- 50 mg in 5 mL in one single-dose vial. It is a clear, colorless, sterile solution.
Somnolence and Fatigue
BRIVIACT causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) [see Adverse Reactions (6.1)]. In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 25% of patients randomized to receive BRIVIACT at least 50 mg/day (20% at 50 mg/day, 26% at 100 mg/day, and 27% at 200 mg/day) compared to 14% of patients who received placebo. The risk is greatest early in treatment but can occur at any time.
Dizziness and Disturbance in Gait and Coordination
BRIVIACT causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination) [see Adverse Reactions (6.1)]. In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive BRIVIACT at least 50 mg/day compared to 10% of patients who received placebo. The risk is greatest early in treatment but can occur at any time.
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 × 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 × 109/L).
Adverse Reactions with BRIVIACT Injection
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.
Comparison by Sex
There were no significant differences by sex in the incidence of adverse reactions.
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as BRIVIACT, during pregnancy. Encourage patients who are taking BRIVIACT during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
There are no adequate data on the developmental risks associated with use of BRIVIACT in pregnant women. In animal studies, brivaracetam produced evidence of developmental toxicity (increased embryofetal mortality and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, and long-term neurobehavioral changes in rat offspring) at maternal plasma exposures greater than clinical exposures [see Data].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Oral administration of brivaracetam (0, 150, 300, or 600 mg/kg/day) to pregnant rats during the period of organogenesis did not produce any significant maternal or embryofetal toxicity. The highest dose tested was associated with maternal plasma exposures (AUC) approximately 30 times exposures in humans at the maximum recommended dose (MRD) of 200 mg/day.
Oral administration of brivaracetam (0, 30, 60, 120, or 240 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal mortality and decreased fetal body weights at the highest dose tested, which was also maternally toxic. The highest no-effect dose (120 mg/kg/day) was associated with maternal plasma exposures approximately 4 times human exposures at the MRD.
When brivaracetam (0, 150, 300, or 600 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, decreased growth, delayed sexual maturation (female), and long-term neurobehavioral changes were observed in the offspring at the highest dose. The highest no-effect dose (300 mg/kg/day) was associated with maternal plasma exposures approximately 7 times human exposures at the MRD.
Brivaracetam was shown to readily cross the placenta in pregnant rats after a single oral (5 mg/kg) dose of 14C-brivaracetam. From 1 hour post dose, radioactivity levels in fetuses, amniotic fluid, and placenta were similar to those measured in maternal blood.
No data are available regarding the presence of brivaracetam in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Studies in lactating rats have shown excretion of brivaracetam or metabolites in milk [see Data].
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BRIVIACT and any potential adverse effects on the breastfed infant from BRIVIACT or from the underlying maternal condition.
Following a single oral (5 mg/kg) dose of 14C-brivaracetam to lactating rats, radioactivity was secreted in milk and rapidly reached levels similar to those in plasma.
BRIVIACT tablets are for oral administration and contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, betadex (β-cyclodextrin), anhydrous lactose, magnesium stearate, and film coating agents specified below:
10 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide
25 mg and 100 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, black iron oxide
50 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, red iron oxide
75 mg tablets: polyvinyl alcohol, talc, polyethylene glycol 3350, titanium dioxide, yellow iron oxide, red iron oxide, black iron oxide
BRIVIACT oral solution contains 10 mg of brivaracetam per mL. The inactive ingredients are sodium citrate, anhydrous citric acid, methylparaben, sodium carboxymethylcellulose, sucralose, sorbitol solution, glycerin, raspberry flavor, and purified water.
BRIVIACT injection is a clear, colorless liquid provided as a sterile, preservative-free solution. BRIVIACT injection contains 10 mg brivaracetam per mL for intravenous administration. One vial contains 50 mg of brivaracetam drug substance. It contains the following inactive ingredients: sodium acetate (trihydrate), glacial acetic acid (for pH adjustment to 5.5), sodium chloride, and water for injection.
Interactions with Alcohol
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.
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 (2.1)]). 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.
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.
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.
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 (8.6)].
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 (2.5) and Use in Specific Populations (8.7)].
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
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.
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.
In Vivo Assessment of Drug Interactions
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 (7.2) and (7.3)]. The interactions are summarized in Table 3.
Table 3: Drug Interactions Between BRIVIACT and Concomitant Antiepileptic Drugs
|Concomitant AED||Influence of AED on BRIVIACT ||Influence of BRIVIACT on AED|
|Carbamazepine||26% decrease in plasma concentration||None for carbamazepine|
|Increase of carbamazepine-epoxide metabolite|
Brivaracetam is a reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. The carbamazepine epoxide plasma concentration increased up to 198% at a BRIVIACT dose of 100 mg twice daily.
[see Drug Interactions (7.2)]
|Oxcarbazepine||None||None on the active monohydroxy metabolite derivative (MHD)|
|Phenobarbital||19% decrease in plasma concentration||None|
|Phenytoin||21% decrease in plasma concentration||Up to 20% increase in plasma concentration|
[see Drug Interactions (7.3)]
At a supratherapeutic dose of 400 mg/day brivaracetam, there was a 20% increase in phenytoin plasma concentration.
Drug Interaction Studies with Other 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 (2.6) and Drug Interactions (7.1)].
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.
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.
- 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|
- 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|
Suicidal Behavior and Ideation
Counsel patients, their caregivers, and/or families that antiepileptic drugs, including BRIVIACT, may increase the risk of suicidal thoughts and behavior, and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to report behaviors of concern immediately to a healthcare provider [see Warnings and Precautions (5.1)].
Neurological Adverse Reactions
Counsel patients that BRIVIACT causes somnolence, fatigue, dizziness, and gait disturbance. These adverse reactions, if observed, are more likely to occur early in treatment but can occur at any time. Advise patients not to drive or operate machinery until they have gained sufficient experience on BRIVIACT to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.2)].
Psychiatric Adverse Reactions
Advise patients that BRIVIACT causes changes in behavior (e.g., aggression, agitation, anger, anxiety, and irritability) and psychotic symptoms. Instruct patients to report these symptoms immediately to their healthcare provider [see Warnings and Precautions (5.3)].
Hypersensitivity: Bronchospasm and Angioedema
Advise patients that symptoms of hypersensitivity including bronchospasm and angioedema can occur with BRIVIACT. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity [see Warnings and Precautions (5.4)].
Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of BRIVIACT without consulting with their healthcare provider. BRIVIACT should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.5)].
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during BRIVIACT therapy. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].
Counsel patients that BRIVIACT may be taken with or without food. Instruct patients that BRIVIACT tablets should be swallowed whole with liquid and not chewed or crushed [see Dosage and Administration (2.2)].
Advise patients that the dosage of BRIVIACT oral solution should be measured using a calibrated measuring device and not a household teaspoon. Instruct patients to discard any unused BRIVIACT oral solution after 5 months of first opening the bottle [see Dosage and Administration (2.2)].
BRIVIACT Tablets, BRIVIACT Oral Solution, and BRIVIACT Injection manufactured for
Smyrna, GA 30080
BRIVIACT® is a registered trademark of the UCB Group of Companies.
©2017, UCB, Inc., Smyrna, GA 30080
All rights reserved.