ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in labeling:Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)] Neurological Adverse Reactions [see Warnings and Precautions (5.2)] Psychiatric Adverse Reactions [see Warnings and Precautions (5.3)] Hypersensitivity: Bronchospasm and Angioedema [see Warnings and Precautions (5.4)] Serious Dermatologic Reactions [see Warnings and Precautions (5.5)]Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.6)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)] Neurological Adverse Reactions [see Warnings and Precautions (5.2)] Psychiatric Adverse Reactions [see Warnings and Precautions (5.3)] Hypersensitivity: Bronchospasm and Angioedema [see Warnings and Precautions (5.4)] Serious Dermatologic Reactions [see Warnings and Precautions (5.5)]. Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.6)] Adults: Most common adverse reactions (at least 5% for brivaracetam oral solution and at least 2% more frequently than placebo) are somnolence/sedation, dizziness, fatigue, and nausea/vomiting. (6.1)Pediatric Patients: Most common adverse reactions are similar to those seen in adult patients. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 oral solution was administered as adjunctive therapy to 2,437 patients. Of these patients, 1,929 were treated for at least months, 1,500 for at least 12 months, 1,056 for at least 24 months, and 758 for at least 36 months. total of 1,558 patients (1,099 patients treated with brivaracetam oral solution and 459 patients treated with placebo) constituted the safety population in the pooled analysis of Phase placebo-controlled studies in patients with partial-onset seizures (Studies 1, 2, and 3) [see Clinical Studies (14)]. The adverse reactions presented in Table 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 controlled epilepsy studies, adverse events occurred in 68% of patients treated with brivaracetam oral solution and 62% treated with placebo. The most common adverse reactions occurring at frequency of at least 5% in patients treated with brivaracetam oral solution 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 oral solution at the recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, compared to 4% in patients randomized to receive placebo.Table lists adverse reactions for brivaracetam oral solution that occurred at least 2% more frequently for brivaracetam oral solution doses of at least 50 mg/day than placebo.Table 4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Adult Patients with Partial-Onset Seizures (Brivaracetam oral solution50 mg/day, 100 mg/day, and 200 mg/day) Adverse Reactions Brivaracetam Oral Solution (N=803)%Placebo (N=459)%Gastrointestinal disorders Nausea/vomiting symptoms 3 Constipation 0 Nervous system disorders Somnolence and sedation 16 Dizziness 12 Fatigue 4 Cerebellar coordination and balance disturbances 1 Psychiatric disorders Irritability 1 Cerebellar coordination and balance disturbances includes ataxia, balance disorder, coordination abnormal, and nystagmus.There was no apparent dose-dependent increase in adverse reactions listed in Table with the exception of somnolence and sedation.Pediatric PatientsSafety of brivaracetam oral solution was evaluated in two open-label, safety and pharmacokinetic trials in pediatric patients months to less than 16 years of age. Across studies of pediatric patients with partial onset seizures, 186 patients received brivaracetam oral solution or tablet, of whom 123 received brivaracetam for at least 12 months. Adverse reactions reported in clinical studies of pediatric patients were generally similar to those seen in adult patients. Decreased appetite was also observed in these pediatric trials.Hematologic AbnormalitiesBrivaracetam oral solution can cause hematologic abnormalities. In the Phase controlled adjunctive epilepsy studies, total of 1.8% of brivaracetam oral solution -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 oral solution-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 109/L).Comparison by SexThere were no significant differences by sex in the incidence of adverse reactions.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of brivaracetam oral solution. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and Subcutaneous Tissue Disorders: Serious dermatologic reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) [see Warnings and Precautions (5.5)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The precise mechanism by which brivaracetam oral solution exerts its anticonvulsant activity is not known. Brivaracetam displays high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.. 12.2 Pharmacodynamics. Interactions with AlcoholIn pharmacokinetic and pharmacodynamic interaction study in healthy subjects, co-administration of brivaracetam oral solution (single dose 200 mg [2 times greater than the highest recommended single dose]) and ethanol (continuous intravenous infusion to achieve blood alcohol concentration of 60 mg/100 mL during hours) increased the effects of alcohol on psychomotor function, attention, and memory. Co-administration of brivaracetam oral solution and ethanol caused larger decrease from baseline in saccadic peak velocity, smooth pursuit, adaptive tracking performance, and Visual Analog Scale (VAS) alertness, and larger increase from baseline in body sway and in saccadic reaction time compared with brivaracetam oral solution alone or ethanol alone. The immediate word recall scores were generally lower for brivaracetam oral solution when co-administered with ethanol.Cardiac ElectrophysiologyAt dose times the maximum recommended dose, brivaracetam oral solution did not prolong the QT interval to clinically relevant extent.. 12.3 Pharmacokinetics. Brivaracetam tablets, oral solution, and injection can be used interchangeably. Brivaracetam exhibits linear and time-independent pharmacokinetics at the approved doses.The pharmacokinetics of brivaracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partialonset seizures.AbsorptionBrivaracetam is highly permeable and is rapidly and almost completely absorbed after oral administration. Pharmacokinetics is dose-proportional from 10 to 600 mg (a range that extends beyond the minimum and maximum single-administration dose levels described in Dosage and Administration [see Dosage and Administration (2.1)]). The median Tmax for tablets taken without food is hour (range 0.25 to hours). Co-administration with high-fat meal slowed absorption, but the extent of absorption remained unchanged. Specifically, when 50 mg tablet was administered with high-fat meal, Cmax (maximum brivaracetam plasma concentration during dose interval, an exposure metric) was decreased by 37% and Tmax was delayed by hours, but AUC (area under the brivaracetam plasma concentration versus time curve, an exposure metric) was essentially unchanged (decreased by 5%).DistributionBrivaracetam is weakly bound to plasma proteins (<=20%). The volume of distribution is 0.5 L/kg, value close to that of the total body water. Brivaracetam is rapidly and evenly distributed in most tissues.EliminationMetabolismBrivaracetam 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 metabolites are pharmacologically active.ExcretionBrivaracetam 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 hours.Specific PopulationsAgePediatric Patients (2 months to less than 16 years): An open-label, single-arm, multicenter, pharmacokinetic study with 3- week evaluation period and fixed 3-step up-titration using brivaracetam oral solution was conducted in 99 pediatric patients months to less than 16 years of age. In those patients, plasma concentrations were shown to be dose-proportional. The pediatric pharmacokinetic profile for brivaracetam oral solution was determined in population pharmacokinetic analysis using sparse plasma concentration data obtained in three open-label studies in 255 adult and pediatric patients with epilepsy months to 22 years of age that received intravenous, oral solution, or oral tablet formulations. weight-based dosing regimen is necessary to achieve brivaracetam exposures in pediatric patients month to less than 16 years of age that are similar to those observed in adults treated at effective doses of brivaracetam oral solution [see Dosage and Administration (2.2)]. The estimated plasma clearance was 1.09 L/h, 1.81 L/h, and 3.11 L/h for pediatric patients weighing 11 kg, 20 kg, and 50 kg, respectively. In comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).Geriatric Population: In study in elderly subjects (65 to 79 years old; creatinine clearance 53 to 98 mL/min/1.73 m2) receiving brivaracetam oral solution 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).SexThere were no differences observed in the pharmacokinetics of brivaracetam between male and female subjects.Race/EthnicityA population pharmacokinetic analysis comparing Caucasian and non-Caucasian patients showed no significant pharmacokinetic difference.Renal ImpairmentA study in adult subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73m2 and not requiring dialysis) revealed that the plasma AUC of brivaracetam was moderately increased (21%) relative to healthy controls, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Brivaracetam has not been studied in patients undergoing hemodialysis [see Use in Specific Populations (8.6)]. Hepatic ImpairmentA pharmacokinetic study in adult 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. The effect of hepatic impairment on brivaracetam pharmacokinetics in pediatric patients is expected to be comparable to the effect observed in adults [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)]. Drug Interaction StudiesIn Vitro Assessment of Drug InteractionsDrug-Metabolizing Enzyme InhibitionBrivaracetam 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 uM), suggesting that brivaracetam can inhibit the enzyme in vivo.Drug-Metabolizing Enzyme InductionBrivaracetam at concentrations up to 10 uM 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.TransportersBrivaracetam was not 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 InteractionsDrug Interaction Studies with Antiepileptic Drugs (AEDs)Potential interactions between brivaracetam oral solution (25 mg twice daily to 100 mg twice daily) and other AEDs were investigated in pooled analysis of plasma drug concentrations from all Phase and studies and in population exposure-response analysis of placebo-controlled, Phase studies in adjunctive therapy in the treatment of partial-onset seizures. None of the interactions require changes in the dose of brivaracetam oral solution. Interactions with carbamazepine and phenytoin can be clinically important [see Drug Interactions (7.2) and (7.3)]. The interactions are summarized in Table 5.Table 5: Drug Interactions Between Brivaracetam oral solution and Concomitant Antiepileptic DrugsConcomitant AEDInfluence of AED on Brivaracetam Oral SolutionInfluence of Brivaracetam Oral Solution on AEDCarbamazepine 26% decrease in plasma concentration None for carbamazepine Increase of carbamazepine-epoxide metabolite [see Drug Interactions (7.2)] Lacosamide No data None Lamotrigine None None Levetiracetam None None Oxcarbazepine None None on the active monohydroxymetabolite derivative (MHD) Phenobarbital 19% decrease in plasma concentration None Phenytoin 21% decrease in plasma concentration Up to 20% increase in plasma concentration[see Drug Interactions (7.3)] Pregabalin No data None Topiramate None None Valproic acid None None Zonisamide No data None Brivaracetam is reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. The carbamazepine epoxide plasma concentration increased up to 198% at brivaracetam oral solution dose of 100 mg twice daily. At supratherapeutic dose of 400 mg/day brivaracetam, there was 20% increase in phenytoin plasma concentration. Drug Interaction Studies with Other Drugs Effect of Other Drugs on Brivaracetam Oral Solution Co-administration with CYP inhibitors or transporter inhibitors is unlikely to significantly affect brivaracetam exposure. Co-administration with rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction [see Dosage and Administration (2.6) and Drug Interactions (7.1)].Oral Contraceptives Co-administration of brivaracetam oral solution 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 oral solution 50 mg twice daily with an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) did not significantly influence the pharmacokinetics of either substance. The interaction is not expected to be of clinical significance.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The effectiveness of brivaracetam oral solution in partial-onset seizures with or without secondary generalization was established in 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 to concomitant antiepileptic drugs (AEDs). In each of these studies, 72% to 86% of patients were taking or more concomitant AEDs with or without vagal nerve stimulation. The median baseline seizure frequency across the studies was seizures per 28 days. Patients had 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 partial-onset seizures. The baseline period was followed by 12-week treatment period. There was no titration period in these studies. Study compared doses of brivaracetam oral solution 50 mg/day and 100 mg/day with placebo. Study compared dose of brivaracetam oral solution 50 mg/day with placebo. Study compared doses of brivaracetam oral solution 100 mg/day and 200 mg/day with placebo. Brivaracetam oral solution was administered in equally divided twice daily doses. Upon termination of brivaracetam oral solution treatment, patients were down-titrated over 1-, 2-, and 4-week duration for patients receiving 25, 50, and 100 mg twice daily brivaracetam oral solution, respectively.The primary efficacy outcome in Study and Study was the percent reduction in 7-day partial-onset seizure frequency over placebo, while the primary outcome for Study was the percent reduction in 28-day partial-onset seizure frequency over placebo. The criteria for statistical significance for all studies was p<0.05. Table presents the primary efficacy outcome of the percent change in seizure frequency over placebo, based upon each studys protocol-defined 7- and 28-day seizure frequency efficacy outcome.Table 6: Percent Reduction in Partial-Onset Seizure Frequency over Placebo (Studies 1, 2, and 3) Percent Reduction Over Placebo (%)STUDY 1aPlacebo (n=100) ------- 50 mg/day (n=99) 9.5 100 mg/day (n=100) 17.0 STUDY 2aPlacebo (n=96) ------- 50 mg/day (n=101) 16.9 STUDY 3bPlacebo(n=259) ------ 100 mg/day(n=252) 25.2 200 mg/day(n= 249) 25.7 Statistically significant based on testing procedure with alpha 0.05a Based upon 7-day seizure frequencyb Based upon 28-day seizure frequencyFigure 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 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 right-most categories.Figure 1: Proportion of Patients by Category of Seizure Response for Brivaracetam Oral Solution and Placebo Across all Three Double- Blind TrialsTreatment with LevetiracetamIn Studies and 2, which evaluated brivaracetam oral solution 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 oral solution 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.. briva-fig-1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Adults (16 Years and Older): The recommended starting dosage for monotherapy or adjunctive therapy 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). (2.1)Pediatric Patients (1 Month to less than 16 Years): The recommended dosage is based on body weight and is administered orally twice daily (2.1)Hepatic Impairment: Dose adjustment is recommended for all stages of hepatic impairment. (2.5). Adults (16 Years and Older): The recommended starting dosage for monotherapy or adjunctive therapy 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). (2.1). Pediatric Patients (1 Month to less than 16 Years): The recommended dosage is based on body weight and is administered orally twice daily (2.1). Hepatic Impairment: Dose adjustment is recommended for all stages of hepatic impairment. (2.5). 2.1Dosage Information. Monotherapy or Adjunctive Therapy The recommended dosage for patients month of age and older is included in Table 1. In pediatric patients weighing less than 50 kg, the recommended dosing regimen is dependent upon body weight. When initiating treatment, gradual dose escalation is not required. Dosage should be adjusted based on clinical response and tolerability.Table 1: Recommended Dosage for Patients Month of Age and OlderAge and BodyWeightInitial DosageMinimum and MaximumMaintenance DosageAdults (16 years andolder) 50 mg twice daily(100 mg per day) 25 mg to 100 mg twice daily(50 mg to 200 mg per day) Pediatric patientsweighing50 kg or more 25 mg to 50 mg twice daily(50 mg to 100 mg per day) 25 mg to 100 mg twice daily(50 mg to 200 mg per day) Pediatric patientsweighing 20 kg to lessthan 50 kg 0.5 mg/kg to mg/kg twice daily (1 mg/kg to mg/kg per day) 0.5 mg/kg to mg/kg twice daily (1 mg/kg to mg/kg per day) Pediatric patientsweighing 11 kg to lessthan 20 kg 0.5 mg/kg to 1.25 mg/kg twice daily(1 mg/kg to 2.5 mg/kg per day) 0.5 mg/kg to 2.5 mg/kg twice daily(1 mg/kg to mg/kg per day) Pediatric patientsweighing less than 11kg 0.75 mg/kg to 1.5 mg/kg twice daily (1.5 mg/kg to mg/kg per day) 0.75 mg/kg to mg/kg twice daily (1.5 mg/kg to mg/kg per day) 2.2Administration Instructions for Brivaracetam Oral Solution. Brivaracetam oral solution can be initiated with oral administration.Brivaracetam oral solution may be taken with or without food.Brivaracetam Oral SolutionA calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. 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 nasogastric tube or gastrostomy tube.Discard any unused brivaracetam oral solution remaining after months of first opening the bottle.. 2.4Discontinuation of Brivaracetam Oral Solution. Avoid abrupt withdrawal from brivaracetam oral solution in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6) and Clinical Studies (14)]. 2.5Patients with Hepatic Impairment. The recommended dosage for patients with hepatic impairment is included in Table [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Table 2: Recommended Dosage for Patients with Hepatic ImpairmentAge and BodyWeightInitial DosageMaximum Maintenance DosageAdults (16 years andolder) 25 mg twice daily(50 mg per day) 75 mg twice daily(150 mg per day) Pediatric patientsweighing50 kg or more Pediatric patientsweighing 20 kg to lessthan 50 kg 0.5 mg/kg twice daily(1 mg/kg per day) 1.5 mg/kg twice daily(3 mg/kg per day) Pediatric patientsweighing 11 kg to lessthan 20 kg 0.5 mg/kg twice daily(1 mg/kg per day) mg/kg twice daily(4 mg/kg per day) Pediatric patientsweighing less than 11kg 0.75 mg/kg twice daily(1.5 mg/kg per day) 2.25 mg/kg twice daily(4.5 mg/kg per day) 2.6Co-administration with Rifampin. Increase the brivaracetam oral solution dosage in patients on concomitant rifampin by up to 100% (i.e., double the dosage) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Rifampin: Because of decreased concentrations, increasing brivaracetam oral solution dosage in patients on concomitant rifampin is recommended. (2.6, 7.1)Carbamazepine: Because of increased exposure to carbamazepine metabolite, if tolerability issues arise, consider reducing carbamazepine dosage in patients on concomitant brivaracetam oral solution. (7.2)Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam oral solution. (7.3)Levetiracetam: Brivaracetam oral solution had no added therapeutic benefit when co-administered with levetiracetam. (7.4). Rifampin: Because of decreased concentrations, increasing brivaracetam oral solution dosage in patients on concomitant rifampin is recommended. (2.6, 7.1). Carbamazepine: Because of increased exposure to carbamazepine metabolite, if tolerability issues arise, consider reducing carbamazepine dosage in patients on concomitant brivaracetam oral solution. (7.2). Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam oral solution. (7.3). Levetiracetam: Brivaracetam oral solution had no added therapeutic benefit when co-administered with levetiracetam. (7.4). 7.1 Rifampin. Co-administration with rifampin decreases brivaracetam oral solution plasma concentrations likely because of CYP2C19 induction [see Clinical Pharmacology (12.3)]. Prescribers should increase the brivaracetam oral solution dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin [see Dosage and Administration (2.6 )].. 7.2Carbamazepine. 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 [see Clinical Pharmacology (12.3)].. 7.3Phenytoin. Because brivaracetam oral solution can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant brivaracetam oral solution is added to or discontinued from ongoing phenytoin therapy [see Clinical Pharmacology (12.3)].. 7.4Levetiracetam. Brivaracetam oral solution provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered [see Clinical Studies (14)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Brivaracetam tablets, oral solution, and injection can be used interchangeably. Brivaracetam exhibits linear and time-independent pharmacokinetics at the approved doses.The pharmacokinetics of brivaracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partialonset seizures.AbsorptionBrivaracetam is highly permeable and is rapidly and almost completely absorbed after oral administration. Pharmacokinetics is dose-proportional from 10 to 600 mg (a range that extends beyond the minimum and maximum single-administration dose levels described in Dosage and Administration [see Dosage and Administration (2.1)]). The median Tmax for tablets taken without food is hour (range 0.25 to hours). Co-administration with high-fat meal slowed absorption, but the extent of absorption remained unchanged. Specifically, when 50 mg tablet was administered with high-fat meal, Cmax (maximum brivaracetam plasma concentration during dose interval, an exposure metric) was decreased by 37% and Tmax was delayed by hours, but AUC (area under the brivaracetam plasma concentration versus time curve, an exposure metric) was essentially unchanged (decreased by 5%).DistributionBrivaracetam is weakly bound to plasma proteins (<=20%). The volume of distribution is 0.5 L/kg, value close to that of the total body water. Brivaracetam is rapidly and evenly distributed in most tissues.EliminationMetabolismBrivaracetam 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 metabolites are pharmacologically active.ExcretionBrivaracetam 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 hours.Specific PopulationsAgePediatric Patients (2 months to less than 16 years): An open-label, single-arm, multicenter, pharmacokinetic study with 3- week evaluation period and fixed 3-step up-titration using brivaracetam oral solution was conducted in 99 pediatric patients months to less than 16 years of age. In those patients, plasma concentrations were shown to be dose-proportional. The pediatric pharmacokinetic profile for brivaracetam oral solution was determined in population pharmacokinetic analysis using sparse plasma concentration data obtained in three open-label studies in 255 adult and pediatric patients with epilepsy months to 22 years of age that received intravenous, oral solution, or oral tablet formulations. weight-based dosing regimen is necessary to achieve brivaracetam exposures in pediatric patients month to less than 16 years of age that are similar to those observed in adults treated at effective doses of brivaracetam oral solution [see Dosage and Administration (2.2)]. The estimated plasma clearance was 1.09 L/h, 1.81 L/h, and 3.11 L/h for pediatric patients weighing 11 kg, 20 kg, and 50 kg, respectively. In comparison, plasma clearance was estimated at 3.58 L/h in adult patients (70 kg body weight).Geriatric Population: In study in elderly subjects (65 to 79 years old; creatinine clearance 53 to 98 mL/min/1.73 m2) receiving brivaracetam oral solution 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).SexThere were no differences observed in the pharmacokinetics of brivaracetam between male and female subjects.Race/EthnicityA population pharmacokinetic analysis comparing Caucasian and non-Caucasian patients showed no significant pharmacokinetic difference.Renal ImpairmentA study in adult subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73m2 and not requiring dialysis) revealed that the plasma AUC of brivaracetam was moderately increased (21%) relative to healthy controls, while the AUCs of the acid, hydroxy, and hydroxyacid metabolites were increased 3-fold, 4-fold, and 21-fold, respectively. The renal clearance of these inactive metabolites was decreased 10-fold. Brivaracetam has not been studied in patients undergoing hemodialysis [see Use in Specific Populations (8.6)]. Hepatic ImpairmentA pharmacokinetic study in adult 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. The effect of hepatic impairment on brivaracetam pharmacokinetics in pediatric patients is expected to be comparable to the effect observed in adults [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)]. Drug Interaction StudiesIn Vitro Assessment of Drug InteractionsDrug-Metabolizing Enzyme InhibitionBrivaracetam 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 uM), suggesting that brivaracetam can inhibit the enzyme in vivo.Drug-Metabolizing Enzyme InductionBrivaracetam at concentrations up to 10 uM 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.TransportersBrivaracetam was not 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 InteractionsDrug Interaction Studies with Antiepileptic Drugs (AEDs)Potential interactions between brivaracetam oral solution (25 mg twice daily to 100 mg twice daily) and other AEDs were investigated in pooled analysis of plasma drug concentrations from all Phase and studies and in population exposure-response analysis of placebo-controlled, Phase studies in adjunctive therapy in the treatment of partial-onset seizures. None of the interactions require changes in the dose of brivaracetam oral solution. Interactions with carbamazepine and phenytoin can be clinically important [see Drug Interactions (7.2) and (7.3)]. The interactions are summarized in Table 5.Table 5: Drug Interactions Between Brivaracetam oral solution and Concomitant Antiepileptic DrugsConcomitant AEDInfluence of AED on Brivaracetam Oral SolutionInfluence of Brivaracetam Oral Solution on AEDCarbamazepine 26% decrease in plasma concentration None for carbamazepine Increase of carbamazepine-epoxide metabolite [see Drug Interactions (7.2)] Lacosamide No data None Lamotrigine None None Levetiracetam None None Oxcarbazepine None None on the active monohydroxymetabolite derivative (MHD) Phenobarbital 19% decrease in plasma concentration None Phenytoin 21% decrease in plasma concentration Up to 20% increase in plasma concentration[see Drug Interactions (7.3)] Pregabalin No data None Topiramate None None Valproic acid None None Zonisamide No data None Brivaracetam is reversible inhibitor of epoxide hydrolase resulting in an increased concentration of carbamazepine epoxide, an active metabolite of carbamazepine. The carbamazepine epoxide plasma concentration increased up to 198% at brivaracetam oral solution dose of 100 mg twice daily. At supratherapeutic dose of 400 mg/day brivaracetam, there was 20% increase in phenytoin plasma concentration. Drug Interaction Studies with Other Drugs Effect of Other Drugs on Brivaracetam Oral Solution Co-administration with CYP inhibitors or transporter inhibitors is unlikely to significantly affect brivaracetam exposure. Co-administration with rifampin decreases brivaracetam plasma concentrations by 45%, an effect that is probably the result of CYP2C19 induction [see Dosage and Administration (2.6) and Drug Interactions (7.1)].Oral Contraceptives Co-administration of brivaracetam oral solution 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 oral solution 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). The Medication Guide accompanies the product and can also be accessed by calling 1-877-272-7901.Suicidal Behavior and IdeationCounsel patients, their caregivers, and/or families that antiepileptic drugs, including brivaracetam oral solution, may increase the risk of suicidalthoughts 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 healthcare provider [see Warnings and Precautions (5.1)].Neurological Adverse ReactionsCounsel patients that brivaracetam oral solution 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 oral solution to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.2)].Psychiatric Adverse ReactionsAdvise patients that brivaracetam oral solution causes changes in behavior (e.g., aggression, agitation, anger, anxiety, and irritability) and psychotic symptoms. Instruct patients to report these symptoms immediately to their healthcare provider [see Warnings and Precautions (5.3)].Hypersensitivity: Bronchospasm and AngioedemaAdvise patients that symptoms of hypersensitivity including bronchospasm and angioedema can occur with brivaracetam oral solution. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity [see Warnings and Precautions (5.4)].Serious Dermatologic ReactionsAdvise patients of the early signs and symptoms of serious dermatologic adverse reactions and to report any occurrence immediately to healthcare provider [see Warnings and Precautions (5.5)]. Withdrawal of Antiepileptic DrugsAdvise patients not to discontinue use of brivaracetam oral solution without consulting with their healthcare provider. Brivaracetam oral solution should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6)].PregnancyAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during brivaracetam oral solution therapy. LactationCounsel patients that brivaracetam, the active ingredient in brivaracetam oral solution, is present in breast milk. Instruct patients to discuss with their healthcare provider if they are breastfeeding or intend to breastfeed [see Use in Specific Populations (8.2)].Dosing InstructionsCounsel patients that brivaracetam oral solution may be taken with or without food. Advise patients that the dosage of brivaracetam oral solution should be measured using calibrated measuring device and not household teaspoon. Instruct patients to discard any unused brivaracetam oral solution after months of first opening the bottle [see Dosage and Administration (2.2)]. Manufactured by: Alkem Laboratories Ltd., Mumbai 400 013, INDIA. Distributed by: Ascend Laboratories, LLC Bedminster, NJ 07921.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from the North American Antiepileptic Drug (NAAED) pregnancy registry, prospective cohort study, case reports, and case series are insufficient to identify risk of major birth defects, miscarriage or other maternal or fetal outcomes associated with brivaracetam oral solution use during pregnancy. In animal studies, brivaracetam produced evidence of developmental toxicity (increased embryofetal mortality and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, and long-term neurobehavioral changes in rat offspring) at maternal plasma exposures greater than clinical exposures [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataOral administration of brivaracetam (0, 150, 300, or 600 mg/kg/day) to pregnant rats during the period of organogenesis did not produce any significant maternal or embryofetal toxicity. The highest dose tested was associated with maternal plasma exposures (AUC) approximately 30 times exposures in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration of brivaracetam (0, 30, 60, 120, or 240 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal mortality and decreased fetal body weights at the highest dose tested, which was also maternally toxic. The highest no-effect dose (120 mg/kg/day) was associated with maternal plasma exposures approximately 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 times human exposures at the MRD.Brivaracetam was shown to readily cross the placenta in pregnant rats after single oral (5 mg/kg) dose of 14C-brivaracetam. From hour post dose, radioactivity levels in fetuses, amniotic fluid, and placenta were similar to those measured in maternal blood.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy. Risk SummaryAvailable data from the North American Antiepileptic Drug (NAAED) pregnancy registry, prospective cohort study, case reports, and case series are insufficient to identify risk of major birth defects, miscarriage or other maternal or fetal outcomes associated with brivaracetam oral solution use during pregnancy. In animal studies, brivaracetam produced evidence of developmental toxicity (increased embryofetal mortality and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, and long-term neurobehavioral changes in rat offspring) at maternal plasma exposures greater than clinical exposures [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.DataAnimal DataOral administration of brivaracetam (0, 150, 300, or 600 mg/kg/day) to pregnant rats during the period of organogenesis did not produce any significant maternal or embryofetal toxicity. The highest dose tested was associated with maternal plasma exposures (AUC) approximately 30 times exposures in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration of brivaracetam (0, 30, 60, 120, or 240 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal mortality and decreased fetal body weights at the highest dose tested, which was also maternally toxic. The highest no-effect dose (120 mg/kg/day) was associated with maternal plasma exposures approximately 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 times human exposures at the MRD.Brivaracetam was shown to readily cross the placenta in pregnant rats after single oral (5 mg/kg) dose of 14C-brivaracetam. From hour post dose, radioactivity levels in fetuses, amniotic fluid, and placenta were similar to those measured in maternal blood.. 8.2 Lactation. Risk SummaryData from published literature indicate that brivaracetam is present in human milk. There is insufficient information on the effects of brivaracetam on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for brivaracetam oral solution and any potential adverse effects on the breastfed infant from brivaracetam oral solution or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of brivaracetam oral solution have been established in pediatric patients month to less than 16 years of age. Use of brivaracetam oral solution in these age groups is supported by evidence from adequate and well-controlled studies of brivaracetam oral solution in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in pediatric patients months to less than 16 years of age [see Dosage and Administration (2.1), Warnings and Precautions (5.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Safety and effectiveness in pediatric patients below the age of month have not been established.Juvenile Animal Toxicity DataThe 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 (approximately equivalent to neonatal through adolescent development in humans) 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, no-effect dose was not established; the lowest dose tested in juvenile rats was associated with plasma exposures (AUC) approximately times those in children and adolescents at the recommended maintenance dose. 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 times, respectively, those in children and adolescents at the recommended maintenance dose.. 8.5 Geriatric 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 oral solution 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 [see Clinical Pharmacology (12.3)].. 8.6Renal 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 oral solution is not recommended in this patient population [see Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. Because of increases in brivaracetam oral solution exposure, dosage adjustment is recommended for all stages of hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation. (5.1)Neurological Adverse Reactions: Monitor for somnolence and fatigue, and advise patients not to drive or operate machinery until they have gained sufficient experience on brivaracetam oral solution. (5.2)Psychiatric Adverse Reactions: Behavioral reactions including psychotic symptoms, irritability, depression, aggressive behavior, and anxiety; monitor patients for symptoms. (5.3)Hypersensitivity: Bronchospasm and Angioedema: Advise patients to seek immediate medical care. Discontinue and do not restart brivaracetam oral solution if hypersensitivity occurs. (5.4)Serious Dermatologic Reactions: Discontinue brivaracetam oral solution unless an alternative etiology is established (5.5)Withdrawal of Antiepileptic Drugs: brivaracetam oral solution should be gradually withdrawn. (5.6). Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation. (5.1). Neurological Adverse Reactions: Monitor for somnolence and fatigue, and advise patients not to drive or operate machinery until they have gained sufficient experience on brivaracetam oral solution. (5.2). Psychiatric Adverse Reactions: Behavioral reactions including psychotic symptoms, irritability, depression, aggressive behavior, and anxiety; monitor patients for symptoms. (5.3). Hypersensitivity: Bronchospasm and Angioedema: Advise patients to seek immediate medical care. Discontinue and do not restart brivaracetam oral solution if hypersensitivity occurs. (5.4). Serious Dermatologic Reactions: Discontinue brivaracetam oral solution unless an alternative etiology is established (5.5). Withdrawal of Antiepileptic Drugs: brivaracetam oral solution should be gradually withdrawn. (5.6). 5.1Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including brivaracetam oral solution, 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 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 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 shows absolute and relative risk by indication for all evaluated AEDs.Table 3: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled AnalysisIndicationPlacebo Patients with Events Per 1,000PatientsDrug Patients with Events Per 1,000PatientsRelative Risk: Incidence of Events in Drug Patients/Incidencein Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1,000PatientsEpilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 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 oral solution 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.. 5.2Neurological Adverse Reactions. Brivaracetam oral solution 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 oral solution to gauge whether it adversely affects their ability to drive or operate machinery.Somnolence and Fatigue Brivaracetam oral solution causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) [see Adverse Reactions (6.1)]. In the Phase controlled adjunctive epilepsy trials, these events were reported in 25% of patients randomized to receive brivaracetam oral solution 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 oral solution causes adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination) [see Adverse Reactions (6.1)]. In the Phase controlled adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive brivaracetam oral solution 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.. 5.3Psychiatric Adverse Reactions. Brivaracetam oral solution causes psychiatric adverse reactions. In the Phase controlled adjunctive epilepsy trials, psychiatric adverse reactions were reported in approximately 13% of patients who received brivaracetam oral solution (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). total of 1.7% of adult patients treated with brivaracetam oral solution discontinued treatment because of psychiatric reactions compared to 1.3% of patients who received placebo.Psychiatric adverse reactions were also observed in open-label pediatric trials and were generally similar to those observed in adults [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)]. 5.4Hypersensitivity: Bronchospasm and Angioedema. Brivaracetam oral solution can cause hypersensitivity reactions. Bronchospasm and angioedema have been reported in patients taking brivaracetam oral solution. If patient develops hypersensitivity reactions after treatment with brivaracetam oral solution, the drug should be discontinued. Brivaracetam oral solution is contraindicated in patients with prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients [see Contraindications (4)].. 5.5 Serious Dermatologic Reactions. Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with brivaracetam oral solution. Time to onset of the serious dermatologic reaction ranged from to 45 days after brivaracetam oral solution initiation in reported cases. Brivaracetam oral solution should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest serious dermatologic reaction, use of brivaracetam oral solution should not be resumed and alternative therapy should be considered.. 5.6 Withdrawal of Antiepileptic Drugs. As with most antiepileptic drugs, brivaracetam oral solution should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.4) and Clinical Studies (14)]. But if withdrawal is needed because of serious adverse event, rapid discontinuation can be considered.