Briviact (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a carcinogenicity study in mice, oral administration of brivaracetam (0, 400, 550, or 700 mg/kg/day) for 104 weeks increased the incidence of liver tumors (hepatocellular adenoma and carcinoma) in male mice at the two highest doses tested. At the dose (400 mg/kg) not associated with an increase in liver tumors, plasma exposures (AUC) were approximately equal to those in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration (0, 150, 230, 450, or 700 mg/kg/day) to rats for 104 weeks resulted in an increased incidence of thymus tumors (benign thymoma) in female rats at the highest dose tested. At the highest dose not associated with an increase in thymus tumors, plasma exposures were approximately 9 times those in humans at the MRD.

Mutagenesis

Brivaracetam was negative for genotoxicity in in vitro (Ames, mouse lymphoma, and CHO chromosomal aberration) and in vivo (rat bone marrow micronucleus) assays.

Impairment of Fertility

Oral administration of brivaracetam (0, 100, 200, or 400 mg/kg/day) to male and female rats prior to and throughout mating and early gestation produced no adverse effects on fertility. The highest dose tested was associated with plasma exposures approximately 6 (males) and 13 (females) times those in humans at the MRD.

14 CLINICAL STUDIES

The effectiveness of BRIVIACT in partial-onset seizures with or without secondary generalization was established in 3 fixed-dose, randomized, double-blind, placebo-controlled, multicenter studies (Studies 1, 2, and 3), which included 1550 patients. Patients enrolled had partial-onset seizures that were not adequately controlled with 1 to 2 concomitant antiepileptic drugs (AEDs). In each of these studies, 72% to 86% of patients were taking 2 or more concomitant AEDs with or without vagal nerve stimulation. The median baseline seizure frequency across the 3 studies was 9 seizures per 28 days. Patients had a mean duration of epilepsy of approximately 23 years.

All trials had 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. There was no titration period in these studies. Study 1 compared doses of BRIVIACT 50 mg/day and 100 mg/day with placebo. Study 2 compared a dose of BRIVIACT 50 mg/day with placebo. Study 3 compared doses of BRIVIACT 100 mg/day and 200 mg/day with placebo. BRIVIACT was administered in equally divided twice daily doses. Upon termination of BRIVIACT treatment, patients were down-titrated over a 1-, 2-, and 4-week duration for patients receiving 25, 50, and 100 mg twice daily BRIVIACT, respectively.

The primary efficacy outcome in Study 1 and Study 2 was the percent reduction in 7-day partial-onset seizure frequency over placebo, while the primary outcome for Study 3 was the percent reduction in 28-day partial-onset seizure frequency over placebo. The criteria for statistical significance for all 3 studies was p<0.05. Table 6 presents the primary efficacy outcome of the percent change in seizure frequency over placebo, based upon each study’s protocol-defined 7- and 28-day seizure frequency efficacy outcome.

Table 6: Percent Reduction in Partial-Onset Seizure Frequency over Placebo (Studies 1, 2, and 3)
Percent Reduction Over Placebo(%)
*
Based upon 7-day seizure frequency
Statistically significant based on testing procedure with alpha = 0.05
Based upon 28-day seizure frequency
STUDY 1 *
Placebo(n=100)——-
50 mg/day(n=99)9.5
100 mg/day(n=100)17.0
STUDY 2 *
Placebo(n=96)——-
50 mg/day(n=101)16.9
STUDY 3
Placebo(n=259)——
100 mg/day(n=252)25.2
200 mg/day(n= 249)25.7

Figure 1 presents the percentage of patients by category of reduction from baseline in partial-onset seizure frequency per 28 days for all pooled patients in the 3 pivotal studies. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients with an improvement in percent reduction from baseline partial-onset seizure frequency are shown in the 4 right-most categories.

Figure 1: Proportion of Patients by Category of Seizure Response for BRIVIACT and Placebo Across all Three Double-Blind Trials

Figure 1
(click image for full-size original)

Treatment with Levetiracetam

In Studies 1 and 2, which evaluated BRIVIACT dosages of 50 mg and 100 mg daily, approximately 20% of the patients were on concomitant levetiracetam. Although the numbers of patients were limited, BRIVIACT provided no added benefit when it was added to levetiracetam.

Although patients on concomitant levetiracetam were excluded from Study 3, which evaluated 100 and 200 mg daily, approximately 54% of patients in this study had prior exposure to levetiracetam.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

BRIVIACT Tablets

  • 10 mg are white to off-white, round, film-coated, and debossed with “u10” on one side. They are supplied as follows:
Bottles of 60 tablets NDC 50474-370-66
  • 25 mg are grey, oval, film-coated, and debossed with “u25” on one side. They are supplied as follows:
Bottles of 60 tablets NDC 50474-470-66
Unit dose cartons of 100 tablets NDC 50474-470-09
  • 50 mg are yellow, oval, film-coated, and debossed with “u50” on one side. They are supplied as follows:
Bottles of 60 tablets NDC 50474-570-66
Unit dose cartons of 100 tablets NDC 50474-570-09
  • 75 mg are purple, oval, film-coated, and debossed with “u75” on one side. They are supplied as follows:
Bottles of 60 tablets NDC 50474-670-66
  • 100 mg are green-grey, oval, film-coated, and debossed with “u100” on one side. They are supplied as follows:
Bottles of 60 tablets NDC 50474-770-66
Unit dose cartons of 100 tablets NDC 50474-770-09

BRIVIACT Oral Solution

  • 10 mg/mL is a slightly viscous, clear, colorless to yellowish, raspberry-flavored liquid. It is supplied in amber glass bottles:
300 mL bottles NDC 50474-870-15

BRIVIACT Injection

  • 50 mg/5 mL is a clear, colorless, sterile solution supplied in colorless single-dose glass vials.
Carton of 10 vials NDC 50474-970-75

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.