BRIVIACT

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 BRIVIACT 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 UCB, Inc. at 1-844-599-2273 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, BRIVIACT was administered as adjunctive therapy to 2437 patients. Of these patients, 1929 were treated for at least 6 months, 1500 for at least 12 months, 1056 for at least 24 months, and 758 for at least 36 months. A total of 1558 patients (1099 patients treated with BRIVIACT 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 BRIVIACT and 62% treated with placebo. The most common adverse reactions occurring at a frequency of at least 5% in patients treated with BRIVIACT 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 BRIVIACT 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 BRIVIACT that occurred at least 2% more frequently for BRIVIACT 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 (BRIVIACT 50 mg/day, 100 mg/day, and 200 mg/day) Adverse Reactions BRIVIACT (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 Cerebellar coordination and balance disturbances includes ataxia, balance disorder, coordination abnormal, and nystagmus. 3 1 Psychiatric disorders Irritability 3 1 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 BRIVIACT was 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 BRIVIACT oral solution or tablet, of whom 123 received BRIVIACT 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 Abnormalities BRIVIACT can cause hematologic abnormalities. In the Phase 3 controlled adjunctive epilepsy studies, a total of 1.8% of BRIVIACT-treated patients and 1.1% of placebo-treated patients had at least one clinically significant decreased white blood cell count (<3.0 × 10 9 /L), and 0.3% of BRIVIACT-treated patients and 0% of placebo-treated patients had at least one clinically significant decreased neutrophil count (<1.0 × 10 9 /L). Adverse Reactions with BRIVIACT Injection Adverse reactions with BRIVIACT injection administered to adults and pediatric patients 2 months to 16 years of age were generally similar to those observed with BRIVIACT tablets. Other adverse events that occurred in at least 3% of adult patients who received BRIVIACT injection included dysgeusia, euphoric mood, feeling drunk, and infusion site pain. Comparison by Sex There were no significant differences by sex in the incidence of adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of BRIVIACT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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) ]

7 DRUG INTERACTIONS Rifampin: Because of decreased concentrations, increasing BRIVIACT 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 BRIVIACT. ( 7.2 ) Phenytoin: Because phenytoin concentrations can increase, phenytoin levels should be monitored in patients on concomitant BRIVIACT. ( 7.3 ) Levetiracetam: BRIVIACT had no added therapeutic benefit when co-administered with levetiracetam. ( 7.4 ) 7.1 Rifampin Co-administration with rifampin decreases BRIVIACT plasma concentrations likely because of CYP2C19 induction [see Clinical Pharmacology (12.3) ] . Prescribers should increase the BRIVIACT 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 BRIVIACT can increase plasma concentrations of phenytoin, phenytoin levels should be monitored in patients when concomitant BRIVIACT is added to or discontinued from ongoing phenytoin therapy [see Clinical Pharmacology (12.3) ] . 7.4 Levetiracetam BRIVIACT provided no added therapeutic benefit to levetiracetam when the two drugs were co-administered [see Clinical Studies (14) ].