RUFINAMIDE

1 INDICATIONS AND USAGE Rufinamide tablet is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in pediatric patients 1 year of age and older and in adults. Rufinamide tablet is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in pediatric patients 1 year of age and older, and in adults ( 1 )

2 DOSAGE AND ADMINISTRATION Rufinamide tablets should be given with food. Tablets can be administered whole, as half tablets, or crushed ( 2.2 ) Pediatric patients 1 year and older: Starting daily dose: 10 mg/kg per day in two equally divided doses ( 2.1 ) Increase by 10 mg/kg increments every other day to maximum dose of 45 mg/kg per day, not to exceed 3200 mg per day, in two divided doses ( 2.1 ) Adults: Starting daily dose: 400 to 800 mg per day in two equally divided doses ( 2.1 ) Increase by 400 to 800 mg every other day until a maximum dose of 3200 mg per day, in two divided doses, is reached ( 2.1 ) 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) ] .

3 DOSAGE FORMS AND STRENGTHS 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. 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. Film-coated tablets: 200 mg (pink), 400 mg (pink) ( 3 )

4 CONTRAINDICATIONS Rufinamide tablets are contraindicated in patients with Familial Short QT syndrome [see Warnings and Precautions (5.3) ] . Rufinamide tablet is contraindicated in patients with Familial Short QT syndrome ( 4 )

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) ] Most common adverse reactions (≥10% and greater than placebo) were headache, dizziness, fatigue, somnolence, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 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. 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 …

7 DRUG INTERACTIONS Patients on valproate should begin at a rufinamide tablets dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) ( 7.2 ) Hormonal contraceptives may be less effective with Rufinamide tablet; use additional non-hormonal forms of contraception ( 7.3 ) 7.1 Effects of Rufinamide Tablet on other AEDs Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide C avss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population. Table 6 summarizes the drug-drug interactions of rufinamide tablets with other AEDs. Table 6: Summary of drug-drug interactions of rufinamide Tablets with other antiepileptic drugs AED Co-administered Influence of Rufinamide on AED concentration a) Influence of AED on Rufinamide concentration Carbamazepine Decrease by 7 to 13% b) Decrease by 19 to 26% Dependent on dose of carbamazepine Lamotrigine Decrease by 7 to 13% b) No Effect Phenobarbital Increase by 8 to 13% b) Decrease by 25 to 46% c),d) Independent of dose or concentration of phenobarbital Phenytoin Increase by 7 to 21% b) Decrease by 25 to 46% c),d) Independent of dose or concentration of phenytoin Topiramate No Effect No Effect Valproate No Effect Increase by <16 to 70% c) Dependent on concentration of valproate Primidone Not Investigated Decrease by 25 to 46% c),d) Independent of dose or concentration of primidone Benzodiazepines e) Not Investigated No Effect a) Predictions are based on rufinamide tablet concentrations at the maximum recommended dose of rufinamide tablet. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of rufinamide tablets, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on rufinamide tablets clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on rufinamide tablets clearance. Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (C avss 15 mcg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction. 7.2 Effects of Other AEDs on Rufinamide Tablet Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital, appear to increase the clearance of rufinamide tablets (see Table 6). Given that the majority of clearance of rufinamide tablets is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred, were likely to be more marked in the pediatric population. Valproate Patients stabilized on rufinamide tablet before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a rufinamide tablet dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ] . 7.3 Effects of Rufinamide Tablet on Hormonal Contraceptives Female patients of childbearing age should be warned that the concurrent use of rufinamide tablets with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of con …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Renal impairment: Consider adjusting the rufinamide tablet dose for the loss of drug upon dialysis ( 8.6 ) Not recommended in patients with severe hepatic impairment ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as rufinamide tablets, during pregnancy. Encourage women who are taking rufinamide tablet during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary There are no adequate data on the developmental risks associated with use of rufinamide tablets in pregnant women. In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses [see Data] . 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal data Oral administration of rufinamide (0, 20, 100, or 300 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal weight and increased incidence of fetal skeletal abnormalities at 100 and 300 mg/kg/day, which were associated with maternal toxicity. The maternal plasma exposure (AUC) at the no-adverse effect dose (20 mg/kg/day) for developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD) of 3200 mg/day. Oral administration of rufinamide (0, 30, 200, or 1000 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in embryofetal death, decreased fetal body weight, and increased incidence of fetal visceral and skeletal abnormalities at doses of 200 and 1000 mg/kg/day. The high dose (1000 mg/kg/day) was associated with abortion. Plasma exposure (AUC) at the no-adverse effect dose (30 mg/kg/day) was less than that in humans at the MRHD. When rufinamide was orally administered (0, 5, 30, or 150 mg/kg/day) to pregnant rats throughout pregnancy and lactation, decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and postnatal development was not established. At the lowest dose tested (5 mg/kg/day), plasma exposure (AUC) was less than that in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of rufinamide in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rufinamide tablets and any potential adverse effects on the breastfed infant from rufinamide tablets or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of rufinamide tablets may reduce the effectiveness of hormonal contraceptives containing ethinyl estradiol or norethindrone. Advise women of reproductive potential taking rufinamide tablets who are using a contraceptive containing ethinyl estradiol and norethindrone to use an additional non-hormonal form of contraception [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Infertility The effect of rufinamide on fertility in humans has not been established. Oral administration of rufinamide (20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating, during mating, and during early gestation (females only) resulted in the impairment of fertility at all dose levels tested. The no-effect dose was not established. The plasma exposure level at 20 mg/kg was approximately 0.2 times the human plasma AUC at the MRHD [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectivene …

12.1 Mechanism of Action The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown. The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide (≥ 1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC 50 of 3.8 μM).

11 DESCRIPTION Rufinamide tablet USP is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs). Rufinamide USP has the chemical name 1-[(2,6-difluorophenyl)methyl]-1 H -1,2,3-triazole-4 carboxamide. It has an empirical formula of C 10 H 8 F 2 N 4 O and a molecular weight of 238.2. The drug substance is a white to off white colour powder. Rufinamide is slightly soluble in tetrahydrofuran and in methanol; very slightly soluble in alcohol and in acetonitrile; practically insoluble in water. Rufinamide tablet USP is available for oral administration in film-coated tablets, scored on both sides, containing 200 and 400 mg of rufinamide. Inactive ingredients are colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, methocel K 3 Premium LV hydroxypropyl methyl cellulose, microcrystalline cellulose and sodium lauryl sulfate. The film coating contains hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide. structure

10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. One overdose of 7200 mg per day rufinamide tablets was reported in an adult during the clinical trials. The overdose was associated with no major signs or symptoms, no medical intervention was required, and the patient continued in the study at the target dose. Treatment or Management of Overdose: There is no specific antidote for overdose with rufinamide tablets. If clinically indicated, elimination of unabsorbed drug should be attempted by induction of emesis or gastric lavage. Usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Hemodialysis: Standard hemodialysis procedures may result in limited clearance of rufinamide. Although there is no experience to date in treating overdose with hemodialysis, the procedure may be considered when indicated by the patient’s clinical state.

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.