Is there any literature to support therapeutically interchanging brivaracetam to levetiracetam? If so what would be an appropriate dose conversion(s)?

Is there any literature to support therapeutically interchanging brivaracetam to levetiracetam? If so what would be an appropriate dose conversion(s)?

Comment by InpharmD Researcher

A comprehensive literature search did not reveal any studies directly evaluating the therapeutic interchange of brivaracetam to levetiracetam. Due to efficacy or tolerability issues, the conversion from levetiracetam to brivaracetam has been evaluated with varying dose conversions ranging from 10:1 to 20:1 (levetiracetam: brivaracetam). An indirect comparison found levetiracetam to have greater efficacy and lower probability of causing dizziness than brivaracetam for refractory focal seizures treatment; however, head-to-head trials are needed to determine whether levetiracetam and brivaracetam are therapeutically interchangeable.

Background

A 2016 meta-analysis aimed to compare the efficacy and tolerability of levetiracetam (LEV) and brivaracetam (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 (AEs), 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 AEs 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. [1]

A 2016 review regarding the use of brivaracetam in the treatment of focal and idiopathic generalized epilepsies and status epilepticus included several randomized controlled trials to evaluate the safety and efficacy of brivaracetam. While the authors stated that immediate switch from levetiracetam to brivaracetam at a conversion ratio between 10:1 to 15:1 appears reasonable and might alleviate the behavioral side effects, it was concluded that this conversion may change with further clinical experience. [2]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there any literature to support therapeutically interchanging brivaracetam to levetiracetam? If so what would be an appropriate dose conversion(s)?

Level of evidence

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Please see Tables 1-4 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.

Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey
Design	Retrospective, single-center, chart review N= 101
Objective	To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center
Study Groups	Patient data (N= 101)
Inclusion Criteria	Patients treated with brivaracetam
Exclusion Criteria	N/A
Methods	Medical records of epileptic patients taking brivaracetam were analyzed to assess efficacy under real-world conditions. Starting doses ranged from 25 mg, 50 mg, or 100 mg BID, and patients that switched from levetiracetam to brivaracetam were included. LEV was switched to BRV in 43 patients. Switching from Levetiracetam (LEV) to brivaracetam (BRV) was performed abruptly using the following ratios: LEV 1,000 mg: BRV 50 mg LEV 2,000 mg: BRV 100 mg LEV 3,000 mg: BRV 200 mg
Duration	February to May 2016
Outcome Measures	Responder rates and patients that achieved seizure-free status for the last three months or at the time of last observation carried forward if BRV was discontinued early
Baseline Characteristics		Patient data (N= 101)
	Age, years	42
	Female	54 (53%)
	Etiology Structural causes Unclear	71% 27%
	Presence of partial-onset seizures Generalized tonic-clonic seizure Partial-onset seizures with and without secondary generalization	101 3 98
Results	Endpoint	Patient data (N= 101)
	Responder rates	28 (27.8%)
	Achieved seizure-free status	7%
	The switch from LEV to BRV in 43 patients was performed abruptly without complications. The switch to BRV saw observed aggravation to seizure frequency and severity in 5 cases. In 26 cases (60%), BRV was discontinued and re-switched to LEV, resulting in a retention rate of 40%. The primary reason for re-switching back was due to a lack of clear superiority in efficacy. Six patients switched due to tolerability. Three of them benefitted because of less irritability (n = 2) or somnolence (n = 1).
Adverse Events	Adverse events occurred in 37 patients (37%). The most frequent AEs were dizziness (16%) and somnolence (11%). In single cases, psychiatric adverse events included irritability, aggression, depression, and psychosis.
Study Author Conclusions	If patients are switched from LEV to BRV, the possibility of seizure aggravation should be considered, which happened in 5 cases (11.6% of all switched patients). The previous seizure situation was re-established in them when they were back to LEV.
InpharmD Researcher Critique	Treatment was not standardized, but reflects results from a real-world scenario.

References:

Steinhoff BJ, Bacher M, Bucurenciu I, et al. Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-A monocenter survey. Seizure. 2017;48:11-14. doi:10.1016/j.seizure.2017.03.010

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