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The following adverse reactions are discussed in more details in other sections of labeling: Behavioral abnormalities and Psychotic Symptoms Suicidal Behavior and Ideation Somnolence and Fatigue Anaphylaxis and Angioedema Serious Dermatological Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Coordination Difficulties Hematologic Abnormalities Most common adverse reactions (incidence ≥5% more than placebo) include: somnolence and irritability To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 599-CARE 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. KEPPRA XR Tablets In the controlled clinical study in patients with partial-onset seizures, the most common adverse reactions in patients receiving KEPPRA XR in combination with other AEDs, for events with rates greater than placebo, were irritability and somnolence. Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving KEPPRA XR in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either KEPPRA XR or placebo was added to concurrent AED therapy.

Table 3: Adverse Reactions in the Placebo-Controlled, Adjunctive Study in Patients Experiencing Partial-Onset Seizures KEPPRA XR (N=77) % Placebo (N=79) % Influenza 8 4 Somnolence 8 3 Irritability 7 0 Nasopharyngitis 7 5 Dizziness 5 3 Nausea 5 3 Discontinuation or Dose Reduction in the KEPPRA XR Controlled Clinical Study In the controlled clinical study, 5% of patients receiving KEPPRA XR and 3% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in KEPPRA XR-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash, and respiratory failure. Each of these adverse reactions led to discontinuation in a KEPPRA XR-treated patient and no placebo-treated patients. Immediate-Release KEPPRA Tablets Table 4 lists the adverse reactions in the controlled studies of immediate-release KEPPRA tablets in adult patients experiencing partial-onset seizures. Although the pattern of adverse reactions in the KEPPRA XR study seems somewhat different from that seen in partial-onset seizure controlled studies for immediate-release KEPPRA tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for KEPPRA XR are expected to be similar to those seen with immediate-release KEPPRA tablets. Adults In controlled clinical studies of immediate-release KEPPRA tablets as adjunctive therapy to other AEDs in adults with partial-onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving immediate-release KEPPRA tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release KEPPRA tablets or placebo was added to concurrent AED therapy.

Table 4: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults Experiencing Partial-Onset Seizures KEPPRA (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 Pediatric Patients 4 Years to <16 Years In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial-onset seizures, the adverse reactions most frequently reported with the use of immediate-release KEPPRA in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-release KEPPRA and were more common than in pediatric patients on placebo. In these studies, either immediate-release KEPPRA or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial-Onset Seizures KEPPRA (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Upper Abdominal Pain 9 8 Cough 9 5 Nasal Congestion 9 2 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In controlled pediatric clinical studies in patients 4-16 years of age, 7% of patients treated with immediate-release KEPPRA tablets and 9% of patients on placebo discontinued as a result of an adverse event. In addition, the following adverse reactions were seen in other controlled studies of immediate-release KEPPRA tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and blurred vision. Comparison of Gender, Age and Race There are insufficient data for KEPPRA XR to support a statement regarding the distribution of adverse reactions by gender, age, and race.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of immediate-release KEPPRA tablets. 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.

The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures including in patients with SCN8A mutations. Alopecia has been reported with immediate-release KEPPRA use; recovery was observed in majority of cases where immediate-release KEPPRA was discontinued.