Brivaracetam Oral Solution and Intravenous Injection

BRIVIACT is indicated for the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.

Dosage Forms And Strengths

• 10 mg: white to off white, round, film-coated, and debossed with "u10" on one side.
• 25 mg: grey, oval, film-coated, and debossed with "u25" on one side.
• 50 mg: yellow, oval, film-coated, and debossed with "u50" on one side.
• 75 mg: purple, oval, film-coated, and debossed with “u75” on one side.
• 100 mg: green-grey, oval, film-coated, and debossed with “u100” on one side.

• 10 mg/mL: slightly viscous, clear, colorless to yellowish, raspberry-flavored liquid.

• 50 mg in 5 mL in one single-dose vial. It is a clear, colorless, sterile solution.

Storage And Handling

• 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

• 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

• 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

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Do not freeze BRIVIACT injection or oral solution.

Discard any unused BRIVIACT oral solution remaining after 5 months of first opening the bottle.

BRIVIACT injection vials are single-dose only [see DOSAGE AND ADMINISTRATION].

Manufactured for: UCB, Inc., Smyrna, GA 30080. Revised: Sep 2017.

The following serious adverse reactions are described elsewhere in labeling:

• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Neurological Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity: Bronchospasm and Angioedema [see WARNINGS AND PRECAUTIONS]
• Withdrawal of Antiepileptic Drugs [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In all controlled and uncontrolled trials performed in adult epilepsy patients, BRIVIACT was administered as adjunctive therapy to 2437 patients. Of these patients, 1929 were treated for at least 6 months, 1500 for at least 12 months, 1056 for at least 24 months, and 758 for at least 36 months. A total of 1558 patients (1099 patients treated with BRIVIACT and 459 patients treated with placebo) constituted the safety population in the pooled analysis of Phase 3 placebo-controlled studies in patients with partial-onset seizures (Studies 1, 2, and 3) [see Clinical Studies]. The adverse reactions presented in Table 2 are based on this safety population; the median length of treatment in these studies was 12 weeks. Of the patients in those studies, approximately 51% were male, 74% were Caucasian, and the mean age was 38 years.

In the Phase 3 controlled epilepsy studies, adverse events occurred in 68% of patients treated with BRIVIACT and 62% treated with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with BRIVIACT doses of at least 50 mg/day and greater than placebo were somnolence and sedation (16%), dizziness (12%), fatigue (9%), and nausea and vomiting symptoms (5%).

The discontinuation rates due to adverse events were 5%, 8%, and 7% for patients randomized to receive BRIVIACT at the recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, compared to 4% in patients randomized to receive placebo.

Table 2 lists adverse reactions for BRIVIACT that occurred at least 2% more frequently for BRIVIACT doses of at least 50 mg/day than placebo.

Table 2: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Patients with Partial-Onset Seizures (BRIVIACT 50 mg/day, 100 mg/day, and 200 mg/day)

There was no apparent dose-dependent increase in adverse reactions listed in Table 2 with the exception of somnolence and sedation.

BRIVIACT can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies, a total of 1.8% of BRIVIACT-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 BRIVIACT-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 x 109/L).

Adverse reactions with BRIVIACT injection were generally similar to those observed with BRIVIACT tablets. Other adverse events that occurred in at least 3% of patients who received BRIVIACT injection included dysgeusia, euphoric mood, feeling drunk, and infusion site pain.

There were no significant differences by sex in the incidence of adverse reactions.

There is limited clinical experience with BRIVIACT overdose in humans. Somnolence and dizziness were reported in a patient taking a single dose of 1400 mg (14 times the highest recommended single dose) of BRIVIACT. The following adverse reactions were reported with BRIVIACT overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. In general, the adverse reactions associated with BRIVIACT overdose were consistent with the known adverse reactions.

There is no specific antidote for overdose with BRIVIACT. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rate and rhythm and vital signs is recommended. A certified poison control center should be contacted for updated information on the management of overdose with BRIVIACT. There are no data on the removal of brivaracetam using hemodialysis, but because less than 10% of brivaracetam is excreted in urine, hemodialysis is not expected to enhance BRIVIACT clearance.

Mechanism Of Action

The precise mechanism by which BRIVIACT exerts its anticonvulsant activity is not known. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

Pharmacodynamics

In a pharmacokinetic and pharmacodynamic interaction study in healthy subjects, co-administration of BRIVIACT (single dose 200 mg [2 times greater than the highest recommended single dose]) and ethanol (continuous intravenous infusion to achieve a blood alcohol concentration of 60 mg/100 mL during 5 hours) increased the effects of alcohol on psychomotor function, attention, and memory. Co-administration of BRIVIACT and ethanol caused a larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale (VAS) alertness, and a larger increase from baseline in body sway and in saccadic reaction time compared with BRIVIACT alone or ethanol alone. The immediate word recall scores were generally lower for BRIVIACT when co-administered with ethanol.

At a dose 4 times the maximum recommended dose, BRIVIACT did not prolong the QT interval to a clinically relevant extent.

Pharmacokinetics

BRIVIACT tablets, oral solution, and injection can be used interchangeably. Brivaracetam exhibits linear and time-independent pharmacokinetics at the approved doses.

The pharmacokinetics of brivaracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

Brivaracetam is highly permeable and is rapidly and almost completely absorbed after oral administration. Pharmacokinetics is dose-proportional from 10 to 600 mg (a range that extends beyond the minimum and maximum single-administration dose levels described in Dosage and Administration [see DOSAGE AND ADMINISTRATION]). The median Tmax for tablets taken without food is 1 hour (range 0.25 to 3 hours). Co-administration with a high-fat meal slowed absorption, but the extent of absorption remained unchanged. Specifically, when a 50 mg tablet was administered with a high-fat meal, Cmax (maximum brivaracetam plasma concentration during a dose interval, an exposure metric) was decreased by 37% and Tmax was delayed by 3 hours, but AUC (area under the brivaracetam plasma concentration versus time curve, an exposure metric) was essentially unchanged (decreased by 5%).

Brivaracetam is weakly bound to plasma proteins (≤20%). The volume of distribution is 0.5 L/kg, a value close to that of the total body water. Brivaracetam is rapidly and evenly distributed in most tissues.

Metabolism

Brivaracetam is primarily metabolized by hydrolysis of the amide moiety to form the corresponding carboxylic acid metabolite, and secondarily by hydroxylation on the propyl side chain to form the hydroxy metabolite. The hydrolysis reaction is mediated by hepatic and extra-hepatic amidase. The hydroxylation pathway is mediated primarily by CYP2C19. In human subjects possessing genetic variations in CYP2C19, production of the hydroxy metabolite is decreased 2-fold or 10-fold, while the blood level of brivaracetam itself is increased by 22% or 42%, respectively, in individuals with one or both mutated alleles. CYP2C19 poor metabolizers and patients using inhibitors of CYP2C19 may require dose reduction. An additional hydroxy acid metabolite is created by hydrolysis of the amide moiety on the hydroxy metabolite or hydroxylation of the propyl side chain on the carboxylic acid metabolite (mainly by CYP2C9). None of the 3 metabolites are pharmacologically active.

Excretion

Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 95% of the dose, including metabolites, is excreted in the urine within 72 hours after intake. Fecal excretion accounts for less than 1% of the dose. Less than 10% of the dose is excreted unchanged in the urine. Thirty-four percent of the dose is excreted as the carboxylic acid metabolite in urine. The terminal plasma half-life (t1/2) is approximately 9 hours.

Specific Populations

Geriatric Population

In a study in elderly subjects (65 to 79 years old; creatinine clearance 53 to 98 mL/min/1.73 m2) receiving BRIVIACT 200 mg twice daily (2 times the highest recommended dosage), the plasma half-life of brivaracetam was 7.9 hours and 9.3 hours in the 65 to 75 and >75 years groups, respectively. The steady-state plasma clearance of brivaracetam was slightly lower (0.76 mL/min/kg) than in young healthy controls (0.83 mL/min/kg).

There were no differences observed in the pharmacokinetics of brivaracetam between male and female subjects.

A population pharmacokinetic analysis comparing Caucasian and non-Caucasian patients showed no significant pharmacokinetic difference.

A study in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73m2 and not requiring dialysis) revealed that the plasma AUC of brivaracetam was moderately increased (21%) relative to healthy controls, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Brivaracetam has not been studied in patients undergoing hemodialysis [see Use In Specific Populations].

A pharmacokinetic study in subjects with hepatic cirrhosis, Child-Pugh grades A, B, and C, showed 50%, 57%, and 59% increases in brivaracetam exposure, respectively, compared to matched healthy controls [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Drug Interaction Studies

Drug-Metabolizing Enzyme Inhibition

Brivaracetam did not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4. Brivaracetam weakly inhibited CYP2C19 and would not be expected to cause significant inhibition of CYP2C19 in humans. Brivaracetam was an inhibitor of epoxide hydrolase, (IC50 = 8.2 μM), suggesting that brivaracetam can inhibit the enzyme in vivo.

Drug-Metabolizing Enzyme Induction

Brivaracetam at concentrations up to 10 μM caused little or no change of mRNA expression of CYP1A2, 2B6, 2C9, 2C19, 3A4, and epoxide hydrolase. It is unlikely that brivaracetam will induce these enzymes in vivo.

Transporters

Brivaracetam was not a substrate of P-gp, MRP1, or MRP2. Brivaracetam did not inhibit or weakly inhibit BCRP, BSEP, MATE1, MATE2/K, MRP2, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or P-gp, suggesting that brivaracetam is unlikely to inhibit these transporters in vivo.

Drug Interaction Studies with Antiepileptic Drugs (AEDs)

Potential interactions between BRIVIACT (25 mg twice daily to 100 mg twice daily) and other AEDs were investigated in a pooled analysis of plasma drug concentrations from all Phase 2 and 3 studies and in a population exposure-response analysis of placebo-controlled, Phase 3 studies in adjunctive therapy in the treatment of partial-onset seizures. None of the interactions require changes in the dose of BRIVIACT. Interactions with carbamazepine and phenytoin can be clinically important [see DRUG INTERACTIONS]. The interactions are summarized in Table 3.

Table 3: Drug Interactions Between BRIVIACT and Concomitant Antiepileptic Drugs

Effect of Other Drugs on BRIVIACT

Co-administration with CYP inhibitors or transporter inhibitors is unlikely to significantly affect brivaracetam exposure.

Co-administration with rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Oral Contraceptives

Co-administration of BRIVIACT 200 mg twice daily (twice the recommended maximum daily dosage) with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) reduced estrogen and progestin AUCs by 27% and 23%, respectively, without impact on suppression of ovulation. However, co-administration of BRIVIACT 50 mg twice daily with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not significantly influence the pharmacokinetics of either substance. The interaction is not expected to be of clinical significance.

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 4 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 4: Percent Reduction in Partial-Onset Seizure Frequency over Placebo (Studies 1, 2, and 3)

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

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.