Brivaracetam

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# Overview
Brivaracetam is an anticonvulsant that is FDA approved for the treatment of epilepsy in patients 16 years of age and older with partial-onset seizures.   Common adverse reactions include somnolence/sedation, dizziness, fatigue, and nausea/vomiting (5%).

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Brivaracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.
When initiating treatment, gradual dose escalation is not required. The recommended starting dosage is 50 mg twice daily (100 mg per day). Based on individual patient tolerability and therapeutic response, the dosage may be adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice daily (200 mg per day).
Brivaracetam injection may be used when oral administration is temporarily not feasible. Brivaracetam injection should be administered at the same dosage and same frequency as Brivaracetam tablets and oral solution.
The clinical study experience with Brivaracetam injection is limited to 4 consecutive days of treatment.
- Discontinuation of Brivaracetam
Avoid abrupt withdrawal from Brivaracetam in order to minimize the risk of increased seizure frequency and status epilepticus.
- Patients with Hepatic Impairment
For all stages of hepatic impairment, the recommended starting dosage is 25 mg twice daily (50 mg per day) and the recommended maximum dosage is 75 mg twice daily (150 mg per day).
- Co-administration with Rifampin
Increase the Brivaracetam dosage in patients on concomitant rifampin by up to 100% (i.e., double the dosage).

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brivaracetam in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Brivaracetam in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Brivaracetam in adolescents 16 years of age have been established (same indication and dosage as adults). 
Safety and effectiveness of Brivaracetam in patients less than 16 years of age have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brivaracetam in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Brivaracetam in pediatric patients.

# Contraindications
Hypersensitivity to Brivaracetam or any of the inactive ingredients in Brivaracetam (bronchospasm and angioedema have occurred).

# Warnings
- Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Brivaracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- Table 1: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis
The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Brivaracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Neurological Adverse Reactions
Brivaracetam causes somnolence, fatigue, dizziness, and disturbance in coordination. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Brivaracetam to gauge whether it adversely affects their ability to drive or operate machinery.
- Somnolence and Fatigue
Brivaracetam causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy). In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 25% of patients randomized to receive Brivaracetam 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
Brivaracetam causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination). In the Phase 3 controlled adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive Brivaracetam 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.
- Psychiatric Adverse Reactions
Brivaracetam causes psychiatric adverse reactions. In the Phase 3 controlled adjunctive epilepsy trials, psychiatric adverse reactions were reported in approximately 13% of patients who received Brivaracetam (at least 50 mg/day) compared to 8% of patients who received placebo. Psychiatric events included both non-psychotic symptoms (irritability, anxiety, nervousness, aggression, belligerence, anger, agitation, restlessness, depression, depressed mood, tearfulness, apathy, altered mood, mood swings, affect lability, psychomotor hyperactivity, abnormal behavior, and adjustment disorder) and psychotic symptoms (psychotic disorder along with hallucination, paranoia, acute psychosis, and psychotic behavior). A total of 1.7% of adult patients treated with Brivaracetam discontinued treatment because of psychiatric reactions compared to 1.3% of patients who received placebo.
- Hypersensitivity: Bronchospasm and Angioedema
Brivaracetam can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking Brivaracetam. If a patient develops hypersensitivity reactions after treatment with Brivaracetam, the drug should be discontinued. Brivaracetam is contraindicated in patients with a prior hypersensitivity reaction to Brivaracetam or any of the inactive ingredients.
- Withdrawal of Antiepileptic Drugs
As with most antiepileptic drugs, Brivaracetam should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

# Adverse Reactions

## Clinical Trials Experience
The following serious adverse reactions are described elsewhere in labeling:
- Suicidal Behavior and Ideation
- Neurological Adverse Reactions
- Psychiatric Adverse Reactions
- Hypersensitivity: Bronchospasm and Angioedema
- Withdrawal of Antiepileptic Drugs
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, Brivaracetam 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 Brivaracetam 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). 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 Brivaracetam and 62% treated with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with Brivaracetam 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 Brivaracetam 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 Brivaracetam that occurred at least 2% more frequently for Brivaracetam 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 (Brivaracetam 50 mg/day, 100 mg/day, and 200 mg/day)
BRIVIACT: Brivaracetam's Brand name
There was no apparent dose-dependent increase in adverse reactions listed in Table 2 with the exception of somnolence and sedation.
- Hematologic Abnormalities
Brivaracetam can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies, a total of 1.8% of Brivaracetam-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 Brivaracetam-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0  109/L).
- Adverse Reactions with Brivaracetam Injection
Adverse reactions with Brivaracetam injection were generally similar to those observed with Brivaracetam tablets. Other adverse events that occurred in at least 3% of patients who received Brivaracetam 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.

## Postmarketing Experience
There is limited information regarding Brivaracetam Postmarketing Experience in the drug label.

# Drug Interactions
Co-administration with rifampin decreases Brivaracetam plasma concentrations likely because of CYP2C19 induction. Prescribers should increase the Brivaracetam dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin.
Co-administration with carbamazepine may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine. Though available data did not reveal any safety concerns, if tolerability issues arise when co-administered, carbamazepine dose reduction should be considered.
Because Brivaracetam can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant Brivaracetam is added to or discontinued from ongoing phenytoin therapy.
Brivaracetam provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
C. There are no adequate and well-controlled studies in pregnant women. In animal studies, Brivaracetam produced evidence of developmental toxicity at plasma exposures greater than clinical exposures. Brivaracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 (area under the Brivaracetam plasma concentration versus time curve, an exposure metric, 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.
- Pregnancy Registry
Physicians are advised to recommend that pregnant patients taking Brivaracetam enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brivaracetam in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Brivaracetam during labor and delivery.

### Nursing Mothers
It is not known whether Brivaracetam is excreted in human milk. Studies in rats have shown excretion of Brivaracetam in milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue Brivaracetam, taking into account the importance of the drug to the mother.

### Pediatric Use
Safety and effectiveness of Brivaracetam in adolescents 16 years of age have been established.
Safety and effectiveness of Brivaracetam in patients less than 16 years of age have not been established.
The potential adverse effects of Brivaracetam on postnatal growth and development were investigated in juvenile rats and dogs. Oral administration (0, 150, 300, or 600 mg/kg/day) to rats during the neonatal and juvenile periods of development resulted in increased mortality, decreased body weight gain, delayed male sexual maturation, and adverse neurobehavioral effects at the highest dose tested and decreased brain size and weight at all doses. Therefore, a no-effect dose was not established; the lowest dose tested in juvenile rats was associated with plasma exposures (AUC) approximately 2 times those in adult humans at the maximum recommended dose (MRD) of 200 mg/day. In dogs, oral administration (0, 15, 30, or 100 mg/kg/day) throughout the neonatal and juvenile periods of development induced liver changes similar to those observed in adult animals at the highest dose but produced no adverse effects on growth, bone density or strength, neurological testing, or neuropathology evaluation. The overall no-effect dose (30 mg/kg/day) and the no-effect dose for adverse effects on developmental parameters (100 mg/kg/day) were associated with plasma exposures approximately equal to and 4 times, respectively, adult human exposures at the MRD.

### Geriatic Use
There were insufficient numbers of patients 65 years of age and older in the double-blind, placebo-controlled epilepsy trials (n=38) to allow adequate assessment of the effectiveness of Brivaracetam in this population. In general, dose selection for an elderly patient should be judicious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

### Gender
There is no FDA guidance on the use of Brivaracetam with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Brivaracetam with respect to specific racial populations.

### Renal Impairment
Dose adjustments are not required for patients with impaired renal function. There are no data in patients with end-stage renal disease undergoing dialysis, and use of Brivaracetam is not recommended in this patient population.

### Hepatic Impairment
Because of increases in Brivaracetam exposure, dosage adjustment is recommended for all stages of hepatic impairment.

### Females of Reproductive Potential and Males
The effect of Brivaracetam on labor and delivery in humans is unknown.
- Controlled Substance
Brivaracetam is listed as a Schedule V controlled substance.
- Abuse
In a human abuse potential study, single doses of Brivaracetam at therapeutic and supratherapeutic doses were compared to alprazolam (C-IV) (1.5 mg and 3 mg). Brivaracetam at the recommended single dose (50 mg) caused fewer sedative and euphoric effects than alprazolam; however, Brivaracetam at supratherapeutic single doses (200 mg and 1000 mg) was similar to alprazolam on other measures of abuse.
- Dependence
There was no evidence of physical dependence potential or a withdrawal syndrome with Brivaracetam in a pooled review of placebo-controlled adjunctive therapy studies.

### Immunocompromised Patients
There is no FDA guidance one the use of Brivaracetam in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Administration Instructions for Brivaracetam Tablets and Brivaracetam Oral Solution
Brivaracetam can be initiated with either intravenous or oral administration.
Brivaracetam tablets and oral solution may be taken with or without food.
- Brivaracetam Tablets
Brivaracetam tablets should be swallowed whole with liquid. Brivaracetam tablets should not be chewed or crushed.
- Brivaracetam Oral Solution
A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
When using Brivaracetam oral solution, no dilution is necessary. Brivaracetam oral solution may also be administered using a nasogastric tube or gastrostomy tube.
Discard any unused Brivaracetam oral solution remaining after 5 months of first opening the bottle.
- Preparation and Administration Instructions for Brivaracetam Injection
Brivaracetam injection is for intravenous use only.
- Preparation
Brivaracetam injection can be administered intravenously without further dilution or may be mixed with diluents listed below.
- Diluents
-0.9% Sodium Chloride injection, USP
-Lactated Ringer's injection
-5% Dextrose injection, USP
- Administration
Brivaracetam injection should be administered intravenously over 2 to 15 minutes.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Product with particulate matter or discoloration should not be used. Brivaracetam injection is for single dose only.
- Storage and Stability
The diluted solution should not be stored for more than 4 hours at room temperature and may be stored in polyvinyl chloride (PVC) bags. Discard any unused portion of the Brivaracetam injection vial contents.

### Monitoring
There is limited information regarding Brivaracetam Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Brivaracetam and IV administrations.

# Overdosage
There is limited clinical experience with Brivaracetam 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 Brivaracetam. The following adverse reactions were reported with Brivaracetam overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. In general, the adverse reactions associated with Brivaracetam overdose were consistent with the known adverse reactions.
There is no specific antidote for overdose with Brivaracetam. 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 Brivaracetam. 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 Brivaracetam clearance.

# Pharmacology

## Mechanism of Action
The precise mechanism by which Brivaracetam 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.

## Structure
The chemical name of Brivaracetam is (2S)-2- butanamide. Its molecular formula is C11H20N2O2 and its molecular weight is 212.29. The chemical structure is:
Brivaracetam is a white to off-white crystalline powder. It is very soluble in water, buffer (pH 1.2, 4.5, and 7.4), ethanol, methanol, and glacial acetic acid. It is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane.
- Tablets
Brivaracetam tablets are for oral administration and contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, betadex (-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
- Oral Solution
Brivaracetam 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.
- Injection
Brivaracetam injection is a clear, colorless liquid provided as a sterile, preservative-free solution. Brivaracetam 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.

## Pharmacodynamics
- Interactions with Alcohol
In a pharmacokinetic and pharmacodynamic interaction study in healthy subjects, co-administration of Brivaracetam (single dose 200 mg ) 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 Brivaracetam 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 Brivaracetam alone or ethanol alone. The immediate word recall scores were generally lower for Brivaracetam when co-administered with ethanol.
- Cardiac Electrophysiology
At a dose 4 times the maximum recommended dose, Brivaracetam did not prolong the QT interval to a clinically relevant extent.

## Pharmacokinetics
Brivaracetam tablets, oral solution, and injection can be used interchangeably. Brivaracetam exhibits linear and time-independent pharmacokinetics at the approved doses.
- Absorption
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). 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%).
- Distribution
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.
- Elimination
- 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
- Age
Geriatric Population: In a study in elderly subjects (65 to 79 years old; creatinine clearance 53 to 98 mL/min/1.73 m2) receiving Brivaracetam 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).
- Sex
There were no differences observed in the pharmacokinetics of Brivaracetam between male and female subjects.
- Race/Ethnicity
A population pharmacokinetic analysis comparing Caucasian and non-Caucasian patients showed no significant pharmacokinetic difference.
- Renal Impairment
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.
- Hepatic Impairment
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.
- 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 M), suggesting that brivaracetam can inhibit the enzyme in vivo.
- Drug-Metabolizing Enzyme Induction
Brivaracetam at concentrations up to 10 M 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.
In Vivo Assessment of Drug Interactions
- Drug Interaction Studies with Antiepileptic Drugs (AEDs)
Potential interactions between Brivaracetam (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 Brivaracetam. Interactions with carbamazepine and phenytoin can be clinically important. The interactions are summarized in Table 3.
- Table 3: Drug Interactions Between Brivaracetam and Concomitant Antiepileptic Drugs
BRIVIACT: Brivaracetam's Brand name
Drug Interaction Studies with Other Drugs
- Effect of Other Drugs on Brivaracetam
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.
- Oral Contraceptives
Co-administration of Brivaracetam 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 Brivaracetam 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.

## Nonclinical Toxicology
- 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.

# Clinical Studies
The effectiveness of Brivaracetam as adjunctive therapy 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 Brivaracetam 50 mg/day and 100 mg/day with placebo. Study 2 compared a dose of Brivaracetam 50 mg/day with placebo. Study 3 compared doses of Brivaracetam 100 mg/day and 200 mg/day with placebo. Brivaracetam was administered in equally divided twice daily doses. Upon termination of Brivaracetam treatment, patients were down-titrated over a 1-, 2-, and 4-week duration for patients receiving 25, 50, and 100 mg twice daily Brivaracetam, 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 Brivaracetam and Placebo Across all Three Double-Blind Trials
BRIVIACT: Brivaracetam's Brand name
Treatment with Levetiracetam
In Studies 1 and 2, which evaluated Brivaracetam dosages of 50 mg and 100 mg daily, approximately 20% of the patients were on concomitant levetiracetam. Although the numbers of patients were limited, Brivaracetam 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.

# How Supplied
Tablets
Oral Solution
Injection

## Storage
- Store at 25C (77F); excursions permitted between 15C to 30C (59F to 86F). Do not freeze Brivaracetam injection or oral solution.
- Discard any unused Brivaracetam oral solution remaining after 5 months of first opening the bottle.
- Brivaracetam injection vials are single-dose only.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Suicidal Behavior and Ideation
Counsel patients, their caregivers, and/or families that antiepileptic drugs, including Brivaracetam, 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.
- Neurological Adverse Reactions
Counsel patients that Brivaracetam 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 Brivaracetam to gauge whether it adversely affects their ability to drive or operate machinery.
- Psychiatric Adverse Reactions
Advise patients that Brivaracetam 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.
- Hypersensitivity: Bronchospasm and Angioedema
Advise patients that symptoms of hypersensitivity including bronchospasm and angioedema can occur with Brivaracetam. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity.
- Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of Brivaracetam without consulting with their healthcare provider. Brivaracetam should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.
- Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Brivaracetam 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.
- Dosing Instructions
Counsel patients that Brivaracetam  may be taken with or without food. Instruct patients that Brivaracetam tablets should be swallowed whole with liquid and not chewed or crushed.
Advise patients that the dosage of Brivaracetam oral solution should be measured using a calibrated measuring device and not a household teaspoon. Instruct patients to discard any unused Brivaracetam oral solution after 5 months of first opening the bottle.

# Precautions with Alcohol
In a pharmacokinetic and pharmacodynamic interaction study in healthy subjects, co-administration of Brivaracetam (single dose 200 mg ) 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 Brivaracetam 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 Brivaracetam alone or ethanol alone. The immediate word recall scores were generally lower for Brivaracetam when co-administered with ethanol.

# Brand Names
BRIVIACT

# Look-Alike Drug Names
There is limited information regarding Brivaracetam Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price