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Briviact

Generic Name: Brivaracetam
Class: Anticonvulsants, Miscellaneous
Chemical Name: (αS,4R)-α-ethyl-2-oxo-4-propyl-1-pyrrolidineacetamide
Molecular Formula: C11H20N2O2
CAS Number: 357336-20-0

Introduction

Anticonvulsant; a pyrrolidine derivative.1 5 6 8 9 13

Uses for Briviact

Seizure Disorders

Management (in combination with other anticonvulsants) of partial-onset seizures in adults and adolescents ≥16 years of age.1 2 3 4 24 25

Briviact Dosage and Administration

General

  • Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus.1 (See Discontinuance of Therapy under Cautions.)

  • Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.1 10 11 12 (See Suicidality Risk under Cautions.)

Administration

Administer orally (as tablets or solution).1 29 May administer IV when oral administration temporarily not feasible; manufacturer states clinical experience with IV use is limited to 4 consecutive days of treatment.1

Commercially available brivaracetam tablets, oral solution, and IV injection may be used interchangeably.1

Oral Administration

Administer tablets or oral solution twice daily without regard to food.1

Do not chew or crush tablets.1

Administer oral solution without further dilution.1

Use a calibrated measuring device to measure and administer a dose of the oral solution; do not use a household teaspoon or tablespoon.1

NG Tube

If necessary, may administer oral solution through a nasogastric or gastric feeding tube.1

IV Administration

Administer twice daily as a direct (“bolus”) IV injection or infusion over 2–15 minutes; may administer without further dilution or may be diluted with a compatible solution.1 29 (See Compatibility under Stability.)

Contains no preservatives; discard any partially used vials.1

Dosage

May initiate therapy with either oral or IV administration.1

Gradual dose titration not required when initiating therapy.1

Pediatric Patients

Seizure Disorders
Partial Seizures
Oral

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution.1 May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.1

IV

Adolescents ≥16 years of age: 50 mg twice daily (total daily dose of 100 mg).1 May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.1

Clinical experience with IV administration is limited to 4 consecutive days of treatment.1

Adults

Seizure Disorders
Partial Seizures
Oral

50 mg twice daily (total daily dose of 100 mg) as tablets or oral solution.1 May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.1

IV

50 mg twice daily (total daily dose of 100 mg).1 May decrease to 25 mg twice daily or increase to 100 mg twice daily based on individual patient response and tolerability.1

Clinical experience with IV administration is limited to 4 consecutive days of treatment.1

Special Populations

Hepatic Impairment

Patients with any degree of hepatic impairment: Initially, 25 mg twice daily.1 Do not exceed 75 mg twice daily.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Poor CYP2C19 Metabolizers

Dosage reduction may be required.1 (See Poor CYP2C19 Metabolizers under Cautions.)

Cautions for Briviact

Contraindications

  • Known hypersensitivity to brivaracetam or any ingredients in the formulation.1 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

General Precautions

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1 10 11 12 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1 10 11 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1 10

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1 10 11 12 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.1 10

Balance risk of suicidality with risk of untreated illness.1 10 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.1 12 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.1 12 (See Advice to Patients.)

Neurologic Effects

Adverse neurologic effects may occur; dizziness, disturbances in gait or coordination (e.g., vertigo, nystagmus, balance disorder, ataxia, abnormal coordination), somnolence, and fatigue reported.1 Generally observed early in treatment but can occur at any time during therapy.1

Monitor patients for adverse neurologic effects and advise patients not to drive or operate machinery until the effects of the drug are known.1 (See Advice to Patients.)

Psychiatric Effects

Adverse psychiatric effects may occur, 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, hallucination, paranoia, acute psychosis).1

Monitor patients for adverse psychiatric effects.1

Sensitivity Reactions

Hypersensitivity reactions (i.e., bronchospasm, angioedema) reported; discontinue immediately if patients experience a hypersensitivity reaction.1

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may increase seizure frequency and risk of status epilepticus.1 In general, gradual withdrawal is recommended; however, manufacturer states that prompt withdrawal may be considered if discontinuance of brivaracetam 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 Sedative and euphoric effects reported less frequently than with alprazolam (a schedule IV drug) at recommended therapeutic doses; however, such effects were similar to those produced by alprazolam when brivaracetam administered at supratherapeutic doses.1

No evidence of physical dependence or withdrawal symptoms.1

Specific Populations

Pregnancy

Category C.1

North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients) at 888-233-2334 or .1

Lactation

Not known whether distributed into human milk; distributes into milk in rats.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <16 years of age.1

Geriatric Use

Insufficient experience in geriatric patients ≥65 years of age to establish efficacy.1 Consider greater frequency of decreased hepatic, renal, and/or cardiac function and other concomitant disease and drug therapy when selecting dosage in geriatric patients.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Systemic exposure of brivaracetam is increased in patients with hepatic impairment.1 20 1 (See Hepatic Impairment under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not substantially affected by renal impairment.1 (See Renal Impairment under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Not studied in patients undergoing dialysis; use not recommended.1

Poor CYP2C19 Metabolizers

Increased plasma concentrations in patients who are poor metabolizers of CYP2C19.1 (See Poor CYP2C19 Metabolizers under Dosage and Administration, and also see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Somnolence/sedation,1 3 4 dizziness,1 3 4 fatigue,1 2 3 4 nausea/vomiting,1 3 diarrhea,3 headache,2 insomnia,3 nasopharyngitis.3

Interactions for Briviact

Metabolized to some extent by CYP2C19 and CYP2C9.1

Weak inhibitor of CYP2C19; not expected to be clinically important.1 Inhibits epoxide hydrolase in vitro.1 Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 3A4, nor induce CYP1A2, 2B6, 2C9, 2C19, 3A4, or epoxide hydrolase.1

Not a substrate of P-glycoprotein (P-gp) or multidrug resistance proteins (MRP) 1 and MRP2.1 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

CYP2C19 inhibitors: Potential increased brivaracetam concentrations.1

Pharmacokinetic interactions are unlikely with drugs that inhibit other CYP isoenzymes.1

CYP2C19 inducers: Potential decreased brivaracetam concentrations.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Additive effect on psychomotor impairment, attention, and memory1

Carbamazepine

Decreased plasma brivaracetam concentration by 26%1

Increased exposure to active carbamazepine-epoxide metabolite; carbamazepine exposure not affected1

Consider reducing carbamazepine dosage if concomitant use not tolerated1

Contraceptives, oral

Brivaracetam at twice the recommended maximum daily dosage decreased AUC of estrogen and progestin components of oral contraceptive by 27 and 23%, respectively; no effect on suppression of ovulation1 16

Brivaracetam at the recommended dosage did not substantially affect pharmacokinetics of either drug1 15

Interaction not expected to be clinically important1

Gemfibrozil

Brivaracetam pharmacokinetics not affected18

Lacosamide

No effect on plasma concentrations of lacosamide1

Dosage adjustment of brivaracetam not necessary1

Lamotrigine

No effect on plasma concentrations of brivaracetam or lamotrigine1

Dosage adjustment of brivaracetam not necessary1

Levetiracetam

No additional therapeutic benefit when brivaracetam was added to levetiracetam 1 2 3

No pharmacokinetic interactions observed1

Dosage adjustment of brivaracetam not necessary1

Oxcarbazepine

No effect on plasma concentrations of brivaracetam or the active monohydroxy metabolite of oxcarbazepine (MHD)1

Dosage adjustment of brivaracetam not necessary1

Phenobarbital

Decreased plasma brivaracetam concentrations by 19%; phenobarbital concentrations not affected1

Dosage adjustment of brivaracetam not necessary1

Phenytoin

Decreased plasma brivaracetam concentrations by 21%; increased plasma phenytoin concentrations by up to 20% (at twice the recommended dosage of brivaracetam)1

Dosage adjustment of brivaracetam not necessary1

Monitor phenytoin concentrations when brivaracetam therapy is initiated or discontinued1

Pregabalin

No effect on plasma concentrations of pregabalin1

Dosage adjustment of brivaracetam not necessary1

Rifampin

Decreased systemic exposure to brivaracetam by 45%1 17

Increase dosage of brivaracetam (by up to double)1

Topiramate

No effect on plasma concentrations of brivaracetam or topiramate1

Dosage adjustment of brivaracetam not necessary1

Valproic acid

No effect on plasma concentrations of brivaracetam or valproic acid1

Dosage adjustment of brivaracetam not necessary1

Zonisamide

No effect on plasma concentrations of zonisamide1

Dosage adjustment of brivaracetam not necessary1

Briviact Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration; peak plasma concentrations attained within 1 hour (range 0.25–3 hours) under fasting conditions.1 27 28

Commercially available tablets and oral solution are bioequivalent;21 bioavailability of oral and IV formulations similar.22

Following IV administration, plasma concentrations are higher within the first hour than with oral administration; overall exposure is similar.22

Exhibits dose-proportional pharmacokinetics over a dosage range of 10–600 mg.1 27

Food

Oral administration with high-fat meal slows rate but not extent of absorption.1 27

Special Populations

Patients with hepatic impairment: AUC 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

Renal impairment: Following a single 200-mg oral dose, AUC increased by 21% in patients with severe renal impairment (Clcr <30 mL/minute per 1.73 m2); although renal clearance of some metabolites substantially decreased, not considered clinically important.1 19

Poor CYP2C19 metabolizers: Plasma concentrations were 22 or 42% higher in individuals with one or both variant alleles of CYP2C19, respectively, compared with those with normal CYP2C19 activity.1

Distribution

Extent

Distributes rapidly into most tissues,1 including the CNS.5 14

Plasma Protein Binding

≤20%.1

Elimination

Metabolism

Metabolized primarily by hydrolysis of the amide moiety by hepatic and extrahepatic amidase to form the carboxylic acid metabolite; secondary pathway involves hydroxylation (mediated principally by CYP2C19) to form the hydroxy metabolite.1 26

Elimination Route

Principally excreted in urine; >95% of dose recovered within 72 hours, with <10% excreted as unchanged drug.1 Fecal excretion accounts for <1% of the dose.1

Half-life

Approximately 9 hours.1

Special Populations

Slightly lower clearance observed in geriatric individuals (65–79 years of age) compared with younger adults.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Solution

25°C (may be exposed to 15–30°C).1

Discard unused portions 5 months after container is first opened.1

Parenteral

Injection

25°C (may be exposed to 15–30°C).1

Diluted solutions may be stored at room temperature for up to 4 hours in PVC bags.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Actions

  • Exact mechanism of anticonvulsant action not fully elucidated; may be related to the drug's potent and selective binding affinity for synaptic vesicle protein 2A (SV2A),1 5 6 a transmembrane glycoprotein widely distributed in the CNS that is thought to modulate synaptic vesicle exocytosis and neurotransmitter release.5 7 9 14

  • Structurally and chemically related to levetiracetam;6 8 9 14 demonstrates 15- to 30-fold higher affinity for SV2A than levetiracetam.5 6

  • No apparent 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), GABAA, glycine, or N-methyl-D-aspartate (NMDA) receptors at therapeutic concentrations.5 6

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

  • Risk of suicidality (anticonvulsants, including brivaracetam, may increase risk of suicidal thoughts or actions in about 1 in 500 people).1 10 12 Importance of patients, family members, and caregivers being alert to any day-to-day changes in mood, behavior, and actions; and immediately informing clinician of any new or worrisome behaviors (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

  • Risk of neurologic effects (e.g., somnolence, fatigue, dizziness, gait disturbance), particularly 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 (e.g., aggression, agitation, anger, anxiety, irritability, psychotic symptoms).1 Importance of advising patients, family members, and caregivers to immediately contact 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 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 NAAED Pregnancy Registry.1 (See Pregnancy under 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.)

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.

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

AHFS DI Essentials. © Copyright 2017, Selected Revisions November 22, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 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. [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. [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.

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.

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.

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.

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

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