6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
• Central Nervous System Reactions [see Warnings and Precautions (5.2)]
• QT Shortening [see Warnings and Precautions (5.3)]
• Multi-Organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]
• Leukopenia [see Warnings and Precautions (5.7)]

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.

Adverse Reactions in Adult and Pediatric Patients ages 3 to 17 years of age

In the pooled, double-blind, adjunctive therapy studies in adult and pediatric patients ages 3 to 17 years of age, the most common (≥10%) adverse reactions in rufinamide tablet-treated patients, in all doses studied (200 to 3200 mg per day) with a higher frequency than in patients on placebo were: headache, dizziness, fatigue, somnolence, and nausea.

Table 2 lists adverse reactions that occurred in at least 3% of pediatric patients (ages 3 to less than 17 years) with epilepsy treated with rufinamide tablets in controlled adjunctive studies and were numerically more common in patients treated with rufinamide tablets than in patients on placebo.

At the target dose of 45 mg/kg per day for adjunctive therapy in pediatric patients (ages 3 to less than 17 years), the most common (≥3%) adverse reactions with an incidence greater than in placebo for rufinamide tablets were somnolence, vomiting, and headache.

** Table 2: Adverse Reactions in Pediatric Patients (Ages 3 to less than 17 years) in Pooled Double-Blind Adjunctive Trials**

** Adverse Reaction**	Rufinamide Tablet (N=187)%	Placebo (N=182)%
Somnolence	17	9
Vomiting	17	7
Headache	16	8
Fatigue	9	8
Dizziness	8	6
Nausea	7	3
Influenza	5	4
Nasopharyngitis	5	3
Decreased Appetite	5	2
Rash	4	2
Ataxia	4	1
Diplopia	4	1
Bronchitis	3	2
Sinusitis	3	2
Psychomotor Hyperactivity	3	1
Upper Abdominal Pain	3	2
Aggression	3	2
Ear Infection	3	1
Disturbance in Attention	3	1
Pruritis	3	0

Table 3 lists adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with rufinamide tablets (up to 3200 mg per day) in adjunctive controlled studies and were numerically more common in patients treated with rufinamide tablets than in patients on placebo. In these studies, either rufinamide tablets or placebo was added to the current AED therapy.

At all doses studied of up to 3200 mg per day given as adjunctive therapy in adults, the most common (≥ 3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for rufinamide tablets were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia.

Table 3: Adverse Reactions in Adults in Pooled Double-Blind Adjunctive Trials

Adverse Reaction	Rufinamide Tablet (N=823)%	Placebo (N=376)%
Headache	27	26
Dizziness	19	12
Fatigue	16	10
Nausea	12	9
Somnolence	11	9
Diplopia	9	3
Tremor	6	5
Nystagmus	6	5
Blurred Vision	6	2
Vomiting	5	4
Ataxia	4	0
Upper Abdominal Pain	3	2
Anxiety	3	2
Constipation	3	2
Dyspepsia	3	2
Back Pain	3	1
Gait Disturbance	3	1
Vertigo	3	1

Discontinuation in Controlled Clinical Studies

In controlled, double-blind, adjunctive clinical studies, 9% of pediatric and adult patients receiving rufinamide tablets as adjunctive therapy and 4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide tablet (>1%) used as adjunctive therapy were generally similar in adults and pediatric patients.

In pediatric patients (ages 4 to less than 17 years) double-blind adjunctive clinical studies, 8% of patients receiving rufinamide tablets as adjunctive therapy (at the recommended dose of 45 mg/kg per day) and 2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide tablets (>1%) used as adjunctive therapy are presented in Table 4.

Table 4: Most Common Adverse Reactions Leading to Discontinuation in Pediatric Patients (Ages 4 to less than 17 years) in Pooled Double-Blind Adjunctive Trials

** Adverse Reaction**	Rufinamide Tablet (N=187)%	Placebo(N=182)%
Convulsion	2	1
Rash	2	1
Fatigue	2	0
Vomiting	1	0

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In adult double-blind, adjunctive clinical studies, 10% of patients receiving rufinamide tablets as adjunctive therapy (at doses up to 3200 mg per day) and 6% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide tablets (>1%) used as adjunctive therapy are presented in Table 5.

** Table 5: Most Common Adverse Reactions Leading to Discontinuation in Adult Patients in Pooled Double-Blind Adjunctive Trials**

Adverse Reaction	Rufinamide Tablet (N=823)%	Placebo (N=376)%
Dizziness	3	1
Fatigue	2	1
Headache	2	1
Nausea	1	0
Ataxia	1	0

Pediatric Patients ages 1 to less than 4 years

In a multicenter, parallel group, open-label study comparing rufinamide tablets (45 mg/kg per day) adjunctive treatment (n=25) to the adjunctive treatment with an AED of the investigator’s choice (n=11) in pediatric patients (1 year to less than 4 years of age) with inadequately controlled Lennox-Gastaut Syndrome, the adverse reaction profile was generally similar to that observed in adults and pediatric patients 4 years of age and older treated with rufinamide tablets. Adverse reactions that occurred in at least 2 (8 %) rufinamide tablet-treated patients and with a higher frequency than in the AED comparator group were: vomiting (24%), somnolence (16%), bronchitis (12%), constipation (12%), cough (12%), decreased appetite (12%), rash (12%), otitis media (8%), pneumonia (8%), decreased weight (8%), gastroenteritis (8%), nasal congestion (8%), and pneumonia aspiration (8%).

Other Adverse Reactions Observed During Clinical Trials

Rufinamide tablet has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse reactions occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse reactions, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included in the tables above, those too general to be informative, those related to procedures, and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of rufinamide tablet in their causation cannot be reliably determined.

Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events—those occurring in at least 1/100 patients; infrequent adverse events—those occurring in 1/100 to 1/1000 patients; rare—those occurring in fewer than 1/1000 patients.

Blood and Lymphatic System Disorders: Frequent: anemia. Infrequent: lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia.

Cardiac Disorders: Infrequent: bundle branch block right, atrioventricular block first degree. Metabolic and Nutritional Disorders: Frequent: decreased appetite, increased appetite.

Renal and Urinary Disorders: Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of rufinamide 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.

Dermatologic: Stevens-Johnson syndrome and other serious skin rashes with mucosal involvement.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage Information

Pediatric patients (1 year to less than 17 years)

The recommended starting daily dose of rufinamide tablets in pediatric patients with Lennox-Gastaut Syndrome is approximately 10 mg/kg administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day until a maximum daily dose of 45 mg/kg, not to exceed 3200 mg, administered in two equally divided doses, is reached. It is not known whether doses lower than the target doses are effective.

Adults (17 years and older)

The recommended starting daily dose of rufinamide tablets in adults with Lennox-Gastaut Syndrome is 400 to 800 mg per day administered in two equally divided doses. The dose should be increased by 400 to 800 mg every other day until a maximum daily dose of 3200 mg, administered in two equally divided doses, is reached. It is not known whether doses lower than 3200 mg are effective.

2.2 Administration Information

Administer rufinamide tablets with food. Rufinamide film-coated tablets can be administered whole, as half tablets or crushed.

2.3 Dosing in Patients Undergoing Hemodialysis

Hemodialysis may reduce exposure to a limited (about 30%) extent. Accordingly, adjusting the rufinamide tablets dose during the dialysis process should be considered [see Clinical Pharmacology (12.3)].

2.4 Dosing in Patients with Hepatic Disease

Use of rufinamide tablets in patients with hepatic impairment has not been studied. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7)] .

2.5 Dosing in Patients Taking Valproate

Patients taking valproate should begin rufinamide tablets at a dose lower than 10 mg/kg per day in pediatric patients or 400 mg per day in adults [see Drug Interactions (7.2)] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg per day and to rats at 20, 60, and 200 mg/kg per day for 2 years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is < 0.1 times the MRHD on a mg/m 2 basis.

Mutagenesis

Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg per day) to male and female rats prior to mating and throughout mating, and continuing in females up to day 6 of gestation resulted in impairment of fertility (decreased conception rates and mating and fertility indices; decreased numbers of corpora lutea, implantations, and live embryos; increased preimplantation loss; decreased sperm count and motility) at all doses tested. Therefore, a no-effect dose was not established. The lowest dose tested was associated with a plasma AUC ≈ 0.2 times the human plasma AUC at the MRHD.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Rufinamide Tablets, USP are available containing 200 mg and 400 mg

** Rufinamide Tablets USP, 200 mg:** Pink colored, oblong shaped, film coated tablets, scored on one side, debossed with "E" on one half and "3 I" on other half and score line on the other side.

Bottle of 120 NDC 42571-391-12

**Rufinamide Tablets USP, 400 mg:**Pink colored, oblong shaped, film coated tablets, scored on one side, debossed with "E" on one half and "30" on other half and score line on the other side.

Bottle of 120 NDC 42571-392-12

16.2 Storage and Handling

Store the tablets at 25**°C (77°F); excursions permitted to 15° to 30°C (59°F to 86°**F). Protect from moisture. Replace cap securely after opening.