Summary Basis of Decision for Brivlera

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Brivlera is located below.

Recent Activity for Brivlera

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Brivlera

Updated: 2025-08-26

The following table describes post-authorization activity for Brivlera, a product which contains the medicinal ingredient Brivaracetam. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number(s) (DINs):

  • DIN 02452936 - 10 mg brivaracetam, tablet, oral administration 
  • DIN 02452944 - 25 mg brivaracetam, tablet, oral administration 
  • DIN 02452952 - 50 mg brivaracetam, tablet, oral administration 
  • DIN 02452960 - 75 mg brivaracetam, tablet, oral administration 
  • DIN 02452979 - 100 mg brivaracetam, tablet, oral administration 
  • DIN 02452987 - 10 mg/mL brivaracetam, solution, oral administration 
  • DIN 02452995 - 10 mg/mL brivaracetam, solution, intravenous administration 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 276673

2023-06-28

Issued NOC 2023-12-08

Submission filed as a Level I – Supplement to update the PM to revise the pediatric dosing table. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM. An NOC was issued.

SNDS # 269819

2022-11-17

Issued NOC 2023-04-14

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 261934

2022-03-01

Issued NOC 2022-10-18

Submission filed as a Level I – Supplement for a change in the batch size for the drug product and for a change to the drug product manufacturing process. The information was reviewed and considered acceptable and an NOC was issued.

SNDS # 259174

2021-12-04

Issued NOC 2022-08-26

Submission filed as a Level I – Supplement to add a manufacturing site for the drug substance and for a change to the drug substance manufacturing process. The information was reviewed and considered acceptable and an NOC was issued.

SNDS # 249184

2021-02-04

Issued NOC 2021-06-30

Submission filed as a Level II – Supplement (Safety) to update the PM with safety information and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02452987) market notification

Not applicable

Date of first sale 2020-04-06

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS # 226734

2019-04-11

Issued NOC 2020-03-24

Submission filed as a Level I – Supplement for an expanded pediatric indication: adjunctive therapy in the management of partial-onset seizures in patients 4 years of age and older with epilepsy who are not satisfactorily controlled with conventional therapy. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 224666

2019-02-13

Issued NOL

2019-05-21

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02452995) market notification

Not applicable

Date of first sale

2018-10-10

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS # 204257

2017-03-30

Issued NOC

2017-05-25

 

 

Submission filed as a Level I – Supplement to propose an abbreviated package insert for Part I of the injection dosage form.

The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN(s) 02452936, 02452944, 02452952, 02452960, 02452979) market notification

Not applicable

Date of first sale 2016/ 05/02

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 183355

2015/03/30

Issued NOC 2016/03/09

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Brivlera

Date SBD issued: 2016-07-05

The following information relates to the New Drug Submission for Brivlera.

Brivaracetam
10 mg, 25 mg, 50 mg, 75 mg and 100 mg tablets, oral;
10 mg/mL, solution, oral;
10 mg/mL solution, tablets
10 mg/mL solution, intravenous

Drug Identification Number (DIN):

  • DIN 02452936 - 10 mg, oral tablet
  • DIN 02452944 - 25 mg, oral tablet
  • DIN 02452952 - 50 mg, oral tablet
  • DIN 02452960 - 75 mg, oral tablet
  • DIN 02452979 - 100 mg, oral tablet
  • DIN 02452987 - 10 mg/mL, oral solution
  • DIN 02452995 - 10 mg/mL, intravenous solution

UCB Canada Inc.

New Drug Submission Control Number: 183355

 

On March 9, 2016 Health Canada issued a Notice of Compliance to UCB Canada Inc. for the drug product Brivlera.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Brivlera is favourable as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

 

1 What was approved?

 

Brivlera, an anti-epileptic agent, was authorized as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

There is limited information on the use of Brivlera in subjects >65 years of age.

Brivlera is not indicated for use in pediatric patients (<18 years of age) as there is insufficient data on safety and efficacy of the drug in this population.

Brivlera is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Brivlera was approved for use under the conditions stated in the Brivlera Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Brivlera (brivaracetam) is available as 10 mg, 25 mg, 50 mg, 75 mg and 100 mg tablets, 10 mg/mL oral solution and 10 mg/mL injection. In addition to the medicinal ingredient brivaracetam, Brivlera contains the following non-medicinal ingredients.

  • Tablets: anhydrous lactose, betadex (β-cyclodextrin), black iron oxide (25 mg, 75 mg, 100 mg), croscarmellose sodium, lactose monohydrate, magnesium stearate, polyethylene glycol 3350, polyvinyl alcohol, red iron oxide (50 mg, 75 mg), talc, titanium dioxide, and yellow iron oxide (25 mg, 50 mg, 75 mg, 100 mg).
  • Oral solution: anhydrous citric acid, carboxymethylcellulose sodium, glycerin, methylparaben, purified water, raspberry flavour, sodium citrate, sorbitol solution, and sucralose.
  • Injection solution: glacial acetic acid, sodium acetate (trihydrate), sodium chloride, and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Brivlera Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Brivlera approved?

 

Health Canada considers that the benefit/risk profile of Brivlera is favourable as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy.

Epilepsy is a chronic neurological disorder that affects approximately 3% of the population worldwide. The main symptom of epilepsy is the recurrence of unprovoked seizure attacks. In the majority of cases, it is difficult to manage seizures of any type with a single product (monotherapy). Patients are often maintained on two or more concomitant Anti-Epileptic Drugs (AEDs) to achieve adequate seizure control. Therefore, there remains a need for the development of new drugs which can provide better efficacy along with improved adverse event profile. 

Brivlera has been shown to be efficacious for the management of epilepsy. The market authorization was based on three fixed-dose, randomized, double-blind, placebo-controlled, multicentre trials, namely Studies 1252, 1253 and 1358. In these three clinical trials, 2.5%, 5.1%, and 4.0% of the patients on Brivlera 50 mg/day, 100 mg/day and 200 mg/day respectively, became seizure free during the study compared with 0.5% on placebo.

Adverse events most commonly experienced by patients treated with Brivlera included dizziness, fatigue and somnolence. These issues have been addressed through appropriate labelling in the Brivlera Product Monograph. Serious adverse events in the Brivlera overall group included convulsion, status epilepticus, suicidal ideation and suicide attempt.

A Risk Management Plan (RMP) for Brivlera was submitted by UCB Canada to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The original brand name submitted by the sponsor was Briviact. This name did not pass the Look-alike Sound-alike (LASA) assessment. The sponsor proposed Brivlera as a replacement. This name was accepted.

Overall, the benefits of Brivlera therapy are considered to outweigh the risks. Brivlera has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Brivlera Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Brivlera?

 

Submission Milestones: Brivlera

Submission Milestone Date
Pre-submission meeting: 2015-01-21
Submission filed: 2015-03-30
Screening  
Screening Acceptance Letter issued: 2015-05-23
Review  
Biopharmaceutics Evaluation complete: 2016-02-26
Quality Evaluation complete: 2016-03-08
Clinical Evaluation complete: 2016-03-08
Labelling Review complete: 2016-03-08
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2016-03-09

 

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Brivlera was based on a critical assessment of the Canadian data package. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference in the quality and non-clinical reviews.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Brivlera?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Brivlera is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

The precise mechanism by which brivaracetam (medicinal ingredient in Brivlera) exerts its anti-epileptic effect in humans is not fully understood. Based on animal studies, brivaracetam anti-seizure properties appear to be related to its high-affinity for the synaptic vesicle protein 2A (SV2A) in the brain.

Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein which is found only in the secretory vesicles of neural and endocrine cells. It appears to be unique to vertebrates, but the mechanism by which these proteins regulate secretion is unclear. Based on chemistry and structural data, it appears that the SV2 proteins are considered major facilitators belonging to the superfamily of transport proteins. Other demonstrated actions of this protein include regulation of presynaptic calcium levels which may indirectly play a role in neurotransmission.

So far, three types of SV2 proteins have been identified in mammals. Of these types, SV2 Type A (SV2A) is the most broadly expressed and is believed to be present in all neurons. This protein also appears to be present in (the inhibitory) gamma-aminobutyric acid-ergic neurons. Non-clinical evidence suggests that disruption of SV2A gene may be involved in the production of seizures.

Brivaracetam is primarily metabolized by the liver. While patients with pre-existing liver impairment were excluded from the pivotal trials, data from a pharmacokinetic study suggest that both initial and maximum recommended daily dose of Brivlera in patients with any degree of hepatic impairment should be reduced. This observation has been captured in the Brivlera Product Monograph.

Potential interactions between Brivlera (25 mg twice daily to 100 mg twice daily) and other Anti-Epileptic Drugs (AEDs) were investigated in a pooled analysis. A few drug-drug interactions, such as that with carbamazepine, phenobarbital, and phenytoin were identified and appropriately labelled in the Brivlera Product Monograph.

The submitted comparative bioavailability study EP0007 was reviewed and is considered acceptable. The study satisfactorily bridged the 10 mg, 75 mg, and 100 mg proposed strengths of the Brivlera tablets and the Brivlera solution for injection to the 50 mg tablet used in pivotal Phase III clinical trials. In accordance with Health Canada Therapeutic Products Directorate Guidance on Bioequivalence of Proportional Formulations: Solid Oral Dosage Forms,awaiver was granted from conducting bioequivalence studies with the 25 mg and 50 mg Brivlera tablets on the basis of proportionality to the 75 mg and 100 mg Brivlera tablets used in the bioavailability study.

Comparative bioavailability of brivaracetam between the Brivlera oral solution and the oral tablets used in Phase III clinical trials was also successfully demonstrated in Study N01296.

The effect of a high-fat, high-calorie meal on the pharmacokinetics of brivaracetam after a single-dose administration of the 50mg tablet used during Phase III clinical trials was also evaluated. Food intake reduced the rate of absorption (Cmax) of brivaracetam by approximately 37%. A delay in Tmax from 0.5 to 3.0 hours was also noted when the product was administered under fed conditions. However, no significant difference was observed in the extent of absorption (AUC) of brivaracetam between fasting and fed conditions. Brivlera may be taken with or without food.

Overall, pharmacokinetic and pharmacodynamic studies conducted with Brivlera did not raise any significant safety concerns. The clinical pharmacological data therefore support the use of Brivlera for the approved indication.

For further details, please refer to the Brivlera Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Brivlera as adjunctive therapy in partial-onset seizures was based primarily on three fixed-dose, randomized, double-blind, placebo-controlled, multicentre studies (Studies 1252, 1253, 1358) which included a total of 1,558 patients (1,099 patients were exposed to Brivlera and 459 patients received placebo).

All three studies were similar in design which included an 8-week Baseline period, during which patients were required to have at least 8 partial-onset seizures. The Baseline period was followed by a 12-week Treatment period. As there was no Titration period in any of these studies, patients were initiated and remained on a fixed-dose of study drug throughout the trial. At the end of the Treatment period, a 2-week down-titration was followed by a 2-week drug-free period. In Studies 1252 and 1253, the study drug dose could be decreased once (that is [i.e.] fallback option) during treatment, if necessary for tolerability reasons. Once reduced, the patient was required to remain on this dose for the rest of the Treatment period. No fallback was allowed in 1358.

Study 1252 compared doses of Brivlera 50 mg/day and 100 mg/day with placebo. Study 1253 compared Brivlera 50 mg/day with placebo. Study 1358 compared doses of Brivlera 100 mg/day and 200 mg/day with placebo. All daily doses were administered in two equal intakes, morning and evening.

Across the three studies, in order to be eligible for enrollment patients needed to have partial-onset seizures with or without secondary generalization that is not adequately controlled with one to two concomitant Anti-Epileptic Drugs (AEDs). In Studies 1252 and 1253, approximately 80% of the patients were taking two concomitant AEDs, and in Study 1358, 71% were taking two concomitant AEDs with or without vagal nerve stimulation. The most commonly used AEDs across the three studies were carbamazepine (41%), lamotrigine (25%), valproate (21%), oxcarbazepine (16%), topiramate (14%), phenytoin (10%), and levetiracetam (10%). Patients on levetiracetam were excluded from Study 1358. Across all three studies, the patients' mean age was 38.3 years. The median baseline seizure frequency was 9.0 seizures per 28 days. Mean duration of epilepsy ranged from 22 to 24 years.

For Studies 1252 and 1253, patients were randomized in a 1:1:1:1 ratio to placebo, Brivlera 20 mg/day, Brivlera 50 mg/day, and Brivlera 100 mg/day, for 1252 and placebo, Brivlera 5 mg/day, Brivlera 20 mg/day, and Brivlera 50 mg/day, for 1253. For Study 1358, patients were randomized in a 1:1:1 ratio to placebo, Brivlera 100 mg/day, and Brivlera 200 mg/day, respectively.

In studies 1252 and 1253, randomization was stratified for geographical region and for the use of concomitant levetiracetam (use or no use) at study entry to ensure balance between the four treatment groups. For Study 1358, randomization was stratified by country, levetiracetam status (never used levetiracetam versus [vs] prior levetiracetam use only), and number of AEDs previously used but discontinued prior to study entry (≤2 vs >2 AEDs). For Study 1252 and 1253, the number of patients taking levetiracetam at the time of study entry was limited to 20% of randomized patients. For Study 1358, patients receiving concomitant levetiracetam were excluded from the study.

The primary efficacy endpoint for all three studies was the median percent reduction in 28-day total partial seizure frequency and proportion of patients with ≥50% reduction in seizure frequency from baseline to the end of double-blind treatment phase.

Across the three studies, the completion rates for placebo, Brivlera 50 mg/day, 100 mg/day, and 200 mg/day were 94.7%, 91.3%, 90.1%, and 90.4%, respectively. Very few patients (<0.3%), in either placebo or overall Brivlera arms, discontinued the trials due to lack of efficacy.

Study Results

In Study 1252, a statistically significant treatment effect was not observed for the 50 mg/day dose. The 100 mg/day dose in this study was nominally significant. In Study 1253, the 50 mg/day dose showed a statistically significant treatment effect. In Study 1358, both 100 mg/day and 200 mg/day doses showed a statistically significant treatment effect compared to placebo. The 200 mg/day dose did not provide additional efficacy compared to the 100 mg/day dose.

In these three clinical trials, 2.5% (4/161), 5.1% (17/332) and 4.0% (10/249) of the patients on Brivlera 50 mg/day, 100 mg/day and 200 mg/day respectively, became seizure free during the Treatment period compared with 0.5% (2/418 patients) on placebo.

There were no significant differences in seizure control as a function of gender. Data on race were limited (approximately 28% of the patients were non-Caucasian).

Treatment with Levetiracetam

In Studies 1252 and 1253, which evaluated Brivlera dosages of 50 mg and 100 mg daily, approximately 20% of the patients were on concomitant levetiracetam. Although not powered for this analysis and the number of patients is limited, there was no observed benefit versus placebo when Brivlera was added to levetiracetam.

Patients on concomitant levetiracetam were excluded from Study 1358, which evaluated brivaracetam 100 and 200 mg daily. Approximately 54% of patients in this study had prior exposure to levetiracetam.

For more information, refer to the Brivlera Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 1,099 patients received various doses of Brivlera (5 mg, 20 mg, 50 mg, 100 mg and 200 mg) in the three Phase III, placebo-controlled trials (Studies 1252, 1253, and 1358) described previously in the Clinical Efficacy section. Most common adverse events (AEs) reported in these studies included dizziness, fatigue, and somnolence. With the exception of a few (for example [e.g.] fatigue and somnolence), most events did not appear to be dose-related.

A higher proportion of Brivlera-treated patients discontinued due to AEs (6.6% compared to 3.5% in placebo). Examples of such events include dizziness, depression, and fatigue. Serious adverse events in Brivlera overall group included convulsion (2.5%), status epilepticus (0.8%), suicidal ideation and suicide attempt (0.5% each).

Adverse events reported in association with intravenous administration of the drug were generally similar to those observed with oral administration.

Safety Topics of Special Interest
Hepatic and Renal Impairment

Brivaracetam (the medicinal ingredient in Brivlera) is primarily metabolized by the liver. While patients with pre-existing liver impairment were excluded from the pivotal trials, data from a pharmacokinetic study suggest that both initial and maximum recommended daily dose of Brivlera in patients with any degree of hepatic impairment should be reduced. A statement to this effect has been included in the Brivlera Product Monograph (PM).

A single dose pharmacokinetic study indicated that moderate and severe renal impairment can increase plasma levels of brivaracetam metabolites by 3 to 21-fold. A cautionary statement has been added to the Brivlera Product Monograph as patients with renal impairment were excluded from pivotal trials.

Hematological Events

Brivlera can cause hematologic abnormalities. In the three Phase III placebo-controlled trials (Studies 1252, 1253, and 1358), the most commonly reported treatment-emergent adverse events associated with blood dyscrasia were neutropenia and decrease in neutrophil count. A total of 1.8% of Brivlera-treated patients and 1.1% of placebo-treated patients had at least one clinically significant decreased white blood cell count (<3.0 x 109/L), and 0.3% of Brivlera-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 x 109/L).

Behavioural Disorders

In epilepsy clinical trials, there is evidence Brivlera causes both psychotic (e.g., hallucinations, paranoia, and psychotic disorder) and non-psychotic (e.g., irritability, anxiety, aggression) adverse reactions which are not dose-dependent. In the Phase III placebo-controlled trials, psychiatric events were reported in approximately 13% of patients randomized to receive Brivlera at least 50 mg/day compared to 8% of placebo-treated patients. Non-psychotic events occurred in 12% of the patients treated with Brivlera at least 50mg/day compared to 7% of placebo-treated patients. A total of 1.7% of adult patients treated with Brivlera discontinued treatment due to psychiatric events (e.g., aggression, irritability, depression) compared to 1.3% of patients who received placebo. In the Phase III controlled epilepsy studies, irritability, depression, and anxiety symptoms occurred in 2% of Brivlera-treated patients and 1% of placebo-treated patients.

Other Labelling

Other safety issues which were seen in the clinical program, or are often associated with anti-epileptic drugs were also added to the Warnings and Precautions section of the Brivlera Product Monograph which include: Type I hypersensitivity reactions, somnolence, fatigue, dizziness and gait disorders, behavioural disorders, and hematologic AEs. For further details on these events, refer to the Brivlera Product Monograph.

Other Studies
Long-Term/Open-label Trials

Currently, there is no post-marketing data available for Brivlera. Safety of long-term use of Brivlera in the dose range of 50 mg/day to 200 mg/day is being assessed in a number of ongoing open-label studies. While these trials are still ongoing, preliminary data from some of the trials suggest that the safety profile of this drug in the long term (longer than a few weeks) is similar to that observed in Phase III pivotal trials.

Abuse Potential

In an open-label, cross-over, human abuse potential study of 44 subjects, aged 18 to 55 years, single doses of Brivlera 50 mg, 200 mg and 1,000 mg were compared to placebo and alprazolam (1.5 mg and 3 mg; positive control). While Brivlera showed fewer sedative, euphoric, stimulant, dizziness, and negative effects as compared to alprazolam, it was not significantly different from alprazolam on some measures of balance and positive effects at the supratherapeutic doses (200 mg and 1,000 mg).

Somnolence, euphoric mood, dizziness, and fatigue were the most commonly reported adverse events in this study. Overall, 1000 mg Brivlera was associated with the highest incidence of euphoric mood (66%), followed by the other Brivlera doses (40% at 200 mg, 32% at 50 mg), while the incidence of euphoric mood following alprazolam was lower (17% at both 1.5 mg and 3.0 mg doses). Sedative effects were observed in healthy subjects in the single ascending dose and multiple ascending dose studies; however, no euphoria or stimulant-like effects were observed using controlled pharmacodynamic measures.

In the overall Brivlera clinical program, the incidence of euphoric mood and feeling drunk was 0.5% in patient populations but higher (19.9%) in Phase I studies. The common adverse events associated with abuse were dizziness, somnolence, fatigue and asthenia.

There was no evidence of physical dependence potential or a withdrawal syndrome with Brivlera in a pooled review of placebo-controlled adjunctive therapy studies. However, psychological dependence cannot be excluded because of reports of euphoric type effects even at therapeutic doses.

Pediatrics

The Brivlera Product Monograph clearly identifies that the "safety and efficacy of Brivlera in pediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated." There are limited safety data for children from 1 month to <17 years of age. A total of 152 children (1 month to <17 years of age) were treated with brivaracetam in the adjunctive therapy epilepsy clinical programme. In the pivotal adjunctive trials of epilepsy, there were no young children and only a limited number of patients that were 16 and 17 years old. The sponsor conducted a pharmacokinetic study in 99 patients aged 1 month to <16 years receiving Brivlera oral solution. This study showed that plasma concentrations were dose-proportional in all age groups. Amongst patients 17 years in already conducted trials, about 16% experienced events that led to permanent discontinuation. Examples include aggression (3.3%) and, weight decreased, somnolence, suicidal ideation (1.3% each). This information has been added to the Brivlera Product Monograph.

For more information, refer to the Brivlera Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology, pharmacokinetic, and toxicology studies have characterized the non-clinical profile of brivaracetam, the active ingredient in Brivlera, in sufficient detail to support the intended clinical indication.

Carcinogenicity studies were conducted in mice and rats. Higher incidences of liver tumours were observed in male mice, but are considered to be the result of pleiotrophic effects on the liver that include hepatocellular hypertrophy and induction of microsomal enzymes, a mode of action that is not likely relevant for humans. In rats, there were higher incidences of thyroid tumours, considered secondary to hepatic enzyme induction and also not relevant for humans, and benign thymomas (thymic tumours) in high dose females for which systemic exposure to brivaracetam at the no-effect dose was about nine times that of the maximum recommended human dose (MRHD).

The liver was the main target organ for toxicity in repeated dose studies with different sensitivity across species. The dog was the most sensitive species with no safety margin identified based on systemic exposure. Liver changes were also seen in mice and rats; however no adverse liver changes were seen in monkeys at exposures up to 42 times that at the MRHD.

Brivaracetam did not affect fertility in male and female rats. It was not teratogenic in rats or rabbits, but did result in embryo-fetal toxicity in rabbits at an exposure eight times that at the MRHD. Administration of brivaracetam during the peri- and post-natal period to rat dams resulted in lower body weight gain, a slight increase in age of attainment of vaginal patency, and lower locomotor activity at an exposure 17 times that at the MRHD. Brivaracetam and/or its metabolites readily crossed the placental barrier in rats with maternal blood levels similar to those in the fetus, placenta and amniotic fluid and were excreted into milk of lactating female rats with mean milk/plasma ratio close to unity.

Brivaracetam administration to juvenile rats and dogs resulted in generally comparable findings to those seen in adult animals. There were decreases in rat brain weight at all dose levels, but without microscopic correlates on detailed histopathologic evaluation.

The intravenous formulation of Brivlera is unlikely to cause hemolysis or significant local irritation. Studies conducted in male rats suggest that brivaracetam has low dependence/abuse liability.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Brivlera Product Monograph. In view of the intended use of Brivlera, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Brivlera Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Brivlera has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of Brivlera tablets, oral and intravenous solutions is acceptable when stored at room temperature (15 to 30°C) for up to 36 months.

Proposed limits of drug-related impurities are considered adequately qualified (that is [i.e.] within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Lactose anhydrous and lactose monohydrate used in the manufacture of Brivlera tablets are obtained from cow's milk that is fit for human consumption.

 

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