Rufinamide Drug Information

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

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.

Administration Information Administer rufinamide tablets with food. Rufinamide film-coated tablets can be

administered whole, as half tablets or crushed.

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.

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 .

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 .

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 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.

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.

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.

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) .

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 contraception are recommended when using rufinamide tablets .

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 . 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.

Pediatric Use Safety and effectiveness have been established in pediatric patients 1 to 17 years of age. The effectiveness of rufinamide tablets in pediatric patients 4 years of age and older was based upon an adequate and well-controlled trial of rufinamide tablets that included both adults and pediatric patients, 4 years of age and older, with Lennox Gastaut Syndrome. The effectiveness in patients 1 to less than 4 years was based upon a bridging pharmacokinetic and safety study.

The pharmacokinetics of rufinamide in the pediatric patients, ages 1 to less than 4 years of age is similar to children older than 4 years of age and adults . Safety and effectiveness in pediatric patients below the age of 1 year has not been established. Oral administration of rufinamide (0, 15, 50, or 150 mg/kg) to young rats for 10 weeks starting on postnatal day 7 resulted in decreased brain weights at the mid and high doses and neurobehavioral impairment (learning and memory deficit, altered startle response, decreased locomotor activity) and decreased growth (decreased body weight) at the highest dose tested. The no-effect dose for adverse effects on postnatal development in rats (15 mg/kg) was associated with a plasma exposure (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 3200 mg/day.

Rufinamide tablets are contraindicated in patients with Familial Short QT syndrome . Rufinamide tablet is contraindicated in patients with Familial Short QT syndrome

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.