Brivaracetam

RECENT MAJOR CHANGES SECTION Warnings and Precautions ( 5.5 ) 8/2025

1 INDICATIONS AND USAGE Brivaracetam tablets are indicated for the treatment of partial-onset seizures in patients 1 month of age and older. Brivaracetam tablets are indicated for the treatment of partial-onset seizures in patients 1 month of age and older. ( 1 )

2 DOSAGE AND 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 ) 2.1 Dosage Information Monotherapy or Adjunctive Therapy The recommended dosage for patients 1 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 1 Month of Age and Older Age and Body Weight Initial Dosage Minimum and Maximum Maintenance Dosage Adults (16 years and older) 50 mg twice daily (100 mg per day) 25 mg to 100 mg twice daily (50 mg to 200 mg per day) Pediatric patients weighing 50 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 patients weighing 20 kg to less than 50 kg 0.5 mg/kg to 1 mg/kg twice daily (1 mg/kg to 2 mg/kg per day) 0.5 mg/kg to 2 mg/kg twice daily (1 mg/kg to 4 mg/kg per day) Pediatric patients weighing 11 kg to less than 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 5 mg/kg per day) Pediatric patients weighing less than 11 kg 0.75 mg/kg to 1.5 mg/kg twice daily (1.5 mg/kg to 3 mg/kg per day) 0.75 mg/kg to 3 mg/kg twice daily (1.5 mg/kg to 6 mg/kg per day) 2.2 Administration Instructions for Brivaracetam Tablets Brivaracetam can be initiated with oral administration. Brivaracetam tablets may be taken with or without food. Brivaracetam tablets should be swallowed whole with liquid. Brivaracetam tablets should not be chewed or crushed. 2.4 Discontinuation of Brivaracetam Tablets Avoid abrupt withdrawal from brivaracetam tablets in order to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6) and Clinical Studies ( 14 )]. 2.5 Patients with Hepatic Impairment The recommended dosage for patients with hepatic impairment is included in Table 2 [ see Use in Specific Populations (8.7) and Clinical Pharmacology ( 12.3 ) ] . Table 2: Recommended Dosage for Patients with Hepatic Impairment Age and Body Weight Initial Dosage Maximum Maintenance Dosage Adults (16 years and older) 25 mg twice daily (50 mg per day) 75 mg twice daily (150 mg per day) Pediatric patients weighing 50 kg or more Pediatric patients weighing 20 kg to less than 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 patients weighing 11 kg to less than 20 kg 0.5 mg/kg twice daily (1 mg/kg per day) 2 mg/kg twice daily (4 mg/kg per day) Pediatric patients weighing less than 11 kg 0.75 mg/kg twice daily (1.5 mg/kg per day) 2.25 mg/kg twice daily (4.5 mg/kg per day) 2.6 Co-administration with Rifampin Increase the brivaracetam tablets 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)].

3 DOSAGE FORMS AND STRENGTHS 10 mg: White to off-white, round, biconvex film-coated tablet. Engraved "APO" on one side, "BR" over "10" on the other side. 25 mg: Grey, oval, biconvex film-coated tablet. Engraved "APO" on one side, "BR25" on the other side. 50 mg: Yellow, oval, biconvex film-coated tablet. Engraved "APO" on one side, "BR50" on the other side. 75 mg: Purple, oval, biconvex film-coated tablet. Engraved "APO" on one side, "BR75" on the other side. 100 mg: Green-grey, oval, biconvex film-coated tablet. Engraved "APO" on one side, "BR100" on the other side. Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg (3 )

4 CONTRAINDICATIONS Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam tablets (bronchospasm and angioedema have occurred) [see Warnings and Precautions ( 5.4 )]. Hypersensitivity to brivaracetam or any of the inactive ingredients in brivaracetam tablets. ( 4 )

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 )] Adults : Most common adverse reactions (at least 5% for brivaracetam 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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials performed in adult epilepsy patients, brivaracetam was administered as adjunctive therapy to 2,437 patients. Of these patients, 1,929 were treated for at least 6 months, 1,500 for at least 12 months, 1,056 for at least 24 months, and 758 for at least 36 months. A total of 1,558 patients (1,099 patients treated with brivaracetam and 459 patients treated with placebo) constituted the safety population in the pooled analysis of Phase 3 placebo-controlled studies in patients with partial-onset seizures (Studies 1, 2, and 3) [see Clinical Studies ( 14 )] . The adverse reactions presented in Table 4 are based on this safety population; the median length of treatment in these studies was 12 weeks. Of the patients in those studies, approximately 51% were male, 74% were Caucasian, and the mean age was 38 years. In the Phase 3 controlled epilepsy studies, adverse events occurred in 68% of patients treated with brivaracetam and 62% treated with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with brivaracetam doses of at least 50 mg/day and greater than placebo were somnolence and sedation (16%), dizziness (12%), fatigue (9%), and nausea and vomiting symptoms (5%). The discontinuation rates due to adverse events were 5%, 8%, and 7% for patients randomized to receive brivaracetam at the recommended doses of 50 mg, 100 mg, and 200 mg/day, respectively, compared to 4% in patients randomized to receive placebo. Table 4 lists adverse reactions for brivaracetam that occurred at least 2% more frequently for brivaracetam 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 50 mg/day, 100 mg/day, and 200 mg/day) Adverse Reactions Brivaracetam (N=803) % Placebo (N=459) % Gastrointestinal disorders Nausea/vomiting symptoms 5 3 Constipation 2 0 Nervous system disorders Somnolence and sedation 16 8 Dizziness 12 7 Fatigue 9 4 Cerebellar coordination and balance disturbances* 3 1 Psychiatric disorders Irritability 3 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 4 with the exception of somnolence and sedation. Pediatric Patients Safety of brivaracetam were evaluated in two open-label, safety and pharmacokinetic trials in pediatric patients 2 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 lea …

7 DRUG INTERACTIONS Rifampin : Because of decreased concentrations, increasing brivaracetam 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. ( 7. 2) Phenytoin : Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant brivaracetam. ( 7.3 ) Levetiracetam: Brivaracetam had no added therapeutic benefit when co- administered with levetiracetam. (7.4 ) 7.1 Rifampin Co-administration with rifampin decreases brivaracetam plasma concentrations likely because of CYP2C19 induction [see Clinical Pharmacology ( 12.3 )]. Prescribers should increase the brivaracetam dose by up to 100% (i.e., double the dosage) in patients while receiving concomitant treatment with rifampin [see Dosage and Administration ( 2.6 )]. 7.2 Carbamazepine 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 )]. 7.3 Phenytoin Because brivaracetam can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant brivaracetam is added to or discontinued from ongoing phenytoin therapy [see Clinical Pharmacology ( 12.3 )]. 7.4 Levetiracetam Brivaracetam provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered [see Clinical Studies ( 14 )].

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as brivaracetam tablets, during pregnancy. Encourage patients who are taking brivaracetam tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Available data from the North American Antiepileptic Drug (NAAED) pregnancy registry, a prospective cohort study, case reports, and a case series are insufficient to identify a risk of major birth defects, miscarriage or other maternal or fetal outcomes associated with brivaracetam tablets 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 a 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 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of brivaracetam (0, 150, 300, or 600 mg/kg/day) to pregnant rats during the period of organogenesis did not produce any significant maternal or embryofetal toxicity. The highest dose tested was associated with maternal plasma exposures (AUC) approximately 30 times exposures in humans at the maximum recommended dose (MRD) of 200 mg/day. Oral administration of brivaracetam (0, 30, 60, 120, or 240 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal mortality and decreased fetal body weights at the highest dose tested, which was also maternally toxic. The highest no-effect dose (120 mg/kg/day) was associated with maternal plasma exposures approximately 4 times human exposures at the MRD. When brivaracetam (0, 150, 300, or 600 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, decreased growth, delayed sexual maturation (female), and long-term neurobehavioral changes were observed in the offspring at the highest dose. The highest no-effect dose (300 mg/kg/day) was associated with maternal plasma exposures approximately 7 times human exposures at the MRD. Brivaracetam was shown to readily cross the placenta in pregnant rats after a single oral (5 mg/kg) dose of 14 C-brivaracetam. From 1 hour post dose, radioactivity levels in fetuses, amniotic fluid, and placenta were similar to those measured in maternal blood. 8.2 Lactation Risk Summary Data 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 mother’s clinical need for brivaracetam tablets and any potential adverse effects on the breastfed infant from brivaracetam tablets or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of brivaracetam have been established in pediatric patients 1 month to less than 16 years of age. Use of brivaracetam in these age groups is supported by evidence from adequate and well-controlled studies of brivaracetam in adults with partial-onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in pediatric patients 2 months to less than 16 years of age [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 ), …

12.1 Mechanism of Action The precise mechanism by which brivaracetam exerts its anticonvulsant activity is not known. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

11 DESCRIPTION The chemical name of brivaracetam is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide. Its molecular formula is C 11 H 20 N 2 O 2 and its molecular weight is 212.29 g/mol. The chemical structure is: Brivaracetam is a white to off-white powder. It is very soluble in water, buffer (pH 1.2, 4.5, and 7.4), ethanol, methanol, and glacial acetic acid. It is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane. Brivaracetam tablets are for oral administration and contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, and film coating agents specified below: 10 mg tablets: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide 25 mg and 100 mg tablets: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide 50 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide 75 mg tablets: iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide

10 OVERDOSAGE There is limited clinical experience with brivaracetam overdose in humans. Somnolence and dizziness were reported in a patient taking a single dose of 1,400 mg (14 times the highest recommended single dose) of brivaracetam. The following adverse reactions were reported with brivaracetam overdose: vertigo, balance disorder, fatigue, nausea, diplopia, anxiety, and bradycardia. In general, the adverse reactions associated with brivaracetam overdose were consistent with the known adverse reactions. There is no specific antidote for overdose with brivaracetam. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rate and rhythm and vital signs is recommended. A certified poison control center should be contacted for updated information on the management of overdose with brivaracetam. There are no data on the removal of brivaracetam using hemodialysis, but because less than 10% of brivaracetam is excreted in urine, hemodialysis is not expected to enhance brivaracetam clearance.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Brivaracetam Tablets 10 mg are white to off-white, round, biconvex film-coated tablet. Engraved “APO” on one side, “BR” over “10” on the other side. They are supplied as follows: Bottles of 60 tablets NDC 60505-4723-6 25 mg are grey, oval, biconvex film-coated tablet. Engraved “APO” on one side, “BR25” on the other side. They are supplied as follows: Bottles of 60 tablets NDC 60505-4724-6 50 mg are yellow, oval, biconvex film-coated tablet. Engraved “APO” on one side, “BR50” on the other side. They are supplied as follows: Bottles of 60 tablets NDC 60505-4725-6 75 mg are purple, oval, biconvex film-coated tablet. Engraved “APO” on one side, “BR75” on the other side. They are supplied as follows: Bottles of 60 tablets NDC 60505-4726-6 100 mg are green-grey, oval, biconvex film-coated tablet. Engraved “APO” on one side, “BR100” on the other side. They are supplied as follows: Bottles of 60 tablets NDC 60505-4727-6 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.