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Introduction

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Brivaracetam, a pyrrolidine derivative, is an anticonvulsant.1,5,6,8,9,13

Uses

Partial Seizures

Brivaracetam is used orally in combination with other anticonvulsant agents in the management of partial-onset seizures in adults and adolescents 16 years of age or older.1 The drug also may be used IV in patients in whom oral therapy is temporarily not feasible.1

Efficacy of brivaracetam as adjunctive therapy for partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies of similar design in 1550 patients 16 years of age or older with refractory partial-onset seizures (with or without secondary generalization).1,2,3,4 All 3 studies consisted of an 8-week baseline period followed by a 12-week double-blind treatment period; patients who were receiving stable dosages of 1 or 2 anticonvulsants for at least one month prior to study entry and who had experienced 8 or more partial-onset seizures during the baseline period were randomized to the double-blind treatment portion of these studies.1,2,3,4 The brivaracetam dosages evaluated ranged from 5-200 mg daily (administered in equally divided twice-daily doses with no titration period).1,2,3,4 Study 1 compared brivaracetam dosages of 20, 50, and 100 mg daily with placebo; study 2 compared brivaracetam dosages of 5, 20, and 50 mg daily with placebo; and study 3 compared brivaracetam dosages of 100 and 200 mg daily with placebo.1,2,3,4 Patients in these studies had a mean duration of epilepsy of 23 years and a median baseline seizure frequency of 9 seizures per 28 days; 72-86% of patients were receiving 2 or more concomitantly administered anticonvulsants with or without concurrent vagal nerve stimulation.1,2,3,4 Approximately 20% of patients in studies 1 and 2 were receiving concomitant levetiracetam, while such concomitant therapy was not permitted in study 3.1,2,3,4

Efficacy of brivaracetam was evaluated principally by the percent change in partial-onset seizure frequency (per 7 days in studies 1 and 2, and per 28 days in study 3) from baseline to the end of the treatment period.1,24 In all 3 studies, brivaracetam was more effective than placebo in reducing seizure frequency, but statistical significance of the treatment effect varied based on dosage.1,24,25 Brivaracetam dosages of 100 and 200 mg daily were substantially more effective than placebo in study 3; the percent reduction in seizure frequency was approximately 25% with both dosages.1,4 Brivaracetam 50 mg daily was substantially more effective than placebo in study 2, reducing seizure frequency by 16.9%.1,3 Although numerical reductions in seizure frequency were observed with all dosages of brivaracetam evaluated compared with placebo in study 1 (with a reduction of 9.5% observed with brivaracetam 50 mg daily and a reduction of 17% observed with brivaracetam 100 mg daily), statistical significance could not be established because of the sequential testing strategy employed.1,24 Efficacy was not demonstrated for brivaracetam dosages less than 50 mg daily in any of these studies.2,3,24 Across all studies, a greater proportion of brivaracetam-treated patients had reductions in partial-onset seizure frequency of 50% or greater compared with placebo, while a greater proportion of placebo-treated patients experienced worsening of seizures.1,2,3,4,25

Based on the limited number of patients who were receiving levetiracetam in the principal efficacy studies, concomitant treatment with brivaracetam appeared to provide no additional benefit in reduction of seizure frequency.1,2,3

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Brivaracetam is administered orally (as tablets or oral solution).1 The drug also may be administered IV when oral administration is temporarily not feasible; the manufacturer states that clinical experience with IV brivaracetam is limited to 4 consecutive days of treatment.1,29

Commercially available brivaracetam tablets and oral solution are bioequivalent,21,24 and the bioavailability of the tablets is similar to that of the injection formulation.22,24 All dosage forms can be used interchangeably without dosage adjustment.1,24

Brivaracetam tablets and oral solution are administered orally twice daily without regard to food.1 The tablets should be swallowed whole with liquid, and not chewed or crushed.1 The oral solution is administered without dilution; if necessary, the solution may be administered through a nasogastric or gastric feeding tube.1 When using the brivaracetam oral solution, a calibrated measuring device should be used to measure and administer the prescribed dose; a household teaspoon or tablespoon is not an adequate measuring device.1 Unused portions of the oral solution should be discarded 5 months after the container is first opened.1

Brivaracetam injection is administered twice daily by direct (“bolus”) IV injection or infusion over 2-15 minutes; the drug may be administered IV without further dilution or may be diluted with 0.9% sodium chloride, lactated Ringer's, or 5% dextrose injection.1,29 Diluted solutions of brivaracetam may be stored for up to 4 hours in polyvinyl chloride (PVC) bags at room temperature.1 Brivaracetam injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; the drug should not be administered if discoloration or particulate matter is observed.1 Commercially available brivaracetam injection contains no preservatives and is intended for single use; any partially used vials should be discarded.1

When discontinuing therapy, brivaracetam should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus in patients with seizure disorders.1 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.)

Patients currently receiving or beginning therapy with brivaracetam and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Dosage !!navigator!!

Partial Seizures

For adjunctive therapy of partial-onset seizures in adults and adolescents 16 years of age and older, brivaracetam therapy may be initiated with either oral or IV administration.1 The recommended initial oral or IV dosage of brivaracetam is 50 mg twice daily (total daily dose of 100 mg).1 Gradual dosage titration is not required when initiating therapy.1 Dosage may be decreased to 25 mg twice daily or increased to 100 mg twice daily based on individual patient response and tolerability.1

The manufacturer states that clinical experience with brivaracetam injection is limited to 4 consecutive days of treatment.1

If brivaracetam is used concomitantly with rifampin, dosage of brivaracetam should be increased by up to 100% (i.e., doubled).1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Special Populations !!navigator!!

In patients with any degree of hepatic impairment, the manufacturer recommends an initial brivaracetam dosage of 25 mg twice daily and a maximum dosage of 75 mg twice daily.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in patients with renal impairment.1 Brivaracetam has not been evaluated in patients with end-stage renal disease requiring dialysis; use of the drug in such patients is not recommended.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Patients known to be poor metabolizers of cytochrome P-450 (CYP) 2C19 may require dosage reduction.1 (See Poor CYP2C19 Metabolizers under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

[Section Outline]

Contraindications !!navigator!!

Known hypersensitivity to brivaracetam or any ingredients in the formulation.1 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Warnings/Precautions !!navigator!!

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants.1,10,11,12 FDA has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo.1,10,11,12 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,10,11,12 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,10,11 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,10

Based on the current analysis of the available data, FDA recommends that clinicians inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant be monitored closely for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,10,11,12 Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.1,10

Clinicians who prescribe brivaracetam or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness.1,10 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,12 If suicidal thoughts or behaviors emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,12 (See Advice to Patients.)

Neurologic Effects

Brivaracetam can cause a variety of adverse neurologic effects including dizziness, disturbances in gait or coordination (e.g., vertigo, nystagmus, balance disorder, ataxia, abnormal coordination), and dose-related somnolence and fatigue.1 The risk of such adverse effects is greatest early in treatment but can occur at any time during therapy.1 CNS-related events were among the most common adverse effects associated with brivaracetam in clinical studies.1 In controlled studies in patients with epilepsy, dizziness and disturbances in gait or coordination were reported in 16% of patients receiving brivaracetam at dosages of at least 50 mg daily, compared with 10% of those receiving placebo.1 Somnolence and fatigue-related adverse effects (e.g., asthenia, malaise, hypersomnia, sedation, lethargy) were reported in 20, 26, or 27% of patients receiving brivaracetam 50, 100, or 200 mg daily, respectively, compared with 14% of those receiving placebo.1

Patients receiving brivaracetam should be monitored for adverse neurologic effects and advised not to drive or operate machinery until the effects of the drug are known.1 (See Advice to Patients.)

Psychiatric Effects

Brivaracetam can cause adverse psychiatric effects including nonpsychotic symptoms (e.g., irritability, anxiety, nervousness, aggression, belligerence, anger, agitation, restlessness, depression, tearfulness, apathy, altered mood, labile affect, psychomotor hyperactivity, abnormal behavior, adjustment disorder) and psychotic symptoms (e.g., psychotic disorder or behavior, hallucination, paranoia, acute psychosis).1 In controlled studies in patients with epilepsy, adverse psychiatric effects were reported in 13% of patients receiving brivaracetam at dosages of at least 50 mg daily, compared with 8% of those receiving placebo.1

Patients receiving brivaracetam should be monitored for adverse psychiatric effects.1

Sensitivity Reactions

Hypersensitivity reactions, including bronchospasm and angioedema, have been reported in patients receiving brivaracetam.1 Brivaracetam should be discontinued in patients who experience a hypersensitivity reaction.1 (See Cautions: Contraindications.)

Discontinuance of Therapy

As with all anticonvulsant agents, there is a potential for increased seizure frequency and status epilepticus when brivaracetam therapy is withdrawn abruptly.1 The dosage of brivaracetam should be reduced gradually and abrupt discontinuance should be avoided when discontinuing therapy with the drug.1 However, the manufacturer states that prompt withdrawal may be considered if discontinuance of therapy is necessary because of serious adverse effects.1

Abuse Potential and Dependence

Brivaracetam is subject to control as a schedule V (C-V) drug.1,23 In abuse-potential studies, sedative and euphoric effects were reported less frequently with brivaracetam (at the recommended dose of 50 mg) than alprazolam, a schedule IV drug; however, such effects were similar to those produced by alprazolam when brivaracetam was administered at supratherapeutic doses (200 and 1000 mg).1

There was no evidence of physical dependence or withdrawal symptoms with brivaracetam in controlled clinical studies.1

Specific Populations

Pregnancy

Category C. (See Users Guide.)

The North American Antiepileptic Drug (NAAED) Pregnancy Registry may be contacted at 888-233-2334 (for patients); NAAED registry information also is available on the website [Web].1

Brivaracetam produced developmental toxicity (e.g., decreased fetal weight gain, delayed sexual maturation, long-term neurobehavioral changes) and some evidence of embryolethality when administered orally to pregnant animals at exposure levels higher than those associated with the maximum recommended human dose.1

Lactation

It is not known whether brivaracetam is distributed into human milk; however, the drug is distributed into milk in rats.1 Because many drugs are distributed into human milk, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of brivaracetam have not been established in pediatric patients younger than 16 years of age.1

Geriatric Use

Experience with brivaracetam in patients 65 years of age and older is insufficient to establish efficacy in this age group.1 The manufacturer recommends cautious dosage selection in geriatric patients, taking into consideration the greater frequency of decreased hepatic, renal, and/or cardiac function, and other concomitant medical conditions and drug therapy in this population.1

In a study evaluating the pharmacokinetics of brivaracetam (200 mg twice daily) in geriatric individuals 65-79 years of age with creatinine clearance of 53-98 mL/minute per 1.73 m2, plasma half-life of the drug was 7.9 hours in individuals 65-75 years of age and 9.3 hours in those over 75 years of a brivaracetam clearance was slightly lower in these geriatric individuals compared with healthy younger adults.1

Hepatic Impairment

Systemic exposure of brivaracetam following a single 100-mg oral dose was increased by 50, 57, or 59% in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, respectively;1,20 dosage adjustments are recommended in such patients.1,24 (See Dosage and Administration: Special Populations.)

Renal Impairment

Systemic exposure of brivaracetam following a single 200-mg oral dose was slightly increased (by 21%) in patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m2); although renal clearance of some of the metabolites was substantially decreased, no safety issues were identified.1,19 (See Dosage and Administration: Special Populations.)

The pharmacokinetics of brivaracetam have not been evaluated in patients undergoing dialysis, and use of the drug is not recommended in such patients.1

Poor CYP2C19 Metabolizers

Genetic polymorphism of the cytochrome P-450 (CYP) isoenzyme 2C19 can affect the pharmacokinetics of brivaracetam.1,26 Plasma concentrations of brivaracetam are increased by 22 or 42% in individuals with one or both variant alleles of CYP2C19, respectively, compared with those who have normal CYP2C19 activity.1 Poor metabolizers of CYP2C19 may require dosage reduction of brivaracetam.1

Common Adverse Effects !!navigator!!

Adverse effects reported in at least 5% of patients with partial-onset seizures receiving brivaracetam in controlled clinical trials and at least 2% more frequently than with placebo include somnolence/sedation,1,3,4 dizziness,1,3,4 fatigue,1,2,3,4 nausea/vomiting,1,3 diarrhea,3 headache,2 insomnia,3 and nasopharyngitis.3

Drug Interactions

[Section Outline]

Brivaracetam is metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2C19; additional biotransformation of the metabolites is mediated by CYP2C9.1,18,26 (See Description.)

Brivaracetam is a weak inhibitor of CYP2C19; however, this inhibition is not expected to be clinically important.1 The drug inhibits epoxide hydrolase in vitro.1 Brivaracetam does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4, nor induce CYP1A2, 2B6, 2C9, 2C19, 3A4, or epoxide hydrolase.1

Brivaracetam is not a substrate of the efflux transporters P-glycoprotein (P-gp) or multidrug resistance proteins (MRP) 1 and MRP2.1 The drug does not inhibit P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion transporters (MATE) 1 and MATE2/K, MRP2, organic anion transporters (OAT) 1 and OAT3, organic cation transporters (OCT) 1 and OCT2, or organic anion transport proteins (OATP) 1B1 and OATP1B3.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes !!navigator!!

Concomitant use of CYP2C19 inhibitors may increase plasma brivaracetam concentrations.1 Pharmacokinetic interactions are unlikely with drugs that inhibit other CYP isoenzymes.1

Concomitant use of drugs that induce CYP2C19 may decrease plasma brivaracetam concentrations.1

Gemfibrozil

Concomitant use of brivaracetam and gemfibrozil (a potent CYP2C9 inhibitor) had no effect on the pharmacokinetics of brivaracetam.18

Rifampin

Concomitant use of brivaracetam (single 150-mg oral dose) and rifampin (600 mg daily for 5 days) decreased systemic exposure to brivaracetam by 45%, likely due to CYP2C19 induction.1,17 If brivaracetam is used concomitantly with rifampin, dosage of brivaracetam should be increased (by up to double the current dosage).1

Alcohol !!navigator!!

An additive effect on psychomotor impairment, attention, and memory was observed following administration of brivaracetam (single 200-mg dose) with ethanol (administered by continuous IV infusion).1

Anticonvulsants !!navigator!!

Potential interactions between brivaracetam and other anticonvulsants are based on population pharmacokinetic analyses of data from clinical studies.1

Carbamazepine

Concomitant use of brivaracetam and carbamazepine decreased plasma brivaracetam concentrations by 26%.1 Systemic exposure to carbamazepine was not altered, but exposure to the active carbamazepine-epoxide metabolite was increased by up to 198% with concomitant administration of brivaracetam (100 mg twice daily).1 Although safety issues were not identified, the manufacturer recommends that carbamazepine dosage reduction be considered in patients who do not tolerate such concomitant therapy.1

Levetiracetam

In clinical studies, brivaracetam provided no additional therapeutic benefit to levetiracetam when the drugs were used concurrently.1,2,3 No pharmacokinetic interactions were identified between the drugs.1 Dosage adjustment of brivaracetam is not necessary.1

Phenobarbital

Concomitant use of brivaracetam and phenobarbital decreased plasma brivaracetam concentrations by 19%, but had no effect on phenobarbital concentration.1 Dosage adjustment of brivaracetam is not necessary.1

Phenytoin

Concomitant use of brivaracetam and phenytoin decreased plasma brivaracetam concentrations by 21% and increased plasma phenytoin concentrations by up to 20% (at twice the recommended maximum daily dosage of brivaracetam).1 Dosage adjustment of brivaracetam is not necessary, but the manufacturer states that phenytoin concentrations should be monitored when brivaracetam is initiated or discontinued in patients receiving phenytoin.1

Other Anticonvulsants

Plasma concentrations of brivaracetam are not substantially affected by concomitant use of lamotrigine, oxcarbazepine, topiramate, or valproic acid.1 In addition, brivaracetam does not appear to affect plasma concentrations of lacosamide, lamotrigine, oxcarbazepine (the active monohydroxy metabolite [MHD]), pregabalin, topiramate, valproic acid, or zonisamide.1 Dosage adjustment of brivaracetam is not necessary during concurrent use of these anticonvulsants.1

Oral Contraceptives !!navigator!!

In healthy women, concomitant use of brivaracetam 200 mg twice daily (twice the recommended maximum daily dosage) and an oral contraceptive containing ethinyl estradiol and levonorgestrel decreased systemic exposure of the estrogen and progestin components by 27 and 23%, respectively; suppression of ovulation was not affected.1,16 Concomitant administration of brivaracetam 50 mg twice daily (the recommended dosage) and the same oral contraceptive did not substantially affect the pharmacokinetics of either drug.1,15 The manufacturer states that the interaction is not expected to be clinically important.1

Other Information

Description

Brivaracetam, a pyrrolidine derivative, is an anticonvulsant.1,5,6,8,9,13 The drug is structurally and chemically related to levetiracetam.6,8,9,14 The exact mechanism of action by which brivaracetam exerts its anticonvulsant effects has not been fully elucidated, but may be related to its potent and selective binding affinity for synaptic vesicle protein 2A (SV2A).1,5,6

SV2A is a transmembrane glycoprotein that is widely distributed in the CNS; although its precise role in neurotransmission is not fully understood, it is thought to modulate synaptic vesicle exocytosis and neurotransmitter release.5,7,9,14 Reduced expression of SV2A has been demonstrated in patients with epilepsy, which correlates with data from animal models suggesting that SV2A deficiency increases seizure vulnerability.7,9 The anticonvulsant potency of selective SV2A ligands has been shown to be strongly correlated with their in-vitro binding affinity.6,7 Brivaracetam demonstrates 15- to 30-fold higher affinity for SV2A than levetiracetam.5,6,8,9,13

Brivaracetam does not appear to have effects on other known targets potentially involved in epilepsy, including voltage-gated potassium or calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid A (GABAA), glycine, or N -methyl-D-aspartate (NMDA) receptors at therapeutic concentrations.5,6 Although brivaracetam has demonstrated inhibitory effects on voltage-gated sodium channels, this effect appears to be unrelated to the drug's anticonvulsant activity.5,13

Brivaracetam exhibits dose-proportional pharmacokinetics over a dose range of 10-600 mg.1,27 The drug is rapidly and almost completely absorbed following oral administration; peak plasma concentrations are attained at a median of 1 hour (range: 0.25-3 hours) under fasting conditions.1,27,28 Administration with a high-fat meal slows the rate but not extent of absorption.1,27 Following IV administration of a single 100-mg dose, plasma brivaracetam concentrations were initially higher within the first hour of dosing than with oral administration of the 50- and 100-mg tablets, but the dosage forms were bioequivalent in terms of overall exposure.1,22 Bioequivalence also has been demonstrated between the tablet and oral solution formulations of the drug.21 Brivaracetam distributes readily and rapidly into the CNS; in vitro and animal studies indicate that the drug crosses the blood-brain barrier faster and to a greater extent than levetiracetam, likely due to its increased lipophilicity.5,14 Metabolism of brivaracetam occurs primarily via hydrolysis of the amide moiety by hepatic and extrahepatic amidase to form the carboxylic acid metabolite; a secondary pathway involves hydroxylation (mediated principally by CYP2C19) to form the hydroxy metabolite.1,26 An additional hydroxy acid metabolite is created by further biotransformation of these metabolites.1 None of the identified metabolites are pharmacologically active.1 Brivaracetam and its metabolites are eliminated principally by renal excretion.1 Over 95% of a dose is excreted in the urine within 72 hours, with less than 10% as unchanged brivaracetam; fecal excretion accounts for less than 1% of the dose.1,28 The elimination half-life of brivaracetam is approximately 9 hours.1 The drug is weakly bound (no more than 20%) to plasma proteins.1

Advice to Patients

Importance of advising patients to read the manufacturer's patient information (medication guide).1

Importance of informing patients that brivaracetam may be taken with or without food and that tablets should be swallowed whole with liquid and not chewed or crushed.1

Importance of informing patients who are taking brivaracetam oral solution to use a calibrated measuring device (such as a medicine dropper or cup) to measure and administer the dose; a household teaspoon or tablespoon should not be used.1 Importance of advising patients to discard any unused oral solution 5 months after the container is first opened.1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including brivaracetam, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,10,12 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,10 They should also be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,10 Advise patients, family members, and caregivers to inform clinician immediately if these or any new and worrisome behaviors occur.1,10

Risk of neurologic effects such as somnolence, fatigue, dizziness, and gait disturbance.1 Inform patients, and/or caregivers that the risk of such adverse effects is greatest early in treatment but can occur at any time during therapy.1 Importance of advising patients not to drive or operate machinery until the effects of the drug are known.1

Risk of psychiatric or behavioral effects such as aggression, agitation, anger, anxiety, irritability, and psychotic symptoms.1 Importance of advising patients, family members, and caregivers to immediately contact a clinician if such symptoms occur.1

Risk of hypersensitivity reactions (e.g., bronchospasm, angioedema).1 Importance of instructing patients to seek immediate medical attention if such reactions occur.1

Importance of advising patients not to abruptly discontinue brivaracetam therapy without consulting with their clinician.1 Anticonvulsants should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the North American Antiepileptic Drug Pregnancy Registry.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, depression or other psychiatric disorders, suicidality).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Brivaracetam is subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.1,23

Brivaracetam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

5 mg/5 mL

Briviact® (C-V)

UCB

Tablets, film-coated

10 mg

Briviact® (C-V)

UCB

25 mg

Briviact® (C-V)

UCB

50 mg

Briviact® (C-V)

UCB

75 mg

Briviact® (C-V)

UCB

100 mg

Briviact® (C-V)

UCB

Parenteral

Injection

10 mg/mL (50 mg)

Briviact® (C-V)

UCB

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions November 22, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

References

1. UCB, Inc. Briviact® (brivaracetam) tablets, oral solution, and injection prescribing information. Smyrna, GA; 2016 Jun.

2. Ryvlin P, Werhahn KJ, Blaszczyk B et al. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia . 2014; 55:47-56. [PubMed 24256083]

3. Biton V, Berkovic SF, Abou-Khalil B et al. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia . 2014; 55:57-66. [PubMed 24446953]

4. Klein P, Schiemann J, Sperling MR et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia . 2015; 56:1890-8. [PubMed 26471380]

5. Klitgaard H, Matagne A, Nicolas JM et al. Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia . 2016; 57:538-48. [PubMed 26920914]

6. Gillard M, Fuks B, Leclercq K et al. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol . 2011; 664:36-44. [PubMed 21575627]

7. Kaminski RM, Gillard M, Klitgaard H. Targeting SV2A for discovery of antiepileptic drugs. In: Noebels J, Avoli M, Rogawski M et al, eds. Jasper's basic mechanisms of the epilepsies. 4th ed. Bethesda, MD: National Center for Biotechnology Information; 2012.

8. Matagne A, Margineanu DG, Kenda B et al. Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol . 2008; 154:1662-71. [PubMedCentral][PubMed 18500360]

9. Gao L, Li S. Emerging drugs for partial-onset epilepsy: a review of brivaracetam. Ther Clin Risk Manag . 2016; 12:719-34. [PubMedCentral][PubMed 27217762]

10. US Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidal behavior and ideation and antiepileptic drugs. Rockville, MD; 2008 Jan 31; updated 2008 Dec 16. From the FDA website. [Web]

11. US Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

12. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2012 May 4. [Web]

13. Niespodziany I, André VM, Leclère N et al. Brivaracetam differentially affects voltage-gated sodium currents without impairing sustained repetitive firing in neurons. CNS Neurosci Ther . 2015; 21:241-51. [PubMed 25444522]

14. Nicolas JM, Hannestad J, Holden D et al. Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action. Epilepsia . 2016; 57:201-9. [PubMed 26663401]

15. Stockis A, Watanabe S, Fauchoux N. Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: a randomized, double-blind, placebo-controlled study. Epilepsia . 2014; 55:e27-31. [PubMed 24512385]

16. Stockis A, Rolan P. Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women. J Clin Pharmacol . 2013; 53:1313-21. [PubMed 24386664]

17. Stockis A, Watanabe S, Scheen AJ et al. Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis. Drug Metab Dispos . 2016; 44:792-9. [PubMed 27002062]

18. Nicolas JM, Chanteux H, Rosa M et al. Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects. Drug Metab Dispos . 2012; 40:1466-72. [PubMed 22538270]

19. Sargentini-Maier ML, Sokalski A, Boulanger P et al. Brivaracetam disposition in renal impairment. J Clin Pharmacol . 2012; 52:1927-33. [PubMed 22235139]

20. Stockis A, Sargentini-Maier ML, Horsmans Y. Brivaracetam disposition in mild to severe hepatic impairment. J Clin Pharmacol . 2013; 53:633-41. [PubMed 23649964]

21. Otoul C, Watanabe S, McCabe S et al. Relative Bioavailability and Bioequivalence of Brivaracetam 10 mg/mL Oral Solution and 50-mg Film-Coated Tablet. Clin Pharmacol Drug Dev . 2016; :. [PubMed 27274002]

22. Stockis A, Hartstra J, Mollet M et al. Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus. Epilepsia . 2016; 57:1288-93. [PubMed 27346728]

23. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: placement of brivaracetam into schedule V. 21 CFR Part 1308. Final Rule. [Docket No. DEA-435]. Fed Regist. 2016; 81 (92): 29487-92.

24. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 205836Orig1s000, 205837Orig1s000, 205838Orig1s000: Summary Review. From FDA website. [Web]

25. Ben-Menachem E, Mamenikien R, Quarato PP et al. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology . 2016; 87:314-23. [PubMedCentral][PubMed 27335114]

26. Stockis A, Watanabe S, Rouits E et al. Brivaracetam single and multiple rising oral dose study in healthy Japanese participants: influence of CYP2C19 genotype. Drug Metab Pharmacokinet . 2014; 29:394-9. [PubMed 24717838]

27. Sargentini-Maier ML, Rolan P, Connell J et al. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. Br J Clin Pharmacol . 2007; 63:680-8. [PubMedCentral][PubMed 17223857]

28. Rolan P, Sargentini-Maier ML, Pigeolet E et al. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. Br J Clin Pharmacol . 2008; 66:71-5. [PubMedCentral][PubMed 18341673]

29. Klein P, Biton V, Dilley D et al. Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy. Epilepsia . 2016; 57:1130-8. [PubMed 27221208]

30. Klein P, Biton V, Dilley D et al. Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy. Epilepsia . 2016; 57:1130-8. [PubMed 27221208]