1:15.6
	Improved seizure frequency (n= 19)	1,789.2 ± 731.2	142.1 ± 61.2	184.2 ± 58.6	1:10.1
	Increased seizure frequency (n= 5)	2,250 ± 316.2	165 ± 43.6	180 ± 48.5	1:13.6
	All patients switched from LEV to BRV (n= 60)	2,137.5 ± 967.6	148.8 ± 64.6	178.8 ± 65.8	1:12.7
Adverse Events	The adverse effects reported under both treatments with LEV and BRV were identical in all patients. Common Adverse Events from switching from LEV to BRV: depressive symptoms or mood lability (55%), aggressiveness or irritability (27%), other (somnolence, gait ataxia, gastrointestinal problems, alopecia; 10%)
Study Author Conclusions	The results suggested that for patients experiencing tolerability problems or an insufficient treatment response with LEV, the substitution of LEV treatment by BRV appears to be an interesting option. In a majority of patients who suffered from substantial psychiatric adverse effects from LEV a relevant improvement was achieved by switching to BRV; however, there remains a relevant percentage of patients who complain the same spectrum of psychiatric adverse effects from BRV.
InpharmD Researcher Critique	This trial was not a head-to-head study and the potential of BRV to improve seizure control in patients previously treated with LEV may be due to the limitation of the tolerated LEV dosage. Additionally, the result is subject to bias since the authors received honoraria for lectures from the related pharmaceutical company.

References:

Hirsch M, Hintz M, Specht A, Schulze-bonhage A. Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: A monocenter retrospective outcome analysis. Seizure. 2018;61:98-103.

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam
Design	Prospective, multicenter, open-label, single-arm, phase 3b study N= 29
Objective	To evaluate potential changes in behavioral adverse events (BAEs) among patients who switched to brivaracetam (BRV), without titration, after discontinuing levetiracetam (LEV) because of the occurrence of drug-limiting BAEs considered by the investigators to be related to LEV
Study Groups	Brivaracetam (N= 29)
Inclusion Criteria	Age ≥ 16 years with well-characterized partial-onset seizures (POS) or primary generalized epilepsy; receiving LEV at a recommended therapeutic dose (1 to 3 g/day) expected by the investigator to have benefitted or were benefitting from LEV, but discontinuation of LEV was warranted within 16 weeks of initiation due to BAEs; receiving 2 to 3 antiepileptic drugs (AEDs), including LEV at a dosage that had been stable for ≥ 4 weeks (≥ 12 weeks for phenobarbital, phenytoin, and primidone)
Exclusion Criteria	Experience of cluster or flurry seizures; history or presence of psychogenic nonepileptic seizures; status epilepticus during the year preceding the study; receiving LEV at a recommended therapeutic dose (1 to 3 g/day) > 16 weeks
Methods	A retrospective baseline period during LEV treatment was screened where seizure counts were recorded for 4 weeks and BAEs for up to 16 weeks before switching to BRV. Then patients received the last dose of LEV taken in the morning on Day 1 and received the first dose of BRV 100 mg BID without titration in the evening. Dose adjustments within the range of 50 to 200 mg/day were allowed if necessary. Completers were down-titrated over a maximum of 4 weeks followed by a 2- to 3-week study-drug-free period or entered into a long-term follow-up study without down-titration.
Duration	July 2012 to November 2013
Outcome Measures	Primary outcome: proportion of patients achieving a clinically meaningful reduction in BAEs based on the investigator's overall assessment (investigators answered 'yes' or 'no' to the following question: "Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV?") Secondary outcomes: POS frequency, seizure days for patients with idiopathic generalized epilepsy, seizure freedom (all seizure types), change in health-related quality of life (HRQoL; assessed using Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]), Patient Global Evaluation Scale (P-GES), Investigator Global Evaluation Scale (I-GES) Safety outcomes: an investigator-assessed shift in maximum intensity ('resolved,' 'mild,' 'moderate,' or 'severe') of primary BAEs (BAEs associated with discontinuation of LEV), Investigator Global Evaluation of Behavioral Side Effects (I-GEBSE; 7-point scale ranging from 'marked worsening' to 'marked improvement'), complete abatement of primary BAEs based on investigator assessment, freedom from BAEs, treatment-emergent adverse events (TEAEs), withdrawal due to an adverse event, occurrence of serious adverse events
Baseline Characteristics		Brivaracetam (N= 29)
	Age, years	35.8 ± 11.8
	Female	14 (48.3%)
	Body mass index, kg/m²	27.6 ± 7.1
	Race/ethnicity White Hispanic or Latino	24 (82.8%) 3 (10.3%)
	Epilepsy duration, years	16.2 ± 12.7
	Epileptic seizure profile Partial-onset seizures Simple partial seizures Complex partial seizures Partial evolving to secondarily generalized seizures Primary generalized seizures Absence Atypical absence Myoclonic Clonic Tonic Tonic-clonic Atonic	- 22 (75.9%) 10 (34.5%) 15 (51.7%) 16 (55.2%) 9 (31%) 4 (13.8%) 1 (3.4%) 5 (17.2%) 1 (3.4%) 0 8 (27.6%) 1 (3.4%)
	Concomitant AEDs in ≥ 10% of patients Lamotrigine Topiramate Carbamazepine Lacosamide Oxcarbazepine Valproate Clobazam	- 11 (37.9%) 4 (13.8%) 3 (10.3%) 3 (10.3%) 3 (10.3%) 3 (10.3%) 3 (10.3%)
Results	Endpoint	Brivaracetam (N= 29)
	Clinically meaningful reduction in BAEs	27 (93.1%)
	Median increase in POS, seizures/28 days	0.6
	Seizure freedom	7 (24.1%)
	Change in HRQoL from baseline	12.1 ± 11.4
	Improvement in P-GES	20/26 (76.9%)
	Improvement in I-GES	24/26 (92.3%)
	Reduction in maximum intensity of primary BAEs associated with discontinuation of LEV	27 (93.1%)
	Marked or moderate improvement in BAEs measured by the I-GEBSE	20 (69%)
	Complete abatement from primary BAEs	18 (62.1%)
	Freedom from BAEs	3 (10.3%)
Adverse Events	Common Adverse Events: headache (17.2%), fatigue (10.3%), back pain (10.3%)
	Serious Adverse Events: 1 (3.4%)
	Percentage that Discontinued due to Adverse Events: 2 (6.9%); one case of myoclonic epilepsy and one case of suicidal ideation and suicide attempt
Study Author Conclusions	Results from this small study suggest that patients who experience BAEs warranting the discontinuation of LEV treatment might benefit from a switch to BRV without titration. However, results should be interpreted with caution owing to the small sample size, lack of prospective baseline seizure data, short treatment period, and open-label design. Therefore, further confirmation of these results in future randomized, blinded studies would be of interest.
InpharmD Researcher Critique	The trial was a small study with an open-label design. Additionally, there were several subjective endpoints, which limited the quality of the results due to a high probability of bias.

References:

Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D'Souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav. 2015;52(Pt A):165-168. doi:10.1016/j.yebeh.2015.09.005

Overnight switch from levetiracetam to brivaracetam. Safety and tolerability
Design	Retrospective study N= 41
Objective	To assess the safety and tolerability of an overnight switch from levetiracetam (LEV) to brivaracetam (BRV)
Study Groups	All (N= 41)
Inclusion Criteria	Aged over 16 with all types of epilepsy who underwent an overnight switch from LEV to BRV
Exclusion Criteria	Major psychiatric pathology
Methods	Patients were re-assessed at control follow-up visit 6 months after commencing the new treatment.
Duration	From November 2016 to November 2017
Outcome Measures	Adverse events (AEs), frequency of seizures
Baseline Characteristics		All (N= 41)
	Age, years	40.9 ± 17.8
	Male	21 (51.2%)
	Time since first seizure, years	17.0 ± 12.4
	Etiology of epilepsy Structural Unknown Generalized genetic Unclassified	25 (61.0%) 6 (14.6%) 4 (9.8%) 4 (9.8%)
	Current treatment LEV monotherapy LEV + 1 antiseizure medication (ASM) LEV + 2 ASMs LEV + 3 ASMs LEV + 4 ASMs	15 (36.6%) 12 (29.3%) 11 (26.8%) 1 (2.4%) 2 (4.9%)
	Reason for switch Poor seizure control Side effects Irritability/aggressiveness Depression Drowsiness Dizziness Both	22 (53.6%) 27 (65.9%) 15 (36.6%) 10 (24.4%) 5 (12.2%) 1 (2.4%) 8 (19.5%)
	LEV dose at the time of the switch, mg/day	1,761.0 ± 884.6
	Starting dose of BRV, mg/day	142.0 ± 47.0
Results	Endpoint	All (N= 41)
	AEs	10 (24.4%)
	Change in neuropsychiatric AEs after switching Irritability/aggressiveness Improved Unchanged Worsening Depressive symptoms Improved Unchanged Worsening	12/15 (80.0%) 2/15 (13.3%) 1/15 (6.7%) 7/10 (70.0%) 3/10 (30.0%) 0/10 (0.0%)
	At 1 year of follow-up BRV continued BRV discontinued due to insufficiency or AEs	30 (73.2%) 11 (26.8%)
	Frequency of seizures after switching BRV Previously seizure-free Responder (≥50% reduction in frequency of seizure) Higher frequency	25 (61.0%) 9 (22.0%) 11 (26.8%) 5 (12.2%)
Adverse Events	See Results
Study Author Conclusions	The abrupt overnight switch from LEV to BRV (dosing ratio 15:1 and 10:1) is a safe and well-tolerated therapeutic option, in our small sample. BRV treatment can improve LEV-related neuropsychiatric AEs, which could also increase retention rates. This retrospective Spanish study is representative of current clinical practice, and due to the limited evidence in a real world-setting, it provides valuable information for physicians changing from LEV to BRV.
InpharmD Researcher Critique	The study has limitations inherent to retrospective, open-label, uncontrolled study. Data are limited to the visits after six months; no assessment was made the first few days after the change. A small sample size further limits the confidence of the data.

References:

Abraira L, Salas-Puig J, Quintana M, et al. Overnight switch from levetiracetam to brivaracetam. Safety and tolerability. Epilepsy Behav Rep. 2021;16:100504. Published 2021 Nov 14. doi:10.1016/j.ebr.2021.100504

Treatment with brivaracetam in children – The experience of a pediatric epilepsy center
Design	Cross-sectional retrospective chart review N= 31
Objective	To describe the effectiveness and tolerability of brivaracetam in children for focal and other types of epilepsy
Study Groups	Responders (n= 14) Nonresponders (n= 17)
Inclusion Criteria	Age <20 years, treated with brivaracetam at least two weeks
Exclusion Criteria	Not explicitly stated
Methods	Positive response to treatment was considered when a 50% decrease in seizure frequency occurred after 3 months of brivaracetam treatment. In responders to levetiracetam, positive effect was demonstrated if the patient maintained at least the same seizure control after switching to brivaracetam.
Duration	2017 to 2019
Outcome Measures	Responder rate, positive effect, seizure aggravation
Baseline Characteristics		Responders (n= 14)	Nonresponders (n= 17)	Total (N= 31)
	Age, years (range)	14.3 ± 3.5	13.4 ± 4.5	13.8 ± 4.07 (6 to 20)
	Male	52.4%	47.6%	67.7%
	Age of onset of seizures, years	5.4 ± 4.6	6.0 ± 2.9	5.7 ± 3.7
	Lag period to treatment, years	8.8 ± 4.6	6.8 ± 4.1	7.8 ± 4.4
	Dose, mg/kg	3.6 ± 1.6	4.0 ± 2.0	3.8 ± 1.8
	Duration of treatment, months	10.5 ± 8.4	2.8 ± 2.9*	6.7 ± 7.3
	Number of previous antiepileptic drugs	8.5 ± 4.7	9.5 ± 4.4	9.1 ± 4.5
	Type of epilepsy Focal onset epilepsy Lennox-Gastaut syndrome Absence with eyelid myoclonus Myoclonic-atonic epilepsy	40% 40% 66.7% 66.7%	60% 60% 33.3% 33.3%	64.5% 16.1% 9.7% 9.7%
	Main seizure type Focal onset with impaired awareness Drop attacks Myoclonic absence Focal to bilateral tonic-clonic Focal with preserved awareness	47.1% 57.1% 66.7% 0 0	52.9% 42.9% 33.3% 100% 100%	54.8% 22.6% 9.7% 6.5% 6.5%
	Psychiatric comorbidity	-	-	61%
	Indication for brivaracetam Seizure control Side effects of levetiracetam Both	-	-	61.3% 12.9% 25.8%
	Previously exposed to levetiracetam	-	-	93.5%
	Direct conversion from levetiracetam, n Abrupt (overnight switch) Gradual (over two weeks)	-	-	15 5 10
	* Patients who were nonresponders were treated for a shorter duration of time vs responders (p< 0.01). For patients switched from levetiracetam, the ratio of dosing was 10:1 (from 5:1 to 15:1).
Results	Endpoint	All patients (N= 31)
	Responder rate	14 (45.2%)*
	Positive effect on seizure control in patients previously exposed to levetiracetam	n= 29 13 (44.82%)**
	Seizure aggravation	6 (19.3%)
	* Responder rate for patients under versus over 16 years of age (40% vs. 54.5%; no difference) ** Five patients who were already responders to levetiracetam maintained the same level of seizure control after switching to brivaracetam. Eight patients had better seizure control on brivaracetam than levetiracetam. Two patients who already had a 50% seizure reduction on levetiracetam experienced an added value of brivaracetam, with a 75% and 90% decrease in convulsions. Six patients who previously failed levetiracetam had a 64.17 ± 12.4% seizure reduction on brivaracetam. Gender, age, duration of epilepsy, dosage, previous antiseizure medications, and type of epilepsy did not affect seizure control. Treatment was effective in focal onset seizures, but also in drop attacked for patients with myoclonic-atonic epilepsy or Lennox-Gastuat syndrome. Two patients with absence with eyelid myoclonus had over 90% reduction in seizures and were switched to monotherapy. While brivaracetam was effective in patients with focal onset seizures with impaired awareness, none of the patients with other focal seizures responded to therapy.
Adverse Events	Three patients (9.6%) reported side effects, with one patient developing psychosis that recovered after discontinuing treatment, one patient reporting mild somnolence, and one patient presenting with somnolence and nausea.
Study Author Conclusions	Brivaracetam is an effective treatment in focal, as well as generalized seizures in children. Efficacy in highly drug-resistant seizures as well as in lesional epilepsies, along with negligible side effects, might confer an advantage for brivaracetam treatment. Treatment should be attempted also in children who failed previously on levetiracetam. One should be aware the possibility of seizure exacerbation, but the causes for aggravation are unclear.
InpharmD Researcher Critique	While this study does not provide robust conclusions on the comparative safety and efficacy of brivaracetam and levetiracetam, it may help identify patient populations that can benefit from the addition of brivaracetam or from the switching of levetiracetam to brivaracetam.

References:

Nissenkorn A, Tzadok M, Bar-Yosef O, Ben-Zeev B. Treatment with brivaracetam in children - The experience of a pediatric epilepsy center. Epilepsy Behav. 2019;101(Pt A):106541. doi:10.1016/j.yebeh.2019.106541

Adjunctive brivaracetam in focal and generalized epilepsies: A single-center open-label prospective study in patients with psychiatric comorbidities and intellectual disability
Design	Prospective, observational, single-center study N= 134
Objective	To assess overall efficacy, tolerability, retention rate, and longer-term adverse event (AE) profile of brivaracetam (BRV) in patients with preexisting psychiatric or behavioral comorbidities to those without, and to identify any differences in patients with intellectual disability compared with those with normal range intellect
Study Groups	Study cohort (N= 134)
Inclusion Criteria	Adult patients (aged ≥16 years); focal or generalized epilepsy with or without intellectual disability and/or psychiatric comorbidities
Exclusion Criteria	Not disclosed
Methods	Patients were recruited from a UK hospital and followed up at clinical appointments over 26 months. BRV 25-200 mg/day was prescribed as adjunctive therapy in drug-resistant epilepsy (i.e., failure of adequate trials of two tolerated and appropriately chosen and used anti-epileptic drug [AED] schedules, either monotherapy or combination therapy, to achieve sustained seizure freedom).
Duration	May 2016 to July 2018
Outcome Measures	Primary: proportion of 50% responders; proportion of seizure-free patients Secondary: proportion withdrawing for inefficacy, AEs, or both
Baseline Characteristics		Study cohort (N= 134)
	Mean age, years (range)	40 (17-71)
	Female	80
	Epilepsy type Focal epilepsy Generalized epilepsy Combined generalized and focal epilepsy	76% 19% 5%
	Number of previously tried AEDs 2-3 4-6 7-9 10-11	5% 24% 52% 19%
	Number of concomitant AEDs 1 2 3 4	11% 50% 34% 5%
	Concomitant AEDs LEV (all switched) Carbamazepine Sodium valproate Lamotrigine Pregabalin Zonisamide Topiramate	47% 36% 26% 20% 17% 13% 13%
	Abbreviations: LEV= levetiracetam Brivaracetam was used off-license in 25 patients with generalized epilepsy and seven patients with combined focal and generalized epilepsy. All 63 patients taking LEV were withdrawn off gradually and switched over to BRV; LEV was withdrawn because of inefficacy in 38 (62%) patients and because of worsened depressive symptoms on LEV in 7 (11%) patients.
Results	Endpoint	Study cohort (N= 134)
	Mean treatment duration, months Dose, mg (range)	11 200 (50-200)
	Achievement of ≥50% responder rate Focal epilepsy Generalized epilepsy Combined generalized and focal epilepsy	30 (29%) 10 (25%) 5 (71%)
	No significant difference of ≥50% responder rate and proportion achieving seizure freedom between epilepsy types; nor in proportion of ≥50% responders according to the presence or absence of psychiatric and/or behavioral disorders; nor in proportion of ≥50% responders according to the presence or absence of intellectual disability. In the patients who switched to BRV from LEV due to inefficacy of LEV treatment, 28 (74%) reported no change to seizure frequency, 9 (24%) reported improvement, and 1 (3%) reported worsened seizure control. In the patients who switched to BRV from LEV due to worsened depressive symptoms, 5 (71%) patients had a preexisting diagnosis of depression, with 3 (60%) improved on stopping BRV and 2 (40%) reported further worsened depressive symptoms.
Adverse Events	Common Adverse Events:84 (63%) patients reported at least one AE; most common AEs were sedation and somnolence reported in 35 (26%) patients.
	Serious Adverse Events: Aggression (31 patients), though 17 (55%) patients had preexisting documented challenging and verbal/physically aggressive behavior
	Percentage that Discontinued due to Adverse Events: 27 (20%) patients; sedation, somnolence, and aggression were most common AEs leading to discontinuation.
Study Author Conclusions	This study showed evidence that BRV may be an effective adjunctive therapy in patients with drug-resistant focal or generalized epilepsies whose seizures have previously not responded or tolerated LEV therapy. We demonstrated a higher incidence of treatment-emergent AEs leading to lower retention rates compared with previous studies across all patient groups. There were, however, no significant differences in tolerability between patients with preexisting psychiatric or behavioral comorbidities, or intellectual disability to those without.
InpharmD Researcher Critique	Though patients as young as 17 years of age were included, the mean age of the cohort was 40 years, and so applicability of findings related to brivaracetam in this cohort to adolescents and children is uncertain. Discussion on brivaracetam formulation was not provided, and efficacy and safety of IV versus PO were not analyzed in the study.

References:

Foo EC, Geldard J, Peacey C, Wright E, Eltayeb K, Maguire M. Adjunctive brivaracetam in focal and generalized epilepsies: A single-center open-label prospective study in patients with psychiatric comorbidities and intellectual disability. Epilepsy Behav. 2019;99:106505. doi:10.1016/j.yebeh.2019.106505

Postmarketing Experience with Brivaracetam in the Treatment of Focal Epilepsy in Children and Adolescents
Design	Multicenter, retrospective, uncontrolled study N= 34
Objective	To evaluate the efficiency, retention, safety, and tolerability of brivaracetam in children and adolescents with focal epilepsy
Study Groups	Patients switched from levetiracetam to brivaracetam (n= 20) Patients without recent exposure to levetiracetam (n= 14)
Inclusion Criteria	Children and adolescents aged ≤17 years; diagnosed with focal epilepsy
Exclusion Criteria	Not explicitly stated stated
Methods	Records of children and adolescents aged ≤ 17 years with focal epilepsy treated with brivaracetam in 2016 and 2017 were reviewed. Data collection included demographics, seizure characteristics, and previous antiepileptic drug (AED) usage, with detailed history on levetiracetam exposure and adverse events. Brivaracetam doses were adjusted individually, and patients were monitored for retention, efficacy, and treatment-emergent adverse events (TEAEs) at three, six, and 12 months. Seizure frequency was tracked using medical records and seizure diaries, while retention rates were analyzed using Kaplan–Meier survival curves.
Duration	Trial duration ranged from 25 days to 24 months, with a median exposure to brivaracetam of 180 days.
Outcome Measures	50% responder rate and seizure freedom at three, six, and 12 months; retention rates; TEAEs
Baseline Characteristics	The study included 34 children and adolescents with focal epilepsy, with a mean age of 12.2 years (range: 3 to 17 years) and a slight female majority (56%). The average duration of epilepsy at study entry was 5.2 years, and most participants (74%) had drug-refractory epilepsy, having failed two adequate trials of AEDs. Seizure types varied, with focal onset seizures with impaired awareness being the most common (71%). Structural causes were identified in 41% of participants, while 56% had unknown etiology. At baseline, participants were taking a mean of 1.6 AEDs, with levetiracetam being the most frequently used (59%).
Results	The 50% responder rate at three months was 47% (n= 16), with 29% (n= 10) achieving seizure freedom. At six months, the 50% responder rate was 35% (n= 12), with 12% (n= 4) achieving seizure freedom, while at 12 months, the 50% responder rate dropped to 21% (n= 7), and no patients were seizure-free. Retention rates were high, with 97% of patients continuing treatment at three months, and 88% remaining on brivaracetam at the study's conclusion.
Adverse Events	TEAEs were reported in 12% of patients, including sedation (9%) and psychobehavioral effects such as aggression and irritability (6%). Discontinuation due to TEAEs occurred in 9% (n= 3). The total exposure to brivaracetam across the cohort was 19.7 years.
Study Author Conclusions	Use of brivaracetam in children and adolescents seems to be safe and well-tolerated. The results with 50% responder rate of 47% are consistent with those from randomized controlled trials and postmarketing studies in adults. An immediate switch from levetiracetam to brivaracetam at a ratio of 10:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under levetiracetam and a switch to brivaracetam can be considered in patients with levetiracetam-induced adverse events.
InpharmD Researcher Critique	This study highlights the practical application of brivaracetam in pediatric focal epilepsy, showing promising efficacy and safety. However, its retrospective design and small sample size may limit the generalizability of results.

References:

Schubert-Bast S, Willems LM, Kurlemann G, et al. Postmarketing experience with brivaracetam in the treatment of focal epilepsy in children and adolescents. Epilepsy Behav. 2018;89:89-93. doi:10.1016/j.yebeh.2018.10.018